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 .
Formal Matters
Claims 1-34 were originally presented on 06/08/2023 and are pending and under examination.
Priority
This application is a CIP of 18/186,764, filed 03/20/2023, which is a CIP of 17/734,100, filed 05/01/2022, which claims priority to PRO 63/184,703, filed 05/05/2021.
Information Disclosure Statement
No Information Disclosure Statements have been filed.
Duplicate Claims Warning
Applicant is advised that should claim 9 (and claims dependent therefrom) be found allowable, claim 20 (and claims dependent therefrom), claim 25 (and claims dependent therefrom), and claim 30 (and claims dependent therefrom) will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
In this case, all of claims 9, 20, 25, and 30 recite an identical method step of “administering an effective amount of a composition of an R(-) enantiomer of MDMA or MDA [to an individual]”. The subject population of all of claims 9, 20, 25, and 30 is any and all individuals. Pursuant with MPEP 2111.02, if the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction. Shoes by Firebug LLC v. Stride Rite Children’s Grp., LLC, 962 F.3d 1362, 2020 USPQ2d 10701 (Fed. Cir. 2020). Here, Applicant’s recitations of “reducing neurotoxicity of MDMA or MDA” (Claim 20), “reducing hyperthermia of MDMA or MDA” (Claim 25), and “reducing physical dependent or abuse liability of MDMA or MDA” (Claim 30) in the preambles of Claims 20, 25, and 30 merely state the purpose or intended use of “administering an effective amount of a composition of an R(-) enantiomer of MDMA or MDA to an individual”, rather than any distinct definition of any of the claimed invention’s limitations and therefore are not considered limitations and are of no significance to claim construction.
Claim Rejections - 35 USC § 112(b)
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.
"The primary purpose of this requirement of definiteness of claim language is to ensure that the scope of the claims is clear so the public is informed of the boundaries of what constitutes infringement of the patent. A secondary purpose is to provide a clear measure of what applicants regard as the invention so that it can be determined whether the claimed invention meets all the criteria for patentability and whether the specification meets the criteria of 35 U.S.C. 112, first paragraph with respect to the claimed invention.", (see MPEP § 2173).
Claims 1-34 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.
Recitation of the abbreviation “MDA” in claims 1, 9, 20, 25, and 30 renders the metes and bounds of the claims unclear because the full meaning of the abbreviated term is not recited anywhere in the claims. The first use of an abbreviation in the claims should be preceded by the full meaning of the abbreviated term so as to clearly and unequivocally convey what the abbreviation is an abbreviation for. In this case, “MDA” as recited in the instant claims could reasonably be construed to be an abbreviation for malondialdehyde (CAS No. 542-78-9), 4,4’-Methylenedianiline (CAS No. 101-77-9), or 3,4-Methylenedioxyamphetamine (CAS No. 4764-17-4).
Claims 3-4, 13-14, 23-24, 28-29, and 33-34 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.
Claims 3, 13, 23, 28, and 33 recite the limitation “wherein the R(-) enantiomer of MDMA or MDA includes a prodrug bound thereto, which renders the claims unclear what “a prodrug bound thereto” means. For example, the R(-) enantiomer of MDMA has its own chemical registry number (e.g., 81262-70-6) and cannot “include” a prodrug bound to its structure without chemical modification. Additionally, a “prodrug”, by definition is a chemical compound in which a chemical moiety is metabolized or otherwise cleaved in vivo to release a parent drug compound. As such, it is unclear what “prodrug” Applicants intend to bind to the drugs MDA or MDMA and what parent drug, exactly, it intended to be released. At bottom, it is unclear if MDA or MDMA is intended to be parent drug that is released in vivo by cleavage of a chemical moiety. If such is the case, MDA and MDMA would not have a “prodrug” per se attached thereto as presently claimed.
Claims 9-19 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.
Claims 9-19 are indefinite for reciting the term “a medical condition’, because one of ordinary skill in the art could not reasonably determine the metes and bounds of this limitation. It is unclear if the claimed “medical condition” should be broadly construed to mean any disease. Because Applicants do not provide any definition or meaning of the claimed “a medical condition”, a person of ordinary skill in the art would not know what patient population is intended to be encompassed by the instant claims.
Claims 9-19 are further indefinite because claim 9 recites “A method of treating an individual for a medical condition, including the steps of: ...treating the individual”. This limitation is indefinite because it is not clear from either the Specification or the common teachings in the art how this limitation is intended to limit the claims. For example, it is unclear if “treating the individual” is merely an intended outcome without requiring any positive proactive method step, such as dose, frequency, or route of administration.
Claim 12 is 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 12 is indefinite for reciting “...further including the step of preventing or reducing side effects of neurotoxicity, hyperthermia, and dependence/addiction experienced with racemic MDMA or MDA”. This limitation is indefinite because it is not clear from either the Specification or the common teachings in the art, how this limitation limits the claim. For example, it is unclear if “preventing or reducing side effects of neurotoxicity, hyperthermia, and dependence/addiction experienced with racemic MDMA or MDA” is merely an intended outcome without requiring any positive proactive method step, such as dose, frequency, or route of administration.
Claims 20-24 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 20 recites “A method of reducing neurotoxicity of MDMA and MDA, including the steps of: ...reducing neurotoxicity of MDMA or MDA while treating the individual”. This limitation is indefinite because it is not clear from either the Specification or the common teachings in the art, how this limitation limits the claim. For example, it is unclear if “reducing neurotoxicity of MDMA or MDA while treating the individual” is merely an intended outcome without requiring any positive proactive method step, such as dose, frequency, or route of administration.
Claims 25-29 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 25 recites “A method of reducing neurotoxicity of MDMA and MDA, including the steps of: ...reducing hyperthermia of MDMA or MDA while treating the individual”. This limitation is indefinite because it is not clear from either the Specification or the common teachings in the art, how this limitation limits the claim. For example, it is unclear if “reducing hyperthermia of MDMA or MDA while treating the individual” is merely an intended outcome without requiring any positive proactive method step, such as dose, frequency, or route of administration.
Claims 30-34 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 “A method of reducing neurotoxicity of MDMA and MDA, including the steps of: ...reducing the physical dependence or abuse liability of MDMA or MDA while treating the individual”. This limitation is indefinite because it is not clear from either the Specification or the common teachings in the art, how this limitation limits the claim. For example, it is unclear if “reducing the physical dependence or abuse liability of MDMA or MDA while treating the individual” is merely an intended outcome without requiring any positive proactive method step, such as dose, frequency, or route of administration.
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 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 1-2, 8-10, 12, 18-21, 25-26, and 30-31 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by PITTS ET AL. (Psychopharmacology. 235:377-392 (2018)) (NEWLY CITED).
Claim 1 is directed toward a composition “for use in psychotherapeutic treatment” comprising an R(-) enantiomer of MDMA or MDA. PITTS ET AL. teach that (±)-MDMA comprises S(+) and R(-) enantiomers of MDMA, and that the use of (±)-MDMA as an adjunct to psychotherapy in the treatment of psychiatric and behavioral disorders dates back over 50 years (Abstract). Since (±)-MDMA includes 50% of the R(-) enantiomer and 50% of the S(+) enantiomer of MDMA, and it was known in the art to use (±)-MDMA in psychotherapeutic treatment, claim 1 is anticipated. Claim 2 depends from and further limits claim 1, and recites the limitation wherein the R(-) enantiomer of MDMA or MDA is present in an amount of 10-1000 mg. Pitts teaches that a placebo-controlled phase II trial of (±)-MDMA-assisted psychotherapy included administering therapy sessions with adjunctive (±)-MDMA (125 mg) or placebo (Introduction). Claim 8 depends from and further limits claim 1, and recites the limitation wherein the composition is in an oral dosage form. Pitts cites Mithoefer et al. (J Psychopharmacol. 25(4):439-452 (2011)), when disclosing the placebo-controlled phase II trial of (±)-MDMA-assisted psychotherapy that included adjunctive (±)-MDMA (125 mg). Mithoefer discloses that the (±)-MDMA dose was given in a capsule by mouth (Mithoefer at page 444). Claim 9 is directed toward a method of treating an individual for a medical condition, including the steps of: administering an effective amount of a composition of an R(-) enantiomer of MDMA or MDA; and treating the individual. Pitts discloses clinical trials of using (±)-MDMA adjunctive to psychotherapy, for the treatment of PTSD (Introduction). Claim 10 depends from and further limits claim 9, and recites the limitation wherein the administering step is further defined as administering 10-1000 mg of the R(-) enantiomer of MDMA or MDA (see above discussion regarding claims 2, 8, and 9). Claim 12 depends from claim 9 and further includes the step of preventing or reducing side effects of neurotoxicity, hyperthermia, and dependence/addiction experienced with racemic MDMA or MDA. Pitts discloses that R(-)- MDMA is equally effective in several preclinical studies of therapeutic-like effects, with reduced lability for neurotoxicity, hyperthermia, and abuse (Clinical applications and limitations). Claim 18 depends from and further limits claim 9, wherein the composition is in an oral dosage form (see above discussion regarding claim 8). Claim 19 depends from and further limits claim 9 and recites a list of medical conditions, including post-traumatic stress disorder. Since Pitts teaches using (±)-MDMA in treatment of PTSD, claim 19 is anticipated. Claim 20 is directed toward a method of reducing neurotoxicity of MDMA and MDA, including the steps of administering an effective amount of a composition of an R(-) enantiomer of MDMA or MDA. Pitts teaches that the neurotoxicity of (+)-MDMA is driven by the S(+) enantiomer and that R(-)-MDMA has substantially lower or potentially no neurotoxicity (page 382). Claim 21 depends from and further limits claim 20 and recites the administering step is further defined as administering 10-1000 mg of the R(-) enantiomer of MDMA or MDA (see above discussion regarding claims 2, 8, and 9). Claim 25 is directed toward a method of reducing hyperthermia of MDMA and MDA, including the steps of administering an effective amount of a composition of an R(-) enantiomer of MDMA or MDA. Pitts teaches that a key difference between R(-)-MDMA and S(+)-MDMA is that R(-)-MDMA does not produce hyperthermia (page 382). Claim 26 depends from and further limits claim 25 and recites the administering step is further defined as administering 10-1000 mg of the R(-) enantiomer of MDMA or MDA (see above discussion regarding claims 2, 8, and 9). Claim 30 is directed toward a method of reducing physical dependence or abuse liability of MDMA and MDA, including the steps of administeringg an effective amount of a composition of an R(-) enantiomer of MDMA or MDA. Pitts teaches a human study of the behavioral effects of the enantiomers of (±)-MDMA, that concluded that S(+)-MDMA was the active enantiomer because no dose of R(-)-MDMA produced even “nominal” intoxication, pupil dilation, or jaw clenching, which indicates lower abuse liability (page 384). Claim 31 depends from and further limits claim 30 and recites the administering step is further defined as administering 10-1000 mg of the R(-) enantiomer of MDMA or MDA (see above discussion regarding claims 2, 8, and 9).
Accordingly, claims 1-2, 8-10, 12, 18-21, 25-26, and 30-31 are anticipated by Pitts et al.
Claim(s) 1-2, 7, 9, 17, 20, 25, and 30 is/are rejected under 35 U.S.C. 102(a)(1) as being amticipated by ACQUAS ET AL. (Journal of Neurochemistry, 2007, vol. 102, p.121-132) (NEWLY CITED) as evidenced by CURRY ET AL. (Neuropharmacology, 2018, vol. 128, p.196-206) (NEWLY CITED).
ACQUAS ET AL. teach administering R(-)-MDMA intravenously to male Sprague–Dawley rats (Abstract; p.122, right column, “Surgery”; p.123, left column, “Immunohistochemistry”). They teach R(-)-3,4-MDMA HCl was dissolved in saline (0.64, 1, and 2 mg/mL) and administered intravenously in a volume of 1 mL/kg of body weight (p.123, right column, “Drugs”).
The intended uses/intended results of the administration of R-(-)-MDMA or R-(-)-MDA to an individual recited in claims 20, 25, and 30, i.e., “reducing neurotoxicity of MDMA or MDA”, “reducing hyperthermia of MDMA or MDA”, and/or “reducing physical dependent or abuse liability of MDMA or MDA”, are not afforded patentable weight because they merely recite the intended result of administering R-(-)-MDMA or R-(-)-MDA to an individual. Regardless, CURRY ET AL. teach administration of R-MDMA significantly increased murine social interaction and facilitated extinction of conditioned freezing, yet unlike racemic MDMA, it did not increase locomotor activity, produce signs of neurotoxicity, or increase body temperature (Id.). They teach dissolving R(-)-3,4-methylenedioxymethamphetamine (R-MDMA) in 0.9% sterile saline and administering via intraperitoneal injection at a volume of 10 ml/kg to male C57BL/6 mice aged 10-16 weeks in the fear conditioning experiments and to C57BL/6 mice aged 7-10 weeks in all other experiments (p.197, right column, “Methods”). They teach administering R-MDMA (50 mg/kg) given twice at a two-hour interval (p.198, left column, “Body temperature monitoring”).
Accordingly, Claims 1-2, 7, 9, 17, 20, 25, and 30 are anticipated by Acquas et al.
Claim(s) 1-2, 7, 9, 17, 20, 25, and 30 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by GLENNON ET AL. (Pharmacology, Biochemistry and Behavior, 2002, vol. 72, p.307-311) (NEWLY CITED) as evidenced by CURRY ET AL. (Neuropharmacology, 2018, vol. 128, p.196-206).
GLENNON ET AL. teach administering R(-)-MDA HCl intraperitoneally to male Sprague–Dawley rats (Abstract; p.308-309, “Drug discrimination studies”; Table 1). They teach a solution of R(-)-MDA HCl was administered intraperitoneally and had an ED50 of 1.5 mg/kg (0.4-4.8 mg/kg) (p.309, left column, “Drugs”; p.309, right column, first full paragraph; Fig. 2; Table 1).
The intended uses/intended results of the administration of R-(-)-MDMA or R-(-)-MDA to an individual recited in claims 20, 25, and 30, i.e., “reducing neurotoxicity of MDMA or MDA”, “reducing hyperthermia of MDMA or MDA”, and/or “reducing physical dependent or abuse liability of MDMA or MDA”, are not afforded patentable weight because they merely recite the intended result of administering R-(-)-MDMA or R-(-)-MDA to an individual. Regardless, CURRY ET AL. teach administration of R-MDMA significantly increased murine social interaction and facilitated extinction of conditioned freezing, yet unlike racemic MDMA, it did not increase locomotor activity, produce signs of neurotoxicity, or increase body temperature (Id.). They teach dissolving R(-)-3,4-methylenedioxymethamphetamine (R-MDMA) in 0.9% sterile saline and administering via intraperitoneal injection at a volume of 10 ml/kg to male C57BL/6 mice aged 10-16 weeks in the fear conditioning experiments and to C57BL/6 mice aged 7-10 weeks in all other experiments (p.197, right column, “Methods”). They teach administering R-MDMA (50 mg/kg) given twice at a two-hour interval (p.198, left column, “Body temperature monitoring”).
Accordingly, Claims 1-2, 7, 9, 17, 20, 25, and 30 are anticipated by Glennon et al.
Claim(s) 1-2, 5, 7, 9, 11-12, 15, 17, 20, 22, 25, 27, 30, and 32 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WANG ET AL. (Psychopharmacology, 2007, vol. 189, p.483-488) (NEWLY CITED) as evidenced by CURRY ET AL. (Neuropharmacology, 2018, vol. 128, p.196-206).
WANG ET AL. teach administering R(-)-MDMA dissolved in saline to monkeys via a peristaltic infusion pump (delivering drug injection over 10 s) (Abstract; p.484-485, “Materials and methods”; Fig. 2). The average number of injections per session was about 5, with the dose per injection ranged from 0.1 to 0.8 mg/kg per injection (Figs. 1 and 2).
The intended uses/intended results of the administration of R-(-)-MDMA or R-(-)-MDA to an individual recited in claims 20, 25, and 30, i.e., “reducing neurotoxicity of MDMA or MDA”, “reducing hyperthermia of MDMA or MDA”, and/or “reducing physical dependent or abuse liability of MDMA or MDA”, are not afforded patentable weight because they merely recite the intended result of administering R-(-)-MDMA or R-(-)-MDA to an individual. Regardless, CURRY ET AL. teach administration of R-MDMA significantly increased murine social interaction and facilitated extinction of conditioned freezing, yet unlike racemic MDMA, it did not increase locomotor activity, produce signs of neurotoxicity, or increase body temperature (Id.). They teach dissolving R(-)-3,4-methylenedioxymethamphetamine (R-MDMA) in 0.9% sterile saline and administering via intraperitoneal injection at a volume of 10 ml/kg to male C57BL/6 mice aged 10-16 weeks in the fear conditioning experiments and to C57BL/6 mice aged 7-10 weeks in all other experiments (p.197, right column, “Methods”). They teach administering R-MDMA (50 mg/kg) given twice at a two-hour interval (p.198, left column, “Body temperature monitoring”).
Accordingly, Claims 1-2, 5, 7, 9, 11-12, 15, 17, 20, 22, 25, 27, 30, and 32 are anticipated by Wang et al.
Claim(s) 1-2, 7, 9-10, 17, 20-21, 25-26, and 30-31 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by FRAU ET AL. (Journal of Neurochemistry, 2013, vol. 124, p.69-78) (NEWLY CITED) as evidenced by CURRY ET AL. (Neuropharmacology, 2018, vol. 128, p.196-206).
FRAU ET AL. teach a composition comprising R(-)-MDMA-HCl dissolved in saline (p.70, right column, “Drugs”). They teach R(-)-MDMA-HCl dissolved in saline was administered intraperitoneally (i.p.) in a volume of 10 ml/kg to adult make 12-week-old C57BL/6J mice at a dose of 4 x 10 mg/kg (p.70, right column, “Animals” and “Drugs”; p.71, let column, “Treatments”).
The intended uses/intended results of the administration of R-(-)-MDMA or R-(-)-MDA to an individual recited in claims 20, 25, and 30, i.e., “reducing neurotoxicity of MDMA or MDA”, “reducing hyperthermia of MDMA or MDA”, and/or “reducing physical dependent or abuse liability of MDMA or MDA”, are not afforded patentable weight because they merely recite the intended result of administering R-(-)-MDMA or R-(-)-MDA to an individual. It is noted, however, that Frau et al. teach that administration of R(-)-MDMA-HCl does not induce hyperthermia, while S-(+)-MDMA does (Fig. 5). Regardless, CURRY ET AL. teach administration of R-MDMA significantly increased murine social interaction and facilitated extinction of conditioned freezing, yet unlike racemic MDMA, it did not increase locomotor activity, produce signs of neurotoxicity, or increase body temperature (Id.). They teach dissolving R(-)-3,4-methylenedioxymethamphetamine (R-MDMA) in 0.9% sterile saline and administering via intraperitoneal injection at a volume of 10 ml/kg to male C57BL/6 mice aged 10-16 weeks in the fear conditioning experiments and to C57BL/6 mice aged 7-10 weeks in all other experiments (p.197, right column, “Methods”). They teach administering R-MDMA (50 mg/kg) given twice at a two-hour interval (p.198, left column, “Body temperature monitoring”).
Accordingly, Claims 1-2, 7, 9-10, 17, 20-21, 25-26, and 30-31 are anticipated by Frau et al.
Claim(s) 1-2, 7, 9, 17, 20, 25, and 30 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by CURRY ET AL. (Neuropharmacology, 2018, vol. 128, p.196-206).
CURRY ET AL. teach S,R(+/-)-3,4-methylenedioxymethamphetamine (SR-MDMA) is an amphetamine derivative with pro-social and putative therapeutic effects and that ongoing clinical trials are investigating it as a treatment for PTSD and other conditions. They teach its potential adverse effects such as hyperthermia and neurotoxicity may limit its clinical viability. They hypothesized that R-MDMA would retain prosocial and therapeutic effects but with fewer adverse effects (Abstract). They teach administration of R-MDMA significantly murine social interaction and facilitated extinction of conditioned freezing, yet unlike racemic MDMA, it did not increase locomotor activity, produce signs of neurotoxicity, or increase body temperature (Id.). They teach R-MDMA could be a more viable therapeutic option for the treatment of PTSD and other disorders for which SR-MDMA is currently being investigated (Id.). They teach dissolving R(-)-3,4-methylenedioxymethamphetamine (R-MDMA) in 0.9% sterile saline and administering via intraperitoneal injection at a volume of 10 ml/kg to male C57BL/6 mice aged 10-16 weeks in the fear conditioning experiments and to C57BL/6 mice aged 7-10 weeks in all other experiments (p.197, right column, “Methods”). They teach administering R-MDMA (50 mg/kg) given twice at a two-hour interval (p.198, left column, “Body temperature monitoring”).
Accordingly, Claims 1-2, 7, 9, 17, 20, 25, and 30 are anticipated by Curry et al.
As clearly evident from the above cited prior art, Applicants did not invent compositions comprising R(-)-MDMA or R(-)-MDA, did not invent administering such compositions “to an individual”, nor were Applicants the first to observe that R-MDMA, unlike racemic MDMA, does not increase locomotor activity, produce signs of neurotoxicity, or increase body temperature.
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.
This application currently names joint inventors. In considering patentability of the claims under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
Claims 1-2, 7-12, 17-22, 25-27, and 30-32
Claims 1-2, 7-12, 17-22, 25-27, 30-32, and 35 are rejected under 35 U.S.C. 103(a) as being unpatentable over MITHOEFER ET AL. (Journal of Psychopharmacology, 2010, vol. 25, no. 4, p.439-452) (NEWLY CITED) and OEHEN ET AL. (Journal of Psychopharmacology, 2013, vol. 27, no. 1, p.40-52) (NEWLY CITED) in view of CURRY ET AL. (Neuropharmacology, 2018, vol. 128, p.196-206) and PITTS ET AL. (Psychopharmacology, 2018, vol. 235, p.377-392).
The instant claims recite compositions for use in psychotherapeutic treatment comprising an R(-) enantiomer of MDMA or MDA (Claim 1) and methods that include a step of administering an effective amount of a composition comprising an R(-) enantiomer of MDMA or MDA to “an individual” (Claims 9, 20, 25, and 30). The preambles of claims 9, 20, 25, and 30, i.e., “treating an individual” (Claim 9), “reducing neurotoxicity of MDMA or MDA” (Claim 20), “reducing hyperthermia of MDMA or MDA” (Claim 25), and “reducing physical dependent or abuse liability of MDMA or MDA” (Claim 30) are not afforded patentable weight, pursuant with MPEP 2111.02. If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction. Shoes by Firebug LLC v. Stride Rite Children’s Grp., LLC, 962 F.3d 1362, 2020 USPQ2d 10701 (Fed. Cir. 2020).
MITHOEFER ET AL. teach administering ±3,4-methylenedioxymethamphetamine (MDMA) as an adjunct to psychotherapy. Regarding Claim 19, they teach twenty patients with chronic PTSD were randomly assigned to psychotherapy with concomitant active drug (n = 12) or inactive placebo (n = 8) administered during two 8-hr experimental psychotherapy sessions (Abstract; p.443, right column, “Randomization and blind – Stage 1”). Regarding Claims 2, 8, 10, 18, 21, 26, and 31, they teach MDMA (125 mg) was given in a capsule by mouth (p.444, right column, first full paragraph) and the optional supplemental dose of 62.5 mg MDMA was administered 2-2.5 hours after the initial dose if the investigators judged it to be safe and advisable and the subject agreed to it (paragraph bridging p.444-445).
OEHEN ET AL. teach psychiatrists and psychotherapists in the US (1970s to 1985) and Switzerland (1988–1993) used MDMA legally as a prescription drug, to enhance the
effectiveness of psychotherapy. Regarding Claim 19, to test the safety and efficacy of MDMA-assisted psychotherapy in patients with treatment-resistant PTSD, they teach a randomized, double-blind, active-placebo controlled trial enrolled 12 patients for treatment with either low-dose (25 mg, plus 12.5 mg supplemental dose) or full-dose MDMA (125 mg, plus 62.5 mg supplemental dose). They teach that MDMA-assisted psychotherapy can be safely administered in a clinical setting (Abstract).
CURRY ET AL. teach S,R(+/-)-3,4-methylenedioxymethamphetamine (SR-MDMA) is an amphetamine derivative with pro-social and putative therapeutic effects and that ongoing clinical trials are investigating it as a treatment for PTSD and other conditions. They teach its potential adverse effects such as hyperthermia and neurotoxicity may limit its clinical viability. They hypothesized that R-MDMA would retain prosocial and therapeutic effects but with fewer adverse effects (Abstract). They teach administration of R-MDMA significantly increased murine social interaction and facilitated extinction of conditioned freezing, yet unlike racemic MDMA, it did not increase locomotor activity, produce signs of neurotoxicity, or increase body temperature (Id.). They teach R-MDMA could be a more viable therapeutic option for the treatment of PTSD and other disorders for which SR-MDMA is currently being investigated (Id.). Regarding Claims 7 and 17, they teach dissolving R(-)-3,4-methylenedioxymethamphetamine (R-MDMA) in 0.9% sterile saline and administering via intraperitoneal injection at a volume of 10 ml/kg to male C57BL/6 mice aged 10-16 weeks in the fear conditioning experiments and to C57BL/6 mice aged 7-10 weeks in all other experiments (p.197, right column, “Methods”). They teach administering R-MDMA (50 mg/kg) given twice at a two-hour interval (p.198, left column, “Body temperature monitoring”).
PITTS ET AL. teach the use of (±)-3,4-methylenedioxymethamphetamine ((±)-MDMA) as an adjunct to psychotherapy in the treatment of psychiatric and behavioral disorders dates back over 50 years. They teach the clinical utility of (±)-MDMA is potentially mitigated by a range of demonstrated adverse effects and that one potential solution could lie in the individual S(+) and R(−) enantiomers that comprise (±)-MDMA. They teach the current preclinical evidence suggests that R(−)-MDMA may provide an improved therapeutic index, maintaining the therapeutic effects of (±)-MDMA with a reduced side effect profile, and that future investigations should investigate the therapeutic potential of R(−)-MDMA (Abstract). They teach (±)-MDMA was said to facilitate the therapeutic alliance between patient and therapist, i.e., patients were more at ease, willing to engage in therapy, and to talk honestly about themselves and their problems when (±)-MDMA was administered as an adjunct during therapy (paragraph bridging p.377-378). They teach (±)-MDMA demonstrates enantiospecific effects on multiple receptors, including dopamine, serotonin, and norepinephrine (p.379-380). With regard to reducing neurotoxicity of MDMA and MDA as recited in Claim 20, they teach that while few studies have assessed the toxicity of the individual enantiomers, there is some compelling evidence from rodent studies that the neurotoxicity of (±)-MDMA is driven by the S(+) enantiomer, and that R(−)-MDMA has substantially lower or potentially no neurotoxicity (p.381-382, “Neurotoxicity”). With regard to reducing physical dependence or abuse liability of MDMA and MDA as recited in Claim 30, they teach the one human study of the behavioral effects of the enantiomers of (±)-MDMA concluded that S(+)-MDMA was the active enantiomer because no dose of R(−)-MDMA produced even “nominal” intoxication, pupil dilation, or jaw clenching and that this lack of intoxication following R(−)-MDMA could indicate lower abuse liability. They also teach a study in nonhuman primates suggests that R(−)-MDMA may have lower abuse liability than (±)-MDMA or S(+)-MDMA (p.384, “Abuse-related behavioral effects”). They suggest that, based on the literature reviewed therein, which currently indicates that R(−)-MDMA has reduced DA release and neurotoxic and abuse liability while maintaining equal efficacy in increasing social behavior and enhancing fear conditioning extinction, R(−)-MDMA may permit a greater breadth of clinical viability (p.385, paragraph bridging left and right columns). They teach the reduced liability for toxicity, hyperthermia, and acute hypertension induced by R(−)-MDMA could further increase the clinical utility of MDMA, opening the door to a wider range of psychiatric conditions and treatment regimens. Importantly, they teach that recent preclinical studies on the therapeutic-like effects of (±)-MDMA have shown that R(−)-MDMA is equally efficacious to (±)-MDMA (p.386, left column, first full paragraph). Also see paragraph bridging p.386-387 (“R(−)-MDMA is equally effective in several preclinical studies of therapeutic-like effects, with reduced liability for toxicity, hyperthermia, hypertension, and abuse”).
It would have been obvious to a person of ordinary skill in the art to administer a composition comprising R(−)-MDMA to an individual undergoing psychotherapy because the prior art teaches that R(−)-MDMA is equally effective in several preclinical studies of therapeutic-like effects, with reduced liability for toxicity, hyperthermia, hypertension, and abuse. A person of ordinary skill in the art would have a reasonable expectation of success in formulating R(−)-MDMA into a composition, e.g., a solution or capsule, and administering the composition to an individual because such compositions were already known in the art and expressly taught to be equally effective in several preclinical studies of therapeutic-like effects, with reduced liability for toxicity, hyperthermia, hypertension, and abuse, compared to racemic MDMA.
One exemplary rationale for the Examiner’s determination of obvious is the combination of prior elements according to known methods to yield predictable results. Here, the Examiner finds that the prior art teaches each element claimed, i.e., a teaching of compositions comprising MDMA and administration of such composition to individuals (Mithoefer et al. and Oehen et al.) and a teaching that R(−)-MDMA is equally effective as racemic MDMA in several preclinical studies of therapeutic-like effects, with reduced liability for toxicity, hyperthermia, hypertension, and abuse (Curry et al. and Pitts et al.). The Examiner finds that one of ordinary skill in the art could have combined these elements by known methods, i.e., formulating R(−)-MDMA in known compositions such as solutions or capsules and administering these compositions to an individual. A person of ordinary skill in the art would have recognized that administering a composition comprising R(−)-MDMA would predictable have similar therapeutic efficacy as racemic MDMA with reduced liability for toxicity, hyperthermia, hypertension, and abuse as expressly taught in the cited prior art.
Another exemplary rationale supporting the Examiner’s determination of obviousness is the simple substitution of R(−)-MDMA for racemic MDMA to obtain predictable results. Here, the Examiner finds that the prior art taught a method of administering racemic MDMA to individuals to enhance the effectiveness of psychotherapy (Mithoefer et al. and Oehen et al.). The prior art teaches R(−)-MDMA is equally effective as racemic MDMA in several preclinical studies of therapeutic-like effects, with reduced liability for toxicity, hyperthermia, hypertension, and abuse (Curry et al. and Pitts et al.). As such, a person of ordinary skill in the art could have readily and predictably substituted racemic MDMA with R(−)-MDMA and the results of such substitution, e.g., similar therapeutic efficacy as racemic MDMA with reduced liability for toxicity, hyperthermia, hypertension, and abuse, would have been predictable because they are expressly suggested by the cited prior art.
Claims 2, 10, 21, 26, and 31 require the composition comprises 10-1000 mg R(−)-MDMA and administering 10-1000 mg R(−)-MDMA. Both Mithoefer et al. and Oehen et al. teach a full-dose MDMA is 125 mg plus a 62.5 mg supplemental dose. Pitts et al. teach that maximal effects of R(−)-MDMA were achieved with slightly higher doses of R(−)-MDMA compared to (±)-MDMA. In squirrel monkeys, they teach MDMA dose dependently increased huddling among socially housed conspecifics and increased the number of affiliative vocalizations, with both effects being maximally increased following 1 mg/kg (±)-MDMA. They teach R(−)-MDMA had equivalent efficacy for increasing both behaviors with peak effects at doses of 3.0 and 1.7 mg/kg, respectively (p.383, right column, last paragraph). Accordingly, formulating R(−)-MDMA in the same or higher dose than the 125 mg used for administering (±)-MDMA would have been prima facie obvious and expected to have similar effects to (±)-MDMA while limiting toxicity, hyperthermia, hypertension, and abuse. Furthermore, "[w]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Here, the generally conditions for administering R(−)-MDMA to an individual undergoing psychotherapy are taught in the cited prior art, e.g., 125 mg plus a 62.5 mg supplemental dose administered in a capsule. It is therefore not inventive to discover the optimal dose or administration route of R(−)-MDMA for treating an individual, e.g., a human subject.
Claims 11, 22, 27, and 32 require administering the R(−)-MDMA “daily”. Both Mithoefer et al. and Oehen et al. teach administering MDMA 125 mg plus a 62.5 mg supplemental dose on days of psychotherapy. It would be obvious, therefore, to administer R(−)-MDMA on each day of psychotherapy.
Accordingly, claims 1-2, 7-12, 17-22, 25-27, and 30-32 are properly rejected as being prima facie obvious over the combined teachings of the cited prior art.
Claim(s) 3-5, 13-15, 23-24, 28-29, and 33-34
Claim(s) 3-5, 13-15, 23-24, 28-29, and 33-34 is/are rejected under 35 U.S.C. 103 as being unpatentable over MITHOEFER ET AL. (Journal of Psychopharmacology, 2010, vol. 25, no. 4, p.439-452) and OEHEN ET AL. (Journal of Psychopharmacology, 2013, vol. 27, no. 1, p.40-52) in view of CURRY ET AL. (Neuropharmacology, 2018, vol. 128, p.196-206) and PITTS ET AL. (Psychopharmacology, 2018, vol. 235, p.377-392) as applied to claims 1-2, 7-12, 17-22, 25-27, and 30-32 above, and further in view of ELLIOTT ET AL. (J. Forensic Sci., 2020, vol. 65, no. 3, p.913-920) (NEWLY CITED).
Claims 3-5, 13-15, 23-24, 28-29, and 33-34 require the R-MDMA “includes a prodrug bound thereto”, wherein the prodrug in an amino acid selected from, inter alia, lysine.
The teachings of Mithoefer et al., Oehen et al., Curry et al., and Pitts et al. are as applied to claims 1-2, 7-12, 17-22, 25-27, and 30-32 supra, which teachings are herein incorporated by reference in their entirely and applied equally to claims 3-5, 13-15, 23-24, 28-29, and 33-34.
ELLIOTT ET AL. teach prodrugs of psychoactive substances (Abstract). They teach lisdexamfetamine consists of dextroamphetamine (d-amphetamine) derivatized with the amino acid L-lysine chemically modified with the L-lysine bound to an amine group.
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(p.914, left column, “Amphetamines”; Fig. 1A). They teach that while lisdexamfetamine is itself pharmacologically inactive, in vivo peptidase enzymes associated with red blood cells hydrolyze the amide bond, thereby allowing pharmacological effects being exerted through d-amphetamine. They teach this delayed absorption and metabolic profile for formation of the active drug reduces lisdexamfetamine’s abuse liability and increases its safety profile (Id.). They teach lysine-MDMA has been mentioned in some Internet user forums (p.914, paragraph bridging left and right columns).
It would have been obvious to a person of ordinary skill in the art to chemically modify R(−)-MDMA by attaching an amino acid such as lysine to the free amine group to form a prodrug. The use of known technique to improve a similar product in the same way is prima facie obvious. Here, the prior art teaches racemic MDMA and R(−)-MDMA and teaches R(−)-MDMA would be expected to have similar therapeutic efficacy as racemic MDMA with reduced liability for toxicity, hyperthermia, hypertension, and abuse. The prior art teaches chemical modification of amphetamines into prodrugs via attachment of an amino acid such as lysine to an amine group, which has been applied to d-amphetamine, whereas lysine-MDMA has been mentioned in some Internet user forms (Elliott et al.). Given their close structural similarity, a person of ordinary skill in the art would have recognized that R(−)-MDMA could have predictably been modified in the same way to afford an R(−)-MDMA prodrug.
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A person of ordinary skill in the art would have had a reasonable expectation that the so formed Lysine-R(-)-MDMA prodrug would be physiologically inactive until cleaved by in vivo peptidase enzymes to hydrolyze the amide bond, thereby allowing pharmacological effects being exerted through R(-)-MDMA.
Regarding Claims 5 and 15, which require the composition is in a “continual slow-release formulation”, because a lysine prodrug of R(-)-MDMA would need to be cleaved in vivo by peptidase enzymes to hydrolyze the amide bond thereby releasing the pharmaceutically active R(-)-MDMA, a composition comprising Lysine-R(-)-MDMA prodrug would also be reasonably construed to be a “continual slow-release formulation”, i.e., it would continually release R(-)-MDMA as the Lysine-R(-)-MDMA prodrug is metabolized in vivo.
Accordingly, claims 3-5, 13-15, 23-24, 28-29, and 33-34 are properly rejected as being prima facie obvious over the combined teachings of the cited prior art.
Claim(s) 6 and 16
Claim(s) 6 and 16 is/are rejected under 35 U.S.C. 103 as being unpatentable over MITHOEFER ET AL. (Journal of Psychopharmacology, 2010, vol. 25, no. 4, p.439-452) and OEHEN ET AL. (Journal of Psychopharmacology, 2013, vol. 27, no. 1, p.40-52) in view of CURRY ET AL. (Neuropharmacology, 2018, vol. 128, p.196-206) and PITTS ET AL. (Psychopharmacology, 2018, vol. 235, p.377-392) as applied to claims 1-2, 7-12, 17-22, 25-27, and 30-32 above, and further in view of ERMER ET AL. (Clin. Drug Investig., 2011, vol. 31, no. 6, p.357-370) (NEWLY CITED).
Claims 6 and 16 require the composition comprising R(-)-MDMA is in an intranasal spray form.
The teachings of Mithoefer et al., Oehen et al., Curry et al., and Pitts et al. are as applied to claims 1-2, 7-12, 17-22, 25-27, and 30-32 supra, which teachings are herein incorporated by reference in their entirely and applied equally to claims 6 and 16.
ERMER ET AL. teach a randomized, open-label, pharmacokinetic study of the prodrug stimulant lisdexamfetamine after single oral (PO) versus intranasal (IN) administration. They teach that IN administration of lisdexamfetamine resulted in d-amphetamine plasma concentrations and systemic exposure of d-amphetamine comparable to those seen with PO administration (Abstract).
It would have been obvious to a person of ordinary skill in the art to formulate R(−)-MDMA in a composition that is an intranasal spray formulation. The use of known technique to improve a similar product in the same way is prima facie obvious. Here, the prior art teaches racemic MDMA and R(−)-MDMA and teaches R(−)-MDMA would be expected to have similar therapeutic efficacy as racemic MDMA with reduced liability for toxicity, hyperthermia, hypertension, and abuse. The prior art teaches that intranasal administration of a structurally similar amphetamine resulted plasma concentrations and systemic exposure comparable to those seen with oral administration administration (Ermer et al.). A person of ordinary skill in the art would have recognized that R(−)-MDMA could have predictably been formulated and administered in an intranasal spray form lisdexamfetamine is a prodrug of an amphetamine stimulant and MDMA is an amphetamine-type stimulant. A person of ordinary skill in the art would have had a reasonable expectation that intranasal administration of R(−)-MDMA would have plasma concentrations and systemic exposure comparable to those seen with oral administration.
Accordingly, claims 6 and 16 are properly rejected as being prima facie obvious over the combined teachings of the cited prior art.
Non-Statutory Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be