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 .
Response to Amendment
2. Applicant's amendment and response, submitted March 26, 2026, has been reviewed by the examiner and entered of record in the file. Claims 1, 2, 5, 15, 34, and 35 are amended. Claims 33 and 37-45 are canceled.
3. Claims 1, 2, 5, 6, 15, 20, 22, 32 and 34-45 are under examination and are the subject of this office action.
Previous Claim Rejections - 35 USC § 112
4. Claims 1, 2, 5, 6, 15, 20, 22, and 32-45 were previously rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite regarding the limitation “identifying an individual that consumes or consumed alcohol at a frequency of at least once weekly.”
Previous Claim Rejections - 35 USC § 103
5. Claims 1, 2, 5, 6, 15, 20, 22, and 32-45 were previously rejected under 35 U.S.C. 103 as being unpatentable over Clinical Trials.gov Archive for Study NCT02981173, November 30, 2016, in view of Chaerunisaa et al., Pharmaceutical Formulation Design - Recent Practices: Microcrsytalline Cellulose as Pharmaceutical Excipient (2019), and in view of Bahra et al., Neurology (2002), and further in view of Sewell et al., Neurology (2006).
6. In view of Applicant’s amendatory changes, the previous obviousness rejection is withdrawn, and the following rejection is applied.
New Claim Rejections - 35 USC § 103
7. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
8. Claims 1, 2, 5, 6, 15, 20, 22, 32, and 34-36 are rejected under 35 U.S.C. 103 as being unpatentable over Clinical Trials.gov Archive for Study NCT02981173, (November 30, 2016), in view of Chaerunisaa et al., Pharmaceutical Formulation Design (2019), in view of Sewell et al., Neurology (2006), and in view of Monstad et al., Headache (1995).
9. This rejection is partially newly applied as a result of Applicant’s amendments to the claims.
Claim 1, as amended, is directed to a method of treating a headache disorder, the method comprising:
identifying an individual that is being treated with a triptan for the headache disorder, wherein the headache disorder is selected from the group consisting of migraine and tension-type headache; and
orally administering (claims 2 and 5) a capsule (claim 32) to the identified individual a pharmaceutical composition comprising 1-50 mg isolated psilocybin and at least one pharmaceutically acceptable carrier, diluent, adjuvant, or vehicle, (more specifically orally administering psilocybin at a dose of 0.143 mg/kg (claim 36)), and
treating the headache disorder in the identified individual,
wherein the composition is administered when the individual is experiencing a headache disorder attack, and
wherein the composition is administered as a three dose pulse regimen with a 3 to 7 day separation between doses, followed by administering a second round of the three dose pulse regimen after at least 3 months, and
wherein, during the period of time when the identified individual is being administered the pharmaceutical composition, the identified individual is treated with one or two doses of the triptan per week and the identified individual cannot be administered the pharmaceutical composition within a period of time corresponding to 5 half-lives of the preceding triptan administration.
Claim 6 is drawn to claim 1 and limits wherein the administration reduces migraine headache burden by reducing the number of weekly migraine days (WMD) by at least 25%.
Claim 15, as amended, is directed to a method of treating cluster headache in an individual in need thereof, the method comprising:
identifying an individual that is being treated with a triptan for the cluster headache; and
orally administering (claims 34 and 35) to the identified individual when experiencing a cluster headache, a pharmaceutical composition comprising 1-50 mg isolated psilocybin and at least one pharmaceutically acceptable carrier, diluent, adjuvant or vehicle, (more specifically orally administering psilocybin at a dose of 0.143 mg/kg (claim 20)); and
reducing cluster headache burden in the identified subject, (more specifically, wherein the reduction of cluster headache burden comprises reducing the number of weekly cluster attacks in the identified individual (claim 22)), and
wherein the pharmaceutical composition is administered to the individual [in] a three dose pulse regimen with a 3 to 7 day separation between doses, followed by administering a second round of the three dose pulse regimen,
wherein, during the period of time when the identified individual is being administered the pharmaceutical composition, the identified individual is treated with one or two doses of the triptan per week.
10. Clinical Trials.gov teaches an oral psilocybin pulse regimen for the treatment of chronic cluster headache in a subject in need thereof, wherein high dose psilocybin is administered at a dosage of 0.143 mg/kg in the form of a capsule, in three test days, each separated by 5 days +/- 1- 2 days. Chronic cluster headache meets the limitation of a headache disorder, (a migraine). A dosage amount of psilocybin of 0.143 mg/kg (assuming an average 62 kg human) is 8.866 mg, which falls within the dosage range of “1-50 mg” required by claim 1 (See “Study Description” and “Arms and Interventions”). A pulse regimen comprising three doses, each separated by 5 days +/- 1- 2 days embraces the range of “a 3 to 7 day separation between doses” required by claims 1, 15, and 33. Clinical Trials.gov teaches primary outcomes of a reduction in the frequency and average number of weekly cluster attacks in the individual (See under “Outcome Measures”), thus resulting in the practice of claims 6 and 22.
11. Regarding the dose regimen, dose regimen optimization is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize given the guidance of the prior art. Optimization of parameters (e.g., dose frequency) is a routine practice that would be obvious for a person of ordinary skill in the art to employ. Thus, one of skill in the art would have been motivated to start with the three dose regimen as guided by ClinicalTrials.gov, and modify said regimen by following up with an additional round of the three dose regimen, to optimize the known method of treating migraine, with a reasonable expectation of success.
12. Regarding the limitation that the psilocybin is isolated (required by claims 1 and 15), as stated by the court in Aventis Pharma Deutschland GMBH and King Pharmaceuticals, Inc. v Lupin, Ltd., No 06-1530 (Fed. Cir. 2007), “if it is known that some desirable property of a mixture derives in whole or in part from a particular one of its components, or if the prior art would provide a person of ordinary skill in the art with reason to believe that this is so, the purified compound is prima facie obvious over the mixture even without an explicit teaching that the ingredient should be concentrated or purified. Ordinarily, one expects a concentrated or purified ingredient to retain the same properties it exhibited in a mixture, and for those properties to be amplified when the ingredient is concentrated or purified; isolation of interesting compounds is a mainstay of the chemist’s art. If it is known how to perform such isolation, doing so ‘is likely the product not of innovation but of ordinary skill and common sense’” quoting KSR International Co. v. Teleflex Inc., 127 US 1727 (2007). Thus, nothing unobvious is seen in one of skill in the art administering isolated psilocybin to treat migraine in an identified individual, with a reasonable expectation of success.
13. Regarding the limitation that the psilocybin composition comprises at least one pharmaceutically acceptable carrier, diluent, adjuvant or vehicle, Chaerunisaa et al. teach that microcrystalline cellulose (MCC) “is an excipient of outstanding merit and remains the most widely used direct compression excipient serving as a strong dry binder, tablet disintegrant, an absorbent, filler, or diluent, a lubricant, and anti-adherent… It is used as a binder/ diluent in oral tablet and capsule formulations… MCC has been the most favorite diluent among others due to its low bulk density.” (Page 8, paragraphs 2-4). Thus, one of skill in the art would have been motivated to combine psilocybin with a preferred binder/ diluent such as microcrystalline cellulose in order to formulate an improved psilocybin composition in capsule form, and would have a reasonable expectation of success.
12. As such, Clinical Trials.gov teach a method of treating cluster headache in an individual in need thereof, comprising orally administering a capsule comprising a pharmaceutical composition comprising isolated psilocybin at a dosage of 0.143 mg/kg in a three dose pulse regimen, but do not teach that the individual is being treated with a triptan for said headache disorder.
13. Yet, Sewell et al. teach that principal treatment of a cluster headache attack includes acute treatment with triptans, which are partially effective in 18% of patients and ineffective in 9% of patients (see Table 2 at page 1921). In the same Table, Sewell et al. teach that by administering psilocybin to the cluster headache patients, remission extension is achieved in 91% of said patients.
14. And, Monstad et al. teach that when administered preemptively to cluster headache patients, sumatriptan at a dose of 100 mg t.i.d. did not significantly reduce the number or severity of cluster headache attacks during an established cluster headache period (see abstract). Monstad et al. teach that while sumatriptan is effective when given during the headache phase of cluster or migraine attacks, preemptive treatment with sumatriptan had no effect on the development of moderate to severe cluster or migraine attacks (page 5, first three paragraphs under “Comments”).
15. Thus, one of skill in the art before the effective filing date of the claimed invention, aware that sumatriptan is effective when administered during a headache attack but has no prophylactic efficacy, would have been motivated to administer an additional therapy for cluster headache treatment, such as psilocybin as suggested by Sewell et al., with a reasonable expectation of success.
16. Regarding the frequency of triptan administration, Monstad et al. teach sumatriptan administration at a dose of 100 mg t.i.d. for seven days. And, it has been held that it is within the skill in the art to select optimal parameters, such as dosing regimen, in a composition in order to achieve a beneficial effect. See In re Boesch, 205 USPQ 215 (CCPA 1980). It is also noted that "[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 optimization with a reasonable expectation of success. Therefore nothing unobvious is seen in one skilled in the art before the effective filing date of the claimed invention starting with the dose amount of 100 mg t.i.d. taught by Monstad et al., and optimizing said dose amount and frequency for administration to a cluster headache patient, with a reasonable expectation of success.
17. Sewell et al. go on to teach treating cluster headache comprising administering high dose psilocybin to a patient during a headache attack, (see Table (E)T-1, Case #18, #23, and 24, supplementary material). Sewell et al. teach that said treatment resulted in 100% decrease in the frequency or intensity of headaches, see Table (E)T-1, column labeled “Psilocybin treated period” wherein 100% indicates termination of the cluster period. Case #14 achieved greater than 75% termination of the cluster period. Complete termination of the cluster period, as well as greater than 75% termination of cluster period, both meet the limitation of “reducing the number of weekly migraine days (WMD) by at least 25% in the identified individual” required by claim 6, and the limitation of “reducing the number of weekly cluster attacks in the identified individual” required by claim 22. As such, one of skill in the art before the effective filing date of the claimed invention would have been motivated to administer a pharmaceutical composition comprising isolated psilocybin the individual experiencing a cluster headache, with a reasonable expectation of success.
18. While Sewell et al. teach administration of a single dose of psilocybin to a cluster headache patient, it has been held that it is within the skill in the art to select optimal parameters, such as dosing regimen, in a composition in order to achieve a beneficial effect. See In re Boesch, 205 USPQ 215 (CCPA 1980). It is also noted that "[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 optimization with a reasonable expectation of success. As ClinicalTrials.gov teaches a three dose pulse regimen for psilocybin that is used to treat cluster headache, optimizing dosage variation based on outcome is considered a result effective variable. Thus, it would also have been obvious to have chosen a dosage regimen from among those known to be effective in methods of treating a headache disorder.
19. Thus, in view of Sewell et al. and Monstad et al., one of skill in the art before the effective filing date of the claimed invention would have considered that an individual suffering from cluster headache and taking sumatriptan as a principal treatment, which is not reliably effective for treating said headache, meets the limitation of an individual in need thereof, i.e., an individual in need of additional treatment for cluster headache. One skilled in the art before the effective filing date of the claimed invention would have been motivated to treat said individual receiving principal treatment with a triptan with a pharmaceutical composition comprising isolated psilocybin in order to achieve remission, with a reasonable expectation of success.
20. And, the rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law, please see In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings). Furthermore, MPEP 2144 teaches that the strongest rationale for combining references is a recognition, expressly or impliedly in the prior art or drawn from a convincing line of reasoning based on established scientific principles or legal precedent, that some advantage or expected beneficial result would have been produced by their combination. In the instant case, nothing unobvious is seen in the combined administration of two known compounds which are individually taught for the treatment of cluster headache, in order to achieve an additive effect for treating cluster headache in a patient in need thereof.
As stated by the Court in KSR International Co., v. Teleflex Inc., 127 US 1727 (2007), “when a patent ‘simply arranges old elements with each performing the same function it had been known to perform’ and yields no more than one would expect from such an arrangement, the combination is obvious” (quoting Sakraida v. AG Pro, Inc., 425 US 273 (1976); see also: Merck v. Biocraft (874 F.2d 804, 807 (Fed. Cir. 1989), indicating that it is a matter of obviousness for one of ordinary skill in the art to select a particular component from among many disclosed by the prior art as long as it is taught that the selection will result in the disclosed effect, even when the possible selections number 1200 or in the thousands; Sundance, Inc. v. DeMonte Fabricated, Ltd., 550 F.3d 1356 (Fed. Cir. 2008): a claimed invention is obvious is it is a combination of known prior art elements that would reasonably have been expected to maintain their respective properties or functions after they had been combined.
As such, claims 1, 2, 5, 6, 15, 20, 22, and 34-36 are prima facie obvious.
Response to Arguments
21. Applicant traverses the obviousness rejections, and argues the following points:
(i) Applicant argues that NCT02981173 fails to describe or suggest identifying an individual that is taking a triptan for treatment of the headache disorder; and administering to the identified individual a pharmaceutical composition comprising 1-50 mg isolated psilocybin and at least one pharmaceutically acceptable carrier, diluent, adjuvant, or vehicle. Applicant contends that the Study Details for NCT02981173 lists under its study exclusion criteria "[u]se of vasoconstrictive medications (i.e. sumatriptan, pseudoephedrine, midodrine) in the past two weeks." (Clinicaltrials.gov entry for NCT02981173). Applicant alleges that a subject that takes one or two doses of a triptan weekly while the isolated psilocybin is administered would be excluded from NCT02981173 protocol, because that protocol requires patents who have not received vasoconstrictive medications, such as sumatriptan, for at least 2 weeks before being administered psilocybin. Applicant argues that the exclusion criteria taught in NCT02981173 teach a person of skill in the art away from the claimed therapeutic method, i.e., “[t]here can be no motivation derived from a clinical study reference to administer a therapeutic regimen to a population specifically excluded from the clinical study.” (Applicant’s Remarks, page 9, second paragraph). Applicant argues that there is no teaching of identifying a population of individuals who are being treated with a triptan for a headache disorder as recited in the pending claims and administering to the identified individual a pharmaceutical composition comprising 1-50 mg of isolated psilocybin.
22. Applicant's arguments have been fully considered but they are not persuasive. Regarding the Study Details for NCT02981173, the examiner acknowledges that the study exclusion criteria specifically list "use of vasoconstrictive medications (i.e., sumatriptan, pseudoephedrine, midodrine) in the past two weeks," (Clinicaltrials.gov entry for NCT02981173, page 7). However, “a non-enabling reference may qualify as prior art for the purpose of determining obviousness under 35 U.S.C. 103,” (Symbol Techs. Inc. v. Opticon Inc., 935 F.2d 1569 (Fed. Cir. 1991)). In this case, ClinicalTrials.gov (NCT02981173), teaches a method of treating cluster headache in an individual in need thereof, comprising orally administering a capsule comprising a composition consisting of isolated psilocybin at a dosage of 0.143 mg/kg, in a three dose pulse regimen. While NCT02981173 excludes patients having used a vasoconstrictive medication such as sumatriptan in the past two weeks from the study itself, NCT02981173 does not discourage the use of psilocybin and a triptan for a combined therapeutic treatment in order to achieve an additive effect when treating cluster headache in a patient in need thereof.
(ii) Applicant alleges that while Sewell mentions that cluster headaches respond "less than 20% to abortive medications such as sumatriptan,” (Sewell, p. 1921), this description of triptans is in the context of their traditional use and does not describe identifying such individuals and administering to the identified individual a pharmaceutical composition comprising 1-50 mg of isolated psilocybin. Applicant contends that regardless of this description, Sewell cannot be combined with NCT02981173 for teaching affirmatively identifying triptan-using patients and treating them with a pharmaceutical composition comprising 1-50 mg of isolated psilocybin that are expressly excluded by NCT02981173. Applicant argues that Bahra describes various triptan treatment regimens but fails to describe psilocybin use, and like Sewell, cannot be combined with NCT02981173 and/or Sewell for teaching affirmatively identifying triptan-using patients and treating them with a pharmaceutical composition comprising 1-50 mg of isolated psilocybin that are expressly excluded by NCT02981173. Applicant argues that Chaerunisaa is cited for use of microcrystalline cellulose and does not correct any of the defects identified in any combination of NCT02981173, Sewell, and Bahra.
23. Applicant's arguments have been fully considered but they are not persuasive. Sewell teaches that principal treatment of a cluster headache attack includes acute treatment with triptans, which are partially effective in 18% of patients and ineffective in 9% of patients (see Table 2 at page 1921). In the same Table, Sewell et al. teach that by administering psilocybin to the cluster headache patients, remission extension is achieved in 91% of said patients. Even if Sewell does not require that the patient being treated has taken a triptan, Sewell suggests that cluster headaches respond "less than 20% to abortive medications such as sumatriptan,” (Sewell, p. 1921). Therefore, one of skill in the art would reasonably consider treating a cluster headache patient with principal treatment comprising a triptan and additional treatment with psilocybin, in order to achieve an additive effect in the treatment of cluster headaches, i.e., achieving remission from headaches in said patient.
Conclusion
24. Claims 1, 2, 5, 6, 15, 20, 22, 32, and 34-36 are present in the application. Claims 1, 2, 5, 6, 15, 20, 22, 32 and 34-36 are rejected. No claim is presently allowable.
25. 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.
26. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JANET L COPPINS whose telephone number is (571)272-0680. The examiner can normally be reached Monday-Friday 8:30AM-5PM EST.
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/JANET L COPPINS/Examiner, Art Unit 1628
/AMY L CLARK/Supervisory Patent Examiner, Art Unit 1628
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