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 Amendments
Applicant’s amendments to the claims of November 5, 2025, in response to the Office Action of August 5, 2025, are acknowledged.
Response to Arguments
The Double Patenting and § 101 Rejections are withdrawn in view of the Amendments to the claims.
Applicant argues that the dose of 0.1 to 10 mg/kg claimed is different from that used in the prior art. The prior art used 40 mg/kg in a rat.
While the examiner notes that dosage optimization would be able to optimize to any dose. Moreover, in rebuttal to Applicant’s arguments, the examiner cites: Nair et al., “A simple practice guide for dose conversion between animals and human,” Journal of Basic and Clinical Pharmacy (2016). Nair shows in Table 1 how to convert from an animal dose to a human equivalent dose (HED). A HED requires multiplying the animal dose for a rat by 0.162. Here, if we do this conversion we multiple 40 x 0.162 = 6.48 mg/kg. This is in the middle of the claimed dosage.
Applicant argues that Al-Ghezi is directed to THC and CBD and notes that it did not cause significant suppression of clinical symptoms.
The examiner notes that Al-Gehzi was the quaternary reference cited and it was not used nor needed to show that delta-8-THC can treat MS. The primary reference Wirguin teaches this. As noted in the Office Action, Al-Ghezi was cited to show that given the almost identical chemical structure of delta-9-THC and the claimed compound, there is a reasonable expectation that the claimed API would also correlate with the claimed biomarkers as described by Al-Ghezi. In particular, treatment caused a decrease in CD4+ T cells and IL-17; and an increase in FoxP3, IL-10 and TGF-β. Further, THC and CBD downregulated miR-21, miR-31, miR-146, miR-155, and upregulated others. See Abstract.
The claimed delta-8-THC is taught for administration to treat MS. The claimed dosages is optimizable equivalent for a rat and a human. Aharoni and Al-Ghezi teaches administering the claimed exogenous antigen.
In the second § 103, Paul and Nagarkatti show that claimed biomarkers correlate with disease severity in subjects with MS and cannabinoids cause a downregulation of NK and cytotoxic T lymphocyte activity. The portion of the rejection in this regard is set forth below.
Even further, Paul teaches miRNAs are promising biomarker candidates in MS. Increased expression of miR-21, miR-146a, and miR-155 in PBMC from untreated MS patients compared to healthy controls. See p10, 1st par. Further, Table 1 shows IL-17 as a validated biomarker as well. Another study found that miR-325 expression correlates with disease severity in MS patients and EAE mice. Circulating miRNAs can be detected in plasma, serum, urine, and saliva. See p10, 2nd par.
Nagarkatti teaches cannabinoids were show to cause an imbalance in T cell CD4/CD8 ratio and to downregulate NK and cytotoxic T lymphocyte activity.
Moreover and with further regard to the claims directed to a decrease in a biomarker, the results of administration of a same API to a same subject population through a same route of administration at a same and/or optimizable dose would be expected to yield a decrease in a claimed biomarker consistent with what that agent does and consistent with the claim language. The level of a biomarker is a change that is a response to an active step of administration, which is rendered obvious. As such, Applicant’s arguments are not persuasive.
Status of the Claims
Claims 1, 4-6, and 9-26 are pending and examined.
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.
Claims 1, 4-6, and 9-26 are rejected under 35 U.S.C. 103 as being unpatentable over Wirguin et al., “Suppression of experimental autoimmune encephalomyelitis by cannabinoids,” Immunopharmacology, Vol 29, Issue 3, November-December 1994, pp209-214, in view of Weber et al., “Repetitive Pertussis Toxin Promotes Development of Regulatory T Cells and Prevents Central Nervous System Autoimmune Disease,” PLOS one December 2010, Vol. 5, Issue 12, and in view of Aharoni et al., “Titration of myelin oligodendrocyte glycoprotein (MOG) - Induced experimental autoimmune encephalomyelitis (EAE) model,” Journal of Neuroscience Methods 351 (2021), and in view of Al-Ghezi et al., Combination of Cannabinoids, Δ9- Tetrahydrocannabinol and Cannabidiol, Ameliorates Experimental Multiple Sclerosis by Suppressing Neuroinflammation Through Regulation of miRNA-Mediated Signaling Pathways,” Front. Immunol., 20 August 2019 (co-authored by Applicants), and in view of Eisenstein et al., “Effects of Cannabinoids on T-cell Function and Resistance to Infection,” J Neuroimmune Pharmacol 2015 June;10(2):204-216.
Wirguin teaches delta-8-THC is more stable and less psychotropic than delta-9-THC. Rats that were inoculated for experimental autoimmune encephalomyelitis (EAE) with delta-8-THC for up to 21 days with 40 mg/kg had a significantly reduced incidence and severity of neurologic deficit. The result occurred with oral administration. This may be due to the need for first pass metabolism in the liver to produce an active metabolite. See p212, last par. Cannabinoids also influence immune response. This could lead to significant advances in MS research and therapy. Delta-8-THC was extracted was cannabidiol. As evidenced by Study: Users say delta-8-THC is delta-9’s ‘nicer younger sibling’ - University at Buffalo, January 12, 2022, both delta-8-THC and delta-9-THC naturally occur in the cannabis plant. Thus, when a method comprises administration of cannabis, e.g., it is inclusive of both delta-8-THC and delta-9-THC.
Weber teaches that mice that were injected with pertussis toxin (PTx) were largely protected from subsequent EAE induction that was reflected by a decrease in proliferation and pro-inflammatory differentiation of myelin-reactive T cells. See Abstract. Those with established MS can have infections that trigger T cell activation which is associated with relapse. See p1, par. 2nd. Repetitive treatment with PTx were evaluated for EAE. Inflammatory lesions and extent of inflammatory infiltration was lower in PTx treated group. P3, 2nd full par. Mice that were repetitively pre-treated with PTx were largely protected from subsequent EAE induction. See p3, last par. Pretreatment reduced reactive T cells. Further, in MS frequency and function of Treg have been impaired and restoration of Treg function is a benefit of treatment. Repetitive treatment with PTx elevated frequency of FoxP3 expression. See p5, last par.
Similarly, Aharoni teaches external immunization with MOG peptide and pertussis toxin heavily boosts the immune system. See Abstract. The MEVGWYRSPFSRVVHLYRNGK peptide encompassing amino acids 35–55 of the myelin oligodendrocyte glycoprotein (MOG) was used. MOG peptide was administered at a dose of 200-300 micrograms/mouse and PTx at a dose of 200-500 ng/mouse. See Abstract.
Al-Ghezi teaches inducing EAE with 100-150 micrograms MOG35-55 peptide and IP injection of 200 ng pertussis toxin on day 0 and 400 ng on day 2. Further, mice were administered THC+CBD at a dose of 10mg/kg each THC and CBD. Treatment resulted in attenuated symptoms of clinical EAE. See p4, 6th full par. Treatment caused a decrease in CD4+ T cells and IL-17; and an increase in FoxP3, IL-10 and TGF-β. Further, THC and CBD downregulated miR-21, miR-31, miR-146, miR-155, and upregulated others. See Abstract. Given the almost identical chemical structure of delta-9-THC and the claimed compound, there is a reasonable expectation that that claimed API would also correlate with the claimed biomarkers as described by Al-Ghezi.
Eisenstein teaches: “A considerable number of studies examined which T-cell subsets were affected by the cannabinoid, and the mechanisms by which T-cell function was altered. Δ9 -THC was found to differentially suppress the number of CD8 T-cells and reduce their cytolytic activity (citing Klein et al. 1991;Pross et al. 1990).” P.3, 1st par.
It would have been prima facie obvious to a person of ordinary skill in the art prior to the filing to combine the teachings of Wirguin, Weber, Aharoni, Al-Ghezi, and Eisenstein to arrive at the claimed methods. One would be motivated to do so because Wirguin teaches that the claimed API, delta-8-THC can be administered to reduced incidence and severity of neurologic deficit associated with EAE. This is known model for MS as explained by Aharoni. Further, pretreatment with PTx was shown to mitigate inflammatory lesions and extent of inflammatory infiltration. In addition, mice were largely protected from subsequent EAE induction. Pretreatment reduced reactive T cells, restored Treg function, and elevated frequency of FoxP3 expression. Aharoni teaches inducing EAE with immunization with MOG 35-55 peptide and PTx, to provide a truer model for MS. MOG peptide was administered at a dose of 200-300 micrograms/mouse and PTx at a dose of 200-500 ng/mouse. While Wirguin used delta-8-THC for up to 21 days with 40 mg/kg, Al-Ghezi induced EAE with 100-150 micrograms MOG35-55 peptide and IP injection of 200 ng pertussis toxin while using only 10 mg/kg THC (i.e., delta-9-THC form). According to MPEP 2144.09, A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties." In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979). Overall there is a reasonable and predictable expectation of success in treating a subject with MS with delta-8-THC and it is known to be more stable and less psychotropic than delta-9-THC. Pretreatment with PTx is shown and known to be beneficial at dosages that overlap claims dosages and MOG35-55 peptide is taught to be administered along with PTx by multiple cited references. While the specific biomarkers are not taught to be measured in response to delta-8-THC treatment, treatment is taught to cause the claimed response including: a decrease in CD4+ T cells and IL-17; and an increase in FoxP3, IL-10 and TGF-β. Further, THC and CBD downregulated miR-21, miR-31, miR-146, miR-155, and upregulated others. This has a reasonable expectation of success based on the structural and functional similarities of delta-8 and delta-9 THC, wherein these compounds differ only in the position of a single carbon chain bond. Further, both are found in cannabis.
Claims 1, 4-6, and 9-26 are rejected under 35 U.S.C. 103 as being unpatentable over Wirguin et al., “Suppression of experimental autoimmune encephalomyelitis by cannabinoids,” Immunopharmacology, Vol 29, Issue 3, November-December 1994, pp209-214, in view of Weber et al., “Repetitive Pertussis Toxin Promotes Development of Regulatory T Cells and Prevents Central Nervous System Autoimmune Disease,” PLOS one December 2010, Vol. 5, Issue 12, and in view of Aharoni et al., “Titration of myelin oligodendrocyte glycoprotein (MOG) - Induced experimental autoimmune encephalomyelitis (EAE) model,” Journal of Neuroscience Methods 351 (2021), in view of Al-Ghezi et al., Combination of Cannabinoids, Δ9- Tetrahydrocannabinol and Cannabidiol, Ameliorates Experimental Multiple Sclerosis by Suppressing Neuroinflammation Through Regulation of miRNA-Mediated Signaling Pathways,” Front. Immunol., 20 August 2019 (co-authored by Applicants), in view of Eisenstein et al., “Effects of Cannabinoids on T-cell Function and Resistance to Infection,” J Neuroimmune Pharmacol 2015 June;10(2):204-216, as applied above, and in further view of Paul et al., “Biomarkers in Multiple Sclerosis,” Cold Spring Harb Perspect Med 2019;9:a029058, in view of Nagarkatti et al., (U.S. Pat. No. 8,242,178),
Paul teaches miRNAs are promising biomarker candidates in MS. Increased expression of miR-21, miR-146a, and miR-155 in PBMC from untreated MS patients compared to healthy controls. See p10, 1st par. Further, Table 1 shows IL-17 as a validated biomarker as well. Another study found that miR-325 expression correlates with disease severity in MS patients and EAE mice. Circulating miRNAs can be detected in plasma, serum, urine, and saliva. See p10, 2nd par.
Nagarkatti teaches cannabinoids were show to cause an imbalance in T cell CD4/CD8 ratio and to downregulate NK and cytotoxic T lymphocyte activity.
Paul and Nagarkatti are merely cited to show a predictive direction of claimed biomarkers that would be expected to result with efficacious treatment and administration of claimed cannabinoid.
It would have been prima facie obvious to a person of ordinary skill in the art prior to the filing to combine the teachings of the cited prior art to arrive at the claimed methods. One would be motivated to do so because Wirguin teaches that the claimed API, delta-8-THC can be administered to reduced incidence and severity of neurologic deficit associated with EAE. This is known model for MS as explained by Aharoni. Further, pretreatment with PTx was shown to mitigate inflammatory lesions and extent of inflammatory infiltration. In addition, mice were largely protected from subsequent EAE induction. Pretreatment reduced reactive T cells, restored Treg function, and elevated frequency of FoxP3 expression. Aharoni teaches inducing EAE with immunization with MOG 35-55 peptide and PTx, to provide a truer model for MS. MOG peptide was administered at a dose of 200-300 micrograms/mouse and PTx at a dose of 200-500 ng/mouse. While Wirguin used delta-8-THC for up to 21 days with 40 mg/kg, Al-Ghezi induced EAE with 100-150 micrograms MOG35-55 peptide and IP injection of 200 ng pertussis toxin while using only 10 mg/kg THC (i.e., delta-9-THC form). According to MPEP 2144.09, A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties." In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979). Overall there is a reasonable and predictable expectation of success in treating a subject with MS with delta-8-THC and it is known to be more stable and less psychotropic than delta-9-THC. Pretreatment with PTx is shown and known to be beneficial at dosages that overlap claims dosages and MOG35-55 peptide is taught to be administered along with PTx by multiple cited references. While the specific biomarkers are not taught to be measured in response to delta-8-THC treatment, treatment is taught to cause the claimed response including: a decrease in CD4+ T cells and IL-17; and an increase in FoxP3, IL-10 and TGF-β. Further, THC and CBD downregulated miR-21, miR-31, miR-146, miR-155, and upregulated others. This has a reasonable expectation of success based on the structural and functional similarities of delta-8 and delta-9 THC, wherein these compounds differ only in the position of a single carbon chain bond. Further, both are found in cannabis.
As such, no claim is allowed.
Conclusion
THIS ACTION IS MADE FINAL. 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 extension fee 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 JARED D. BARSKY whose telephone number is (571)-272-2795. The examiner can normally be reached on Monday through Friday from 8:30 to 5:30. If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Amy L. Clark can be reached on 571-272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JARED BARSKY/Primary Examiner, Art Unit 1628