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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on April 24, 2026, has been entered.
Response to Arguments
Applicant’s arguments and declaration have been considered in their entirety.
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.
As noted in the previous Office Action of November 24, 2025, dose optimization would be usable to arrive at an optimal dosage. Moreover, Nair et al., “A simple practice guide for dose conversion between animals and human,” Journal of Basic and Clinical Pharmacy (2016), 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 perform this conversion from the 40 mg/kg in a rat taught by Wirguin to a HED, we arrive at a human dose of 6.48 mg/kg for the HED. This falls within the claimed dosage.
Applicant argues that there may be still be some delta-9 THC in the composition taught by Wirguin as the purity is not described.
The examiner notes that the teachings of Wirguin are focused on examining the effects of delta-8-THC and the instant the claims are “substantially free” of delta-9 THC. Substantially free is defined by the Specification to include less than 10%. Thus, the claims do not exclude an amount of delta-9-THC. Moreover, delta-8-THC is taught to be more stable and less psychotropic than delta-9-THC. Thus, there is a specific motivation and advantage of using it in a pure form. According to M.P.E.P. § 2144.04,
Purer forms of known products may be patentable, but the mere purity of a product, by itself, does not render the product nonobvious.
Factors to be considered in determining whether a purified form of an old product is obvious over the prior art include whether the claimed chemical compound or composition has the same utility as closely related materials in the prior art, and whether the prior art suggests the particular form or structure of the claimed material or suitable methods of obtaining that form or structure. In re Cofer, 354 F.2d 664, 148 USPQ 268 (CCPA 1966).
In this case, there appears to be nothing unpredictable or unknown about the use a compound with known advantages compared to the inclusion of more product that is less stable and more psychotropic.
Applicant argues that EAE does not accurately reflect or mimic human MS.
The examiner notes that EAE is the accepted model for studying MS. In addition, this is the EAE model for multiple sclerosis that was used in the only examples of the instant Specification. See par. 124 and par. 132 of the Specification. While it may be true that a better model exists, Wirguin is intended to teach delta-8-THC as having therapeutic potential in treating multiple sclerosis. As such, a POSA would understand that delta-8-THC, when used at an appropriate HED, can be used to treat MS.
Applicant argues that Al-Ghezi found that treating with THC or CBD alone failed to cause significant suppression of clinical symptoms.
The examiner notes that Al-Ghezi was not cited nor needed to show that delta-8-THC can treat EAE. Al-Ghezi was cited to show that given the almost identical chemical structure of delta-9-THC and delta-8-THC, there is a reasonable expectation that the claimed API would 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.
As an additional note (relevant to the second § 103 rejection set forth below), 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
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 9-5 M-F.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amy 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
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