Status of the Application
This Office Action is in response to the Amendment and Remarks filed 13 July 2026.
The objection to the Specification is withdrawn in view of Applicant’s amendment.
The rejection of claim 12 under 35 USC 112(b) is now moot as said claim has been cancelled.
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 1-3 and 13-20 remain rejected under 35 U.S.C. 103 as being unpatentable over Czap (US 2019/0046598) in view of Pate et al (U.S. 5,977,180) and Chwalisz et al (US 2001/0056068) and in further view of Ghasemi et al (2007 BHY International)
The instant claims are directed to a method for treating or preventing a nitric oxide deficiency or a disease which can be treated or prevented by increasing endogenous nitric oxide levels in a mammal by orally administering a composition comprising an anandamide and a cyclodextrin carrier with a cyclodextrin degrading enzyme. Applicant claims said method wherein the composition further comprises L-arginine or a citrulline.
Czap teaches a method of treating a disease in a mammal using a cyclodextrin inclusion complex delivery vehicle (claim 1) comprising a salivary or microbial amylase (claim 6 and 7) wherein the cyclodextrin in gamma cyclodextrin (claim 21). Czap teaches said method wherein the delivery vehicle comprises a drug and a pharmaceutically acceptable carrier (claim 13). Czap teaches said delivery vehicle can comprise L-arginine (claim 43). Czap teaches that the delivery vehicle can be administered orally (claim 41). Czap teaches that one of ordinary skill in the instant art would use common general knowledge to modify the teachings therein on page 6, paragraph [0057].
Czap does not teach a method of orally administering anandamide or an analogue thereof as a guest molecule in a cyclodextrin inclusion complex formulation.
Pate et al teach a method of treating intraocular hypertension using a composition comprising anandamide analogues and a cyclodextrin (Abstract). Pate et al teach a wide variety of anandamide analogues at columns 3 and 4. Pate et al teach that a gamma cyclodextrin can be used at column 4, lines 52-65. Pate et al teach that a viscosity enhancing agent like hydroxypropylmethyl cellulose can be used in the composition at column 11, lines 57-59. Pate et al teach that arachidonyl ethanolamine (an anandamide analogue) is known to bind the cannabinoid receptor at column 1, lines 58-60. Pate et al teach that there is an advantage to using a cyclodextrin to deliver an anandamide at column 2.
Chwalisz et al teach control, management, treatment and prevention of conditions related to nitric oxide deficiency such as hypertension by administering to a mammal an effective amount of citrulline or a citrulline analogue at claim 3 and 21, and that the composition can further contain L-arginine at claim 23.
Ghasemi et al teach that anandamide increases the production of nitric oxide and can be useful in the treatment of erectile dysfunction.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant claims to modify the teachings of Czap using the teachings of Pate et al to produce a cyclodextrin inclusion complex formulation comprising anandamide or an analogue thereof and a cyclodextrin degrading enzyme. Both Czap and Pate et al teach using gamma cyclodextrin (instant claim 20). Ghasemi et al teaches that anandamide and analogues thereof can increase endogenous nitric oxide levels in a mammal, and Chwalisz et al teach that citrulline and analogues thereof in combination with L-arginine can be also used to increase endogenous nitric oxide levels in a mammal. Hence, the invention of instant claims 1-9 and 17 are obvious in view of these two references. Selection of an anandamide analogue and/or citrulline analogue (instant claims 6-10) would have been a design choice as suggested by both Pate et al and Chwalisz et al. The pharmaceutically acceptable carrier calcium laurate (instant claim 18) would have been a design choice also. Pate et al had suggested including hydroxypropylmethylcellulose (instant claims 13 and 14) would have been a desired addition to the composition even if Applicant’s reason is different from that of the prior art. Finally, measuring nitrous oxide levels in the subject mammal to be treated would have been obvious given the teachings of Chwalisz et al and Ghasemi et al.
Given the teachings of the prior art, one of ordinary skill in the art would have been motivated in modifying the teachings of Czap to use the taught cyclodextrin inclusion complex formulation to administer anandamide or an analogue thereof for the purposes of increasing endogenous nitric oxide levels in a mammal, especially given the teachings of Ghasemi et al.
Given the teachings of Czap and Pate et al, one of ordinary skill in the art would have had a reasonable expectation of success in modifying the prior art to arrive at the method of the instant claims.
Applicant argues that the cited art does not teach or suggest oral administration to a human for treatment of erectile dysfunction of a cyclodextrin inclusion complex formulation that comprises anandamide as a guest molecule, a co-formulated cyclodextrin-degrading enzyme and citrulline (page 5,4th paragraph of the Remarks). Applicant argues that Ghasemi does not disclose the presently claimed “oral administering”, does not disclose “a human” subject, does not disclose “a cyclodextrin inclusion complex”, does not disclose a “cyclodestrin-degrading enzyme” and does not disclose a formulation “comprising citrulline” (page 6, 2nd paragraph of the Remarks). Applicant argues that Ghasemi states “that anandamide had no influence on SNP-induced relation of rat corpus cavernosum (CC) (page 6, 3rd paragraph of the Remarks).
Applicant’s arguments are not found persuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Czap had previously taught the cyclodextrin (CD) inclusion complex formulation including a cyclodextrin degrading enzyme at claims 6-8. Czap teaches oral delivery of the formulation at claim 14. Hence, Czap had taught the general composition of the cyclodextrin inclusion complex formulation used in the instantly claimed method. Ghasemi teaches that the rat CC was relaxed with the NO (nitrous oxide) donor SNP whether the CC was from a diabetic or a non-diabetic (the control) rat on page 1388, center column. Ghasemi teaches that “co-administration of low concentrations of L-arginine and anandamide exerted a synergistic potentiating effect on NANC-mediated relation of the CC from diabetic rats” on page 1388, left column, end of 1st paragraph).
Applicant argues that Ghasemi provided investigations involved a mechanistic tissue-bath study, not a therapeutic teaching of oral treatment in humans (page 7, 1st paragraph of the Remarks). Applicant argues that Ghasemi used 0.3, 1 and 3 mM anandamide in a direct organ-bath exposure and that these concentrations are roughly two to three orders of magnitude higher than the circulating nanomolar AEA levels (anandamide) described in Hillard (2018 make of record in the IDS filed 13 July 2026) on page 7, 2nd paragraph of the Remarks.
Applicant’s arguments are not found persuasive. Hillard’s teaching relates to naturally occurring endocannabinoids not to an administered endocannabinoid. Czap had taught that one of ordinary skill in the art would have used routine experimentation to determine a “therapeutically effective amount” of a CD inclusion complex (page 6, paragraph 0055). Further, the instant claims do not recite any specific concentration or range(s) of any of the recited components of the cyclodextrin inclusion complex formulation. Hence, Applicant is arguing limitations not found in the instant claims.
Applicant argues that Pate teaches a formulation for topical ocular delivery, not oral therapy for erectile dysfunction (page 7, 3rd paragraph of the Remarks). Applicant argues that Chwalisz concerns treatment of nitric oxide deficiency-related disorders with citrulline or citrulline analogues, and it includes broad statements about male impotence and optional combinations with nitric oxide substrates such as L-arginine, and that Chwalisz does not suggest combining citrulline with anandamide in a cyclodextrin inclusion complex formulation, much less with a co-formulated cyclodextrin-degrading enzyme for oral treatment of erectile dysfunction in humans (page 7, 3rd paragraph of the Remarks).
Applicant’s arguments are not found persuasive because Pate teaches the general knowledge of one of ordinary skill in the art before the effective filing date of the instant claims in producing and using a cyclodextrin as a carrier for anandamide and analogues thereof. Chwalisz had taught using an orally administered formulation comprising citrulline or an analogue thereof and L-arginine to increase nitric oxide levels in a mammal to treat male impotence. Ghasemi had taught co-administration of low concentrations of L-arginine and anandamide. Czap had taught a cyclodextrin inclusion complex formulation for delivery of a drug or pro-drug at claim 13, the choice of the drug would be a design choice, and Pate had taught delivering anandamide using a cyclodextrin carrier.
Finally, Applicant argues improper hindsight reconstruction on page 8, 1st paragraph of the Remarks. In response to Applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
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 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.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAVID H KRUSE whose telephone number is (571) 272-0799. The examiner can normally be reached Monday-Friday 7AM-3:30PM.
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/David H Kruse/
Primary Examiner, Art Unit 1663
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