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 .
Status of claims
Claims 1, 3, 6, 8-9 and 27-28 are currently pending and under consideration. Claims 2, 5, and 7 were canceled. Claims 27 and 28 were newly added.
Withdrawn Rejections
The rejection of claims 1-4 and 6-9 are rejected under 35 U.S.C. 103 as being unpatentable over Adler et al. Toxicon, Volume 34, Issue 2, 1996, pages 237-249 (hereafter “Adler”) is withdrawn in view of the amendments and cancellation.
The rejection of claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Adler in view of “Symptomatic treatment of botulism with a clinically approved small molecule", Vazquez Cintron et al., JCI Insight, 2020; 5(2) (hereinafter “Vazquez Cintron”). is withdrawn in view of claim cancellation.
Request for Continued Examination
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 04/16/2026 has been entered.
New Grounds of Rejection due to claim amendment
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 (i.e., changing from AIA to pre-AIA ) 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.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3, 6, 8-9, and 27-28 are rejected under 35 U.S.C. 103 as being unpatentable over Vazquez-Cintron et al., JCI Insight. 2020 Jan 30;5(2):e132891, Siegel et al., Toxicology and Applied Pharm, vol. 84, no. 2, June 1986, pp. 255–63, Sindhurakar et al., Neurorehabil Neural Repair. 2017 Apr;31(4):387-396.
Regarding 1, 3-4, 6, and 28, Vazquez-Cintron (page 3) discloses that 2 mg/kg 3,4-DAP in mice are effective and are also equivalent to the clinical 20 mg oral dose, produces Cmax of 20-200 ng/ml in human, reversing botulism symptoms at clinically acceptable exposure levels. Importantly, Vazquez-Cintron (page 3) also highlights the therapeutic effects of a single dose administration were transient and that symptom relief or symptomatic benefits diminished as plasma concentration declined, or fell below to approximately 25-50 ng/mL. Vazquez-Cintron therefore discloses both the efficacy of 3,4-DAP for treating botulism and the need of maintaining therapeutically effective plasma concentration.
Vazquez-Cintron, however, does not explicitly teach continuous delivery in a human subject.
Siegel (page 260) teaches six botulinum toxin-intoxicated cynomolgus monkeys were administered after 3 to 6 hr with intravenously 3,4-DAP (1.1-2.6 mg/kg) and demonstrated significant clinical improvement thereafter. Siegel (page 260) further teaches administration of additional continuous iv drip (0.78-0.95 mg/kg/hr) was not as effective as the initial treatment. Moreover, Siegel (page 256) discloses administering of 4-aminipyridine (4-AP; 0.35-1.5 mg/kg), a chemical and pharmacological analog 3,4-DAP, to human botulism patients, substantially restored transmitter release and reversed peripheral paralysis. Thus, Siegel explicitly demonstrates that both 3,4-DAP and 4-AP are well-known in the art as effective treatments for botulism. Given that 3,4-DAP and 4-AP are structural analogs, a POSITA would reasonably consider applying the dosing guidance established for 4-AP to 3,4-DAP, and arrive to a dosing range corresponding to 0.35-1.5 mg/kg/ for 3,4-DAP to human botulism patients, and thus arrive at the claimed invention. This is because both compounds demonstrate similar therapeutic dose ranges and comparable activity against botulism. Therefore, the combined teachings of Vazquez-Cintron and Siegel disclose treatment of human subject with a dosing range corresponding to 0.35-1.5 mg/kg/hr for 3,4-DAP, which overlaps with the claimed administration of about 0.1 mg/kg/hr to about 2 mg/kg/hr.
Regarding steady-state plasma, Vazquez-Cintron (page 3), as mentioned previously, discloses that 20-mg oral dose (3,4-DAP in humans) results in a Cmax of 30-200 ng/mL, wherein symptomatic benefits diminished once plasma levels decreased below 25-50 ng/mL. Additionally, Sindhurakar (page 391-392) teaches continuous 4-AP infusion at approximately 0.36 mg/kg/hr over 5 hours, resulting in plasma concentrations of approximately 70-140 ng/ml. Therefore, a POSITA would have found it obvious to integrate the dosing guidance as disclosed by the combined teachings of Vazquez-Cintron, Siegel and Sindhurakar, to achieve steady-state levels of 70-140 ng/ml, and to arrive at the claimed invention.
Regarding at least 3 days, although Vazquez-Clinton (page 2-4) does not teach continuous infusion for at least 3 days, however, Vazquez-Clinton (page 1-4) teaches that single dose treatment of 3,4-DAP is short-lived, suggesting that sustained administration is necessary to maintain therapeutic effect during botulism intoxication. This is supported by Adler (page 1382 and 1386) disclosing that a 7-day sustained delivery 3,4-DAP via minipump, which provides a constant, uninterrupted release of the drug which is required throughout the period of botulism intoxication to main muscle function. Therefore, a POSITA would have been motivated to employ continuous 3,4-DAP dosing for a duration sufficient to maintain therapeutic benefit. Since Adler’s disclosure of a 7-day treatment period, thus, selecting a continuous infusion to at least about 3 days would represent a predictable optimization of duration within the broader 1 to 7-day sustained-delivery framework taught in the prior art to preserve therapeutic effect. Therefore, it would have been obvious with a reasonable expectation of success to a POSITA at the time of filing of the instant application to combine the teachings of Vazquez-Cintron, Siegel, Sindhurakar, and Adler to administer a continuous infusion of 3,4-DAP in the range of 0.35-1.5 mg/kg/hr in a human subject for at least 3 days, to achieve steady-state levels of 70-140 ng/ml, to arrive at the claimed invention which represents a variation of the combined prior art’s disclosure.
Regarding claim 8, the combined teachings of Vazquez-Cintron (page 1-6), Adler (page 1381-1385) and Siegel (page 255-259) disclosing that 3,4-DAP infusion is effective against BoNT serotypes A.
Regarding claim 9, Adler (abstract) teaches “the ability of 3,4-diaminopyridine (3,4-DAP) to antagonize muscle paralysis following local injection of botulinum neurotoxin A (BoNT/A) complex.” Therefore, it would have been obvious to a POSITA at the time of this application’s filing to combine the teachings of Vazquez-Cintron, Siegel, Sindhurakar, and Adler to administer a continuous infusion to treat localized botulinum toxin intoxication.
Regarding claim 28, Vazquez-Cintron (page 9) teaches co-administration of antitoxin with 3,4-DAP:
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Therefore, in view of the combined teachings of Vazquez-Cintron, Siegel, Sindhurakar, and Adler, a POSITA would have been motivated with a reasonable expectation of success to co-administer HBAT with 3,4-DAP to neutralize circulating toxin with 3,4-DAP’s ability to restore neuromuscular function. Thus, “wherein the botulism comprises localized botulinum neurotoxin intoxication” represents a predictable combination of known therapies addressing complementary aspects of botulism pathology.
Response to Arguments
Applicant argues the 103-rejection based on Adler and Adler-2 is no longer applicable in view of the claim amendments. This is because the cited references fail to teach or suggest the newly added limitations requiring administration to a human subject and achieving the recited steady-state plasma concentration parameters. Applicant’s argument is not persuasive because the newly cited references teach administration 3,4-DAP by continuous infusion to human subjects for the treatment of botulism using dosing rates within and overlapping the claimed range of about 0.35-1.5 mg/kg/hr in a human subject to achieve steady-state levels of 70-140 ng/ml. Thus, the claimed invention represents a variation or optimization of known treatment methods employing continuous infusion of 3,4-DAP in human subjects as taught by the combined teachings of Vazquez-Cintron, Siegel, Sindhurakar, and Adler.
Applicant argues that Adler and Aler-2 were published more than 27 years ago and yet there has been no clinically approved treatment for botulism based on 3,4-DAP that has emerged. Applicant, therefore, asserts the claimed invention would not have been obvious in view of Adler and Adler-2. Applicant’s argument is not persuasive because of absence of a clinically approved treatment following publication of Adler and Adler-2 does not establish that the claimed invention would have been nonobvious. It is important to note that determination of obviousness under U.S.C 103 is based on what the prior art would have taught or suggested to a POSITA at the time of the invention, rather than on whether the disclosed subject matter ultimately achieved commercial success or regulatory approval. Thus, neither commercialization nor approval by regulatory agency is a prerequisite for a prior-art reference to provide relevant teaching supporting an obviousness determination.
Response to 35 U.S.C. § 103 Rejection over Adler in view of Vazquez-Cintron
Applicant argues that Vazquez-Cintron does not provide reason or motivation to administer 3,4-DAP to a human subject via continuous infusion. Applicant’s argument is not persuasive, because the newly cited references in view Vazquez-Cintron teach administration 3,4-DAP by continuous infusion to human subjects for the treatment of botulism using dosing rates within and overlapping the claimed range of about 0.35-1.5 mg/kg/hr in a human subject to achieve steady-state levels of 70-140 ng/ml. Furthermore, Applicant 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).
Conclusion
No claims are allowed.
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/P.P.E./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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