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- 9 are currently pending and under consideration. Claims 10, 14-19 and 21-26 were canceled.
Withdrawn Rejections
The rejection of claims 19 and 21 under 35 U.S.C. 102(a)(1) as being anticipated by US 2015/0353467 A1 to Guyon et al., (hereinafter, “Guyon”) is withdrawn in view of claim cancellation.
The rejection of claims 10-12, 16-17, 22 and 24 under 35 U.S.C. 103 as being unpatentable over Siegel et al., Toxicology and Applied Pharmacology, 84, 2, pp 255-263 {1986) ("Siegel") in view of Guyon et al. US 20150353467 ("Guyon") is withdrawn in view of claim cancellation.
The rejection of claim 18 under 35 U.S.C. 103 as being unpatentable over Siegel and Guyon as applied to claims 10- 12, 16- 17, 22 and 24 above and further in view of Adler et al. Toxicon, Volume 34, Issue 2, 1996, pages 237-249 ("Adler") is withdrawn in view of claim cancellation.
The rejection of claims 14, 15 and 23 under 35 U.S.C. 103 as being unpatentable over Siegel and Guyon as applied to claims 10- 12, 16- 17, 22 and 24 above and further in view of Vazquez-Cintron is withdrawn in view of claim cancellation.
The rejection of claim 25 under 35 U.S.C. 103 as being unpatentable over Guyon in view of Siegel is withdrawn in view of claim cancellation.
The rejection of claim 26 under 35 U.S.C. 103 as being unpatentable over Guyon in view of Adler is withdrawn in view of claim cancellation.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has been timely paid, the finality of the previous Office action has been withdrawn pursuant to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 08/20/2025 has been entered.
According to MPEP 706.07(b), for an application in which an RCE has been filed, claims
may be finally rejected in the first action following the filing of the RCE (with a submission and
fee under 37 CFR 1.114 ) when all the claims in the application after the entry of the submission
under 37 CFR 1.114 and any entered supplemental amendments (A) are identical to, patentably
indistinct from, or have unity of invention with the claims in the application prior to the entry of
the submission under 37 CFR 1.114 (in other words, restriction (including lack of unity of
invention) would not have been proper if the new or amended claims had been entered prior to
the filing of the RCE), and (B) would have been properly finally rejected on the grounds and art
of record in the next Office action if they had been entered in the application prior to the filing of
the RCE under 37 CFR 1.114.
Maintained Rejections
Claim Rejections - 35 USC § 103
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”).
Regarding claim 1, Adler teaches, in the first paragraph of page 237, the induction of local paralysis of the rat extensor digitorum longus muscle by subcutaneous injections of one of botulinum serotypes A, B, E and F. In the course of investigating the decay of 3,4-diaminopyridine’s beneficial effects over time, Adler teaches 3,4-diaminopyridine intravenous infusion, under the header “Mechanism underlying the decay of tension after 3,4-DAP infusion”, page 241:
“To determine whether this decay was due to decreases in the effective 3,4-DAP levels or to reductions in the responsiveness of the muscle, multiple 3,4-DAP injections were undertaken.”
Adler’s infusion process consists of intravenous administration of 3,4-diaminopyridine in response to diminished neurological activity following the initial positive response to 3,4-diaminopyridine injection. Adler’s infusion comprises an approximately evenly-spaced repetitive administration of discrete 3,4-diaminopyridine boluses.
While the definition given in specification paragraph ¶ [0067] recites infusion durations, it is silent about the rate of 3,4-diaminopyridine administration during said infusion, i.e., whether it is at a fixed rate, increasing or decreasing rate(s), or, as in Adler, a “pulsed” administration. The Adler infusion schedule just outlined therefore qualifies as a “continuous infusion” under the definition given in ¶ [0067].
The Examiner instead interprets “continuous infusion” in the context of specification paragraphs ¶ [0007] and ¶ [0008], wherein steady administration over the infusion interval, such as “3 mg/kg of the subject's body weight per hour”, are recited. Therefore, 3,4-diaminopyridine, as detailed on page 237 and 238, despite being administered in discrete doses, exhibits rapid and sustained pharmacological effect through repeat administration, suggesting a form of continuous infusion in a broader sense. This could be considered by one of ordinary skill in the art as functionally equivalent to traditional continuous infusion.
As evidence by Adler-2 teaches the use of 3,4-DAP delivered via a continuous infusion using osmotic minipumps to treat BoNT/A-induced muscle paralysis. Given that the same author, Adler, employs continuous infusion, osmotic minipumps, for the same undelaying treatment goal; thus, this further indicates that using 3,4-DAP via continuous infusion is not a novel concept. Thus, it would have been obvious for a person of ordinary skill in the art (POSITIA) to modify the teachings of Adler by incorporating the term continuous infusion to arrive at the claimed invention, because the concept of treating BoNT/A-induced muscle paralysis with 3,4-DAP via a continuous infusion is known in the art as disclosed by Adler in view of the evidence by Adler-2. (Adler et al. Toxicon, vol. 38, no. 10, Oct. 2000, pp. 1381–88. (“Adler-2”)).
Moreover, given Adler’s repeated successes of rapidly, if temporarily, restoring locally-intoxicated nerve function with each intravenous 3,4-diaminopyridine administration, it would have been obvious to one of ordinary skill in the art at the time of this application’s filing to increase the injection frequency to minimize the decrease of 3,4-diaminopyridine’s beneficial effects seen in Adler Figure 1, page 240. Furthermore, it would have been obvious to one of ordinary skill in the art at the time of this application’s filing that the limit of increased administration frequency is zero dosing interval, i.e., a continuous infusion of the type described in specification paragraphs ¶ [0007] and ¶ [0008].
Regarding claim 2, Adler teaches 3,4-diaminopyridine infusion, but does not explicitly teach wherein the effective amount of 3,4-diaminopyridine is infused at a rate of about 0.5 mg/kg of the subject’s body weight per hour to about 3 mg/kg of the subject's body weight per hour. It would have been obvious to one of ordinary skill in the art at the time of this application’s filing to adjust the infusion technique of Adler (page 241) by routine experimentation to modify dosing regimens wherein the effective amount of 3,4-diaminopyridine is infused at a rate of between about 0.5 mg/kg of the subject's body weight per hour to about 4 mg/kg of the subject's body weight per hour.
Regarding claim 3, Adler teaches 3,4-diaminopyridine infusion, but does not explicitly teach wherein the effective amount of 3,4-diaminopyridine is infused at a rate of about 1.4 mg/kg of the subject's body weight per hour. It would have been obvious to one of ordinary skill in the art at the time of this application’s filing to adjust the infusion technique of Adler (page 241) by routine experimentation to modify dosing regimens wherein the effective amount of 3,4-diaminopyridine is infused at a rate of about 1.4 mg/kg of the subject's body weight per hour.
Regarding claim 4, Adler teaches 3,4-diaminopyridine infusion, but does not explicitly teach wherein the effective amount of 3,4-diaminopyridine is provided in a total daily dose ranging from about 80 mg to about 160 mg of 3,4-diaminopyridine, or the equivalent amount of the pharmaceutically acceptable salt thereof. It would have been obvious to one of ordinary skill in the art at the time of this application’s filing to adjust the infusion technique of Adler (page 241) to modify dosing regimens wherein the effective amount of 3,4-diaminopyridine is provided in a total daily dose ranging from about 80 mg to about 160 mg of 3,4-diaminopyridine, or the equivalent amount of the pharmaceutically acceptable salt thereof, by routine experimentation to optimize the therapeutic effect.
Regarding claim 6, Adler teaches 3,4-diaminopyridine infusion, but does not explicitly teach therein the administration of 3,4-diaminopyridine or the equivalent amount of the pharmaceutically acceptable salt thereof to attain a steady-state plasma concentration of about 120 ng/ml of 3,4-diaminopyridine in the subject. It would have been obvious to one of ordinary skill in the art at the time of this application’s filing to adjust the infusion technique of Adler (page 241) to modify the dosing amount and duration wherein the administration of 3,4-diaminopyridine, or the equivalent amount of the pharmaceutically acceptable salt thereof, achieves a steady-state plasma concentration of about 120 ng/mL of 3,4-diaminopyridine in the subject by routine experimentation to optimize the therapeutic effect.
Regarding claim 7, Adler teaches 3,4-diaminopyridine infusion to treat botulinum toxin intoxication, but does not explicitly teach therein the administration of 3,4-diaminopyridine or the equivalent amount of the pharmaceutically acceptable salt thereof by continuous infusion for a plurality of consecutive days. It would have been obvious to one of ordinary skill in the art at the time of this application’s filing to extend the infusion technique of Adler (page 241) to a plurality of consecutive days.
Regarding claim 8, Adler teaches that 3,4-diaminopyridine infusion is effective against BoNT serotypes A and E (2nd paragraph, page 237). It would have been obvious to a person of ordinary skill in the art at the time of this application’s filing to adjust the infusion technique taught by Adler to attain continuous infusion to treat botulinum toxins of serotype A and E.
Regarding claim 9, Adler teaches (Abstract, page 239 et seq,) the infusion of 3,4 diaminopyridine for localized botulinum intoxication. It would have been obvious to a person of ordinary skill in the art at the time of this application’s filing to adjust the infusion technique taught by Adler to attain continuous infusion to treat localized botulinum toxin intoxication.
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”).
While Adler teaches 3,4-diaminopyridine infusion methods, Adler does not teach a human subject. Vazquez-Cintron teaches in the last paragraph of page 3, “In comparison, a 20 mg oral dose results in a Cmax of 30-200 ng/mL 3,4-DAP in humans...suggesting that 3,4-DAP reversed botulism symptoms at clinically acceptable exposure levels”) It would have been obvious to a person of ordinary skill in the art at the time of this application’s filing to adjust the infusion technique of Adler to continuous infusion treatment of human subjects.
Response to Arguments
Applicant argues that multiple bolus injection creates fluctuating plasma levels with peaks and troughs that can reduce efficacy or cause toxicity, whereas continuous infusion produces a smooth, steady plasma concentration. Thus, Applicant argues that Adler’s bolus dosing cannot predict that continuous infusion would be safe.
While Applicant is correct that bolus injection and continuous infusion produce distinct concentration-time profile; however, it is important to note that Adler discloses a pharmacokinetic pattern that resembles that of a continuous infusion in effect rather than the form. In fact, it is known in the art that pharmacokinetically, repeated dosing at short intervals, such as every-half life, can mimic a continuous infusion once the steady state is reached, as an example. As evidence by Birkett teaches the following:
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(Birkett D. Pharmacokinetics made easy 11 Designing dose regimens. Aust Prescr 1996;19:76-8.)
Therefore, the fact that Adler teaches that 2,3-DAP was administered repeatedly over a 6-hour period, as an example, while maintaining a sustained efficacy with no loss of pharmacological effect between injection. This indicates that plasma concentration remained within the therapeutic window throughout the dosing period, consistent with continuous exposure. Therefore, Adler’s teachings clearly provide evidence that the repeated administration of 3,4-DAP infusion produced a safe and sustained therapeutic efficacy over serval hours, clearly mimicking continuous infusion pharmacodynamics. Furthermore, given that Adler-2, same author as Adler teaches continuous infusion delivery of 3,4-DAP though osmotic minipumps for the same purpose, thus a POSITA would reasonably infer that the bolus regimen by Adler’s teachings represent a type of continuous infusion of 3,4-DAP.
B. Modifying Adler's Multiple Bolus Injections to Continuous Infusion Is Not Routine
Optimization
Applicant argues that multiple bolus injection and continuous infusion produce different plasma concentration profiles, leading to significant difference in efficacy and toxicity. And the fact that Adler teaches 4 mg/kg, Applicant further argues that according to Dr. McNutt’s opinion that such a dose may not be safe in humans, and thus a POSITA would not be motivated to modify the bolus dosing to continuous infusion. Applicant’s argument is not persuasive, because, although there are pharmacokinetic differences between bolus and continuous infusion, Adler clearly demonstrates that repeat bolus dosing maintains consistent therapeutic efficacy without evidence of toxicity or loss of responsiveness. While Adler mentions that seizures and other side-effects have been reported with K+ channel blockers like 3,4-DAP, this association is consistent in the art. However, Adler does not specifically report any adverse effect associated with the 4mg/kg intravenous dosing. Thus, according to Adler, the 4mg/kg dose is safe and effective in the animal model, without noted toxicity or safety concerns; serving as a valid adjusted dose in humans. Furthermore, it is well known in the art that repeated dosing at short intervals, such as every-half life, can mimic a continuous infusion once the steady state is reached, thus, this supports the reasonable expectation that continuous infusion of 3,4-DAP would be both effective and safe, providing an obvious and predictable improvement over bolus dosing, as evidence by Adler-2. Therefore, contrary to Applicant’s contention, a POSITA would be motivated to modify the dosing regimen towards continuous infusion, as demonstrated by Adler’s teachings in view of the evidence by Adler-2.
C. Applicant Unexpectedly Found that Significantly Lower Doses of 3,4-DAP, Administered by Continuous Infusion, Are Effective in Treating Botulism
Applicant further argues that a POSITA would not expect that lowering the of 3,4-DAP dose from a high to lower dose would be effective and safe when administered via continuous infusions. Applicant’s argument is not persuasive because Adler clearly demonstrates that 3,4-DAP can restore neuromuscular function even after complete botulinum toxin-induced paralysis, with no loss of responsiveness, suggesting that lower but sustained plasma concentration could maintain therapeutic efficacy over time. The study also demonstrates that the therapeutic effect of 3,4-DAP continues in muscle paralyzed up to 14 days, even in the context of muscle atrophy, this then suggest a robust and consistent pharmacodynamic response not strictly dependent on peak plasma levels. Therefore, Applicant’s argument is not persuasive because a POSITA would reasonably expect that a lower, sustained infusion could replicate or even optimize the therapeutic outcomes seen with bolus dosing, due to the effectiveness demonstrated in Adler’s disclosure. Therefore, Adler’s teachings clearly support the concept, in view of the evidence by Adler-2, that maintaining effectiveness plasma levels through continuous infusion, without the peaks and troughs associated with intermittent high-dose administration, would still yield significant therapeutic benefit.
III. 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 via continuous infusion. Applicant’s argument is not persuasive, because Vazquez-Cintron clearly teaches the therapeutic effectiveness of 3,4-DAP in treating botulism. In addition, even if Vazquez-Cintron does not explicitly disclose continuous infusion, the Vazquez-Cintron’s teachings of 3,4-DAP clinical utility, combined Adler’s disclosure in view of the evidence by Adler-2; a POSITA would have been reasonably motivated to pursue a continuous infusion. 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.
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 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 date of this final action.
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/P.P.E./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622