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 .
Priority
This application claims priority to foreign application TW111149872, filed on 26 December 2022. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. The effective filing date is 26 December 2022.
Status of Application, Amendments, and/or Claims
Applicant’s response on 11 February 2026 is acknowledged. Claims 1-3, 5, 7, 9, 11, and 15 are amended, claims 4, 8, and 12 are cancelled. Claims 1-3, 5-7, 9-11, and 13-15 are pending and the subject of this office action.
Withdrawn Objections/Rejections
In addition to prior art and 112 rejections, mentioned below, there were multiple objections to the specification and drawings, as well as an issue with the sequence listing, all of which have been overcome in the amendments implemented on 11 February 2026. In the office action of 12 November 2025, claims 4, 8, and 12 were rejected under 35 U.S.C. 112(b), due to uncertainty in regard to the actual sequence being reference (SEQ ID NO: 1), which has been addressed in the most recent amendments. Claims 4, 8, and 12 have been cancelled, as mentioned above, but the limitations established in claim 4 have been added to independent claim 1. Claims 1-3 and 5-7 were rejected under 35 USC 102(a)(1) over WO 2007/023298. In the amended version of these claims, the applicant has introduced additional limitations that render the claims unanticipated. Claims 9-11 and 13-15 were rejected under 35 USC 103 over WO 2007/023298, US 2023/0406919 A1, and Ascoli CA, et al. (2018) Overlooked benefits of using polyclonal antibodies. Biotechniques. 65(3):127-136; claims 1, 5, and 9 were rejected under 35 USC 103 over WO 2007/023298 and Marban, et al. (1998) Structure and function of voltage-gated sodium ion channels. J. Physiol. 508:647-657 (herein Marban). Applicant’s arguments concerning unexpected results are not persuasive and the following prior art rejections remain.
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.
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.
Claims 1-3, 5-7 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2007/023298 A2 (Ming Lei and Bin Gao) 1 March 2007 (herein Lei) in view of Marban et al. (1998) Structure and function of voltage-gated sodium channels. J. Physiol. 508:647–657 (herein Marban) and Xu L, et al. (2019) Voltage-gated sodium channels: structures, functions, and molecular modeling. Drug Discov Today. 2019 Jul;24(7):1389-1397 (herein Xu).
In regards to claim 1, Lei teaches anti-Nav1.5 antibodies that target the pore-forming region, specifically the S5 segment of the Nav1.5α subunit, and are capable of inhibiting Na+ flow in electrophysiological assays (page 18 line 34 – page 19 line 5, page 3 lines 11-19 and figures 4 and 5).
Lei does not teach using a peptide comprising SEQ ID 1 for generating polyclonal antibodies. Marban and Xu teach this deficiency.
Marban teaches that the pore forming region of Nav proteins is comprised of S5-P-S6 segments from domains 1-4 of the Nav protein (paragraph 5). A sequence search indicates that SEQ ID NO:1 consists of amino acids corresponding to the S5 segment of domain 2, within the pore forming region, of the mouse Nav1.5 protein. In light of the teaching of Lei, it would have been obvious to those of ordinary skill in the art prior to the filing of the present invention to use a peptide comprised of an amino acid sequence corresponding to pore forming region of Nav1.5, as defined by Marban, in order to generate antibodies capable of inhibiting the function of the Nav1.5 protein. Marban teaches the targeting of the pore-forming region of Nav1.5, but does not provide sufficient motivation for the selection of SEQ ID NO: 1 as a target, nor is there motivation to target domain 2 over the other four domains. Xu teaches this motivation.
Xu provides a review of the state of computational and structural advances, regarding sodium ion channels, at the time around the filing of the instant application. In this review Xu notes that the high sequence homology, >70%, makes the design of isoform-specific Nav modulators difficult. As shown by the sequence alignments below, in order to address this problem one would have been motivated to select antigens selected from the N-terminus of either domain two or three, as these regions of Nav1.5 diverge from other Nav isoforms. This narrows the rather broad range, taught by Marban, which teaches targeting the pore-forming region, down to two small stretches of the Nav1.5 amino acid sequence. This presents a situation where there exists a design need and a finite number of options, therefore targeting either sequence would be obvious to try, see 550 U.S. at 421, 82 USPQ2d at 1397.
Domain 1 Pore Loop:
mNav15 NSSDAGTCPEGYRCLKAGENPDHGYTSFDSFAWAFLALFRLMTQDCWERLYQQTLRSAGK 60
hNav15 NSSDAGTCPEGYRCLKAGENPDHGYTSFDSFAWAFLALFRLMTQDCWERLYQQTLRSAGK 60
hNAv17 FSTDSGQCPEGYTCVKIGRNPDYGYTSFDTFSWAFLALFRLMTQDYWENLYQQTLRAAGK 60
hNav12 NSSDAGQCPEGYICVKAGRNPNYGYTSFDTFSWAFLSLFRLMTQDFWENLYQLTLRAAGK 60
hNav14 NSSDAGHCPEGYECIKTGRNPNYGYTSYDTFSWAFLALFRLMTQDYWENLFQLTLRAAGK 60
*:*:* ***** *:* *.**::****:*:*:****:******** **.*:* ***:***
mNav15 IYMIFFMLVIFLGSFYLVN 79
hNav15 IYMIFFMLVIFLGSFYLVN 79
hNAv17 TYMIFFVVVIFLGSFYLIN 79
hNav12 TYMIFFVLVIFLGSFYLIN 79
hNav14 TYMIFFVVIIFLGSFYLIN 79
*****:::********:*
Domain 2 Pore Loop:
mNav15 --VGMQLFGKNYSELRHRISDSGLLPRWHMMDFFHAFLIIFRILCGEWIETMWDCMEVSG 58
hNav15 AVVGMQLFGKNYSELRD--SDSGLLPRWHMMDFFHAFLIIFRILCGEWIETMWDCMEVSG 58
hNAv17 --VGMQLFGKSYKECVCKINDDCTLPRWHMNDFFHSFLIVFRVLCGEWIETMWDCMEVAG 58
hNav12 --VGMQLFGKSYKECVCKISNDCELPRWHMHDFFHSFLIVFRVLCGEWIETMWDCMEVAG 58
hNav14 --VGMQLFGKSYKECVCKIALDCNLPRWHMHDFFHSFLIVFRILCGEWIETMWDCMEVAG 58
********.*.* . ****** ****:***:**:***************:*
mNav15 QSLCLLVFLLVMVIGNLVVL 78
hNav15 QSLCLLVFLLVMVIGNLVVL 78
hNAv17 QAMCLIVYMMVMVIGNLVVL 78
hNav12 QTMCLTVFMMVMVIGNLVVL 78
hNav14 QAMCLTVFLMVMVIGNLVVL 78
*::** *:::**********
Domain 3 Pore Loop:
mNav15 YTIVNNKSECESFNVT-GELYWTKVKVNFDNVGAGYLALLQVATFKGWMDIMYAAVDSRG 59
hNav15 YTIVNNKSQCESLNLT-GELYWTKVKVNFDNVGAGYLALLQVATFKGWMDIMYAAVDSRG 59
hNav14 ISEVNNKSECESLMHT-GQVRWLNVKVNYDNVGLGYLSLLQVATFKGWMDIMYAAVDSRE 59
hNav12 VSVVNNYSECKALIESNQTARWKNVKVNFDNVGLGYLSLLQVATFKGWMDIMYAAVDSRN 60
hNAv17 ASQVPNRSECFALMNVSQNVRWKNLKVNFDNVGLGYLSLLQVATFKGWTIIMYAAVDSVN 60
: * * *:* :: * ::***:**** ***:********** ********
mNav15 YEEQPQWEDNLYMYIYFV 77
hNav15 YEEQPQWEYNLYMYIYFV 77
hNav14 KEEQPQYEVNLYMYLYFV 77
hNav12 VELQPKYEDNLYMYLYFV 78
hNAv17 VDKQPKYEYSLYMYIYFV 78
: **::* .****:***
Domain 4 Pore Loop:
mNav15 VMFIYSIFGMANFAYVKWEAGIDDMFNFQTFANSMLCLFQITTSAGWDGLLSPILNTGPP 60
hNav15 VMFIYSIFGMANFAYVKWEAGIDDMFNFQTFANSMLCLFQITTSAGWDGLLSPILNTGPP 60
hNav14 VMFIYSIFGMSNFAYVKKESGIDDMFNFETFGNSIICLFEITTSAGWDGLLNPILNSGPP 60
hNav12 VMFIYAIFGMSNFAYVKREVGIDDMFNFETFGNSMICLFQITTSAGWDGLLAPILNSGPP 60
hNAv17 VMFIYAIFGMSNFAYVKKEDGINDMFNFETFGNSMICLFQITTSAGWDGLLAPILNSKPP 60
*****:****:****** * **:*****:**.**::***:*********** ****: **
mNav15 YCDPNLPNSNG-SRGNCG 77
hNav15 YCDPTLPNSNG-SRGDCG 77
hNav14 DCDPNLENPGTSVKGDCG 78
hNav12 DCDPDKDHPGSSVKGDCG 78
hNAv17 DCDPKKVHPGSSVEGDCG 78
*** : . .*:**
Based on these teachings it would have been obvious to target SEQ ID NO:1, when choosing an antigen to generate polyclonal antibodies. As taught by Marban and Lei, targeting the pore-forming region carries with it a high likelihood of producing channel blocking antibodies. The combined teachings of Xu and Marban make the selection of SEQ ID NO:1 obvious, due to higher likelihood of generating a Nav1.5-specific pool of antibodies. Although, this is not the stated goal of the applicant, it still provides motivation for targeting the sequence (see MPEP 2144).
Regarding claim 2, Lei teaches polyclonal anti-Nav1.5 antibodies that target cardiac Nav1.5 channels demonstrated by the example provided in which Nav1.5 antibodies label rat ventricular myocytes when used in immunostaining assays (page 19 lines 17-19).
Regarding claim 3, Lei teaches polyclonal anti-Nav1.5 antibodies that target the pore-forming region and demonstrates that these antibodies are capable of inhibiting Na+ current in electrophysiological assays (page 18 line 34 – page 19 line 5, page 3 lines 11-19 and figures 4 and 5).
Regarding claim 5, Lei teaches a composition including anti-Nav1.5 antibody or antibodies and a pharmaceutically acceptable carrier (page 13 lines 12-14).
Regarding claim 6, as stated above Lei teaches anti-Nav1.5 antibodies that targets cardiac Nav1.5 channels. This is demonstrated by the immunostaining example, in which the antibodies were used for immunostaining of rat ventricular myocytes (page 19 lines 17-19). Furthermore, Lei also teaches a composition including the antibody/antibodies and a pharmaceutical carrier (page 13 lines 12-14).
Regarding claim 7, Lei teaches polyclonal anti-Nav1.5 antibodies that target the pore-forming region and demonstrates that these antibodies are capable of inhibiting Na+ current in electrophysiological assays (page 18 line 34 – page 19 line 5, page 3 lines 11-19 and figures 4 and 5). As stated above the Lei also teaches a composition including the antibody/antibodies and a pharmaceutical carrier (page 13 lines 12-14).
Claims 9-11 and 13-15 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2007/023298 A2 (Ming Lei and Bin Gao) 1 March 2007 (herein Lei), Marban et al. (1998) Structure and function of voltage-gated sodium channels. J. Physiol. 508:647–657 (herein Marban) and Xu L, et al. (2019) Voltage-gated sodium channels: structures, functions, and molecular modeling. Drug Discov Today. 2019 Jul;24(7):1389-1397 (herein Xu) in view of WO2022120215 A1 (herein Gabelli) with Ascoli CA and Aggeler B. (2018) Overlooked benefits of using polyclonal antibodies. Biotechniques. 65(3):127-136 (herein Ascoli) providing additional evidentiary value.
Regarding claim 9, Lei, Marban, and Xu teach polyclonal antibodies targeting an epitope within SEQ ID NO:1, as described in the 35 U.S.C. 103 rejection of claim 1.
Lei, Marban, and Xu do not teach a method for treating and/or preventing cardiac arrhythmia, comprising administering a pharmaceutical composition comprising an effective amount of polyclonal antibodies targeting a sodium ion channel. Gabelli teaches this deficiency.
Gabelli teaches the method of administering a composition containing single-domain antibodies targeting Nav1.5, which upon binding can inhibit the activity of the channel (i.e. prevent the channel from transitioning from one state to another or prevent the flow of sodium ions), as a treatment for cardiac arrhythmia (page 12, [0127][0128], page 2, [0020]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the inhibitory single-domain antibodies for use in treating cardiac arrhythmia, taught by Gabelli, with inhibitory polyclonal antibodies, taught by Lei, Marban, and Xu. The use of polyclonal antibodies has several advantages compared to the use of single-domain antibodies. One such advantage is the ability of polyclonal antibodies to target multiple epitopes resulting in relatively higher sensitivity and an enhanced tolerance to variations in the antigen, as taught by Ascoli (Section 2 paragraph 3). Also, the production of polyclonal antibodies is often faster and requires less specialized training and equipment than the screening required for single-domain antibodies or the generation of hybridomas in the case of monoclonal antibodies, as taught by Ascoli (section 3).
Regarding claim 10, Lei, Marban, Xu, Gabelli, and Ascoli teach the method of treating or preventing cardiac arrhythmia through administering a composition containing an effective amount of polyclonal antibodies targeting the sodium ion channel, as discussed above.
Lei further teaches polyclonal anti-Nav1.5 antibodies that targets cardiac Nav1.5 channels demonstrated by the example provided in which Nav1.5 antibodies label rat ventricular myocytes when used in immunostaining assays (page 19 lines 17-19).
Regarding claim 11, Lei, Marban, Xu, Gabelli, and Ascoli teach the method of treating or preventing cardiac arrhythmia through administering a composition containing an effective amount of polyclonal antibodies targeting the sodium ion channel, as discussed above.
Lei further teaches polyclonal anti-Nav1.5 antibodies that targets the pore-forming region and demonstrates that these antibodies are capable of inhibiting Na+ current in electrophysiological assays (page 18 line 34 – page 19 line 5, page 3 lines 11-19 and figures 4 and 5).
Regarding claim 13, Lei, Marban, Xu, Gabelli, and Ascoli teach the method of treating or preventing cardiac arrhythmia through administering a composition containing an effective amount of polyclonal antibodies targeting the sodium ion channel, as discussed above.
Importantly, with regards to this claim, atrial fibrillation is a form of cardiac arrhythmia. Atrial fibrillation has been associated with gain of function mutations in the SCN5A gene, encoding Nav1.5 (Li et al. (2009) Gain-of-function mutation of Nav1.5 in atrial fibrillation enhances cellular excitability and lowers the threshold for action potential firing. Biochem Biophys Res Commun. Feb 27;380(1):132-7). Furthermore, atrial fibrillation is treated with class 1c anti-arrhythmic drugs (i.e. drugs that block cardiac sodium channels, the teachings of Lei and Gabelli clearly disclose an invention utilizing a similar mechanism of action. It would have been obvious to an individual possessing ordinary skill in the art prior to the filing of the current invention to apply the teachings of Lei and Gabelli to the treatment of atrial fibrillation.
Regarding claim 14, Lei, Marban, Xu, Gabelli, and Ascoli teach the method of treating or preventing cardiac arrhythmia through administering a composition containing an effective amount of polyclonal antibodies targeting the sodium ion channel, as discussed above.
Lei teaches a pharmaceutical composition containing polyclonal Nav1.5 antibodies that targets the pore-forming region of the channel and a pharmaceutically acceptable carrier that that is suitable for parenteral administration (page 13 lines 15-21).
Regarding claim 15, Lei, Marban, Xu, Gabelli, and Ascoli teach the method of treating or preventing cardiac arrhythmia through administering a composition containing an effective amount of polyclonal antibodies targeting the sodium ion channel, as discussed above.
Lei teaches polyclonal anti-Nav1.5 antibodies that targets the pore-forming region and demonstrates that these antibodies are capable of inhibiting Na+ current in electrophysiological assays (page 18 line 34 – page 19 line 5, page 3 lines 11-19 and figures 4 and 5).
Response to Arguments
Applicant's arguments filed on 11 February 2026 have been fully considered. The applicant’s argument that the polyclonal antibodies targeting epitope(s) within the amino acid sequence corresponding to SEQ ID NO:1, display unexpected results is not persuasive.
The applicant argues that the polyclonal antibodies disclosed, possess unexpected properties (i.e. minimal QRS prolongation), and that this overcomes a long-standing problem in the art—toxicity associated with QRS prolongation. The applicant states that that any agent blocking the Nav1.5 channel would inherently cause QRS widening. The prior art calls this assertion into question. Lu HR, et al. (2010) Predicting drug-induced slowing of conduction and pro-arrhythmia: identifying the 'bad' sodium current blockers. Br J Pharmacol. 2010 May;160(1):60-76 (herein Lu) teaches that Class 1b antiarrhythmic drugs, such as lidocaine, are characterized by their ability to block sodium channels with minimal effect on QRS duration (Figure 3 and Page 5 paragraph 4). Thus, the observed results are not entirely unexpected.
Most importantly, as discussed in the 35 U.S.C. 103 rejection of claim 1, the prior art teaches that production of polyclonal antibodies targeting an antigen consisting of the epitopes found within SEQ ID NO:1 would have been obvious to one skilled in the art. The applicant has not performed any novel screening processes to the pool of antibodies to enrich/select for antibody populations that possess any novel function other than binding Nav1.5. This coupled with current specification failure to provide any structural/mechanistic explanation for the claimed unexpected safety profile means that it is entirely likely that any individual could generate a pool of antibodies possessing the same characteristics, using known art at the time of filing (discussed above).
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MATTHEW CURRAN METCALF whose telephone number is (571)272-5520. The examiner can normally be reached 7:30AM-5:00PM.
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/MATTHEW CURRAN METCALF/Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647
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