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 the Claims
Claims 1-3 and 42-58 are pending (claim set as filed on 07/13/2026).
Priority
This application is a 371 of PCT/IL2021/051424 filed on 11/30/2021, which has a provisional application no.: 63/119,033 filed on 11/30/2020.
Withdrawal of Rejections
The response and amendments filed on 07/13/2026 are acknowledged. Any previously applied minor objections and/or minor rejections (i.e., formal matters), not explicitly restated herein for brevity, have been withdrawn necessitated by Applicant’s formality corrections and/or amendments. For the purposes of clarity of the record, the reasons for the Examiner’s withdrawal, and/or maintaining if applicable, of the substantive or essential claim rejections are detailed directly below and/or in the Examiner’s response to arguments section.
The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claim Objection
Claim 53 is objected to for a minor misspelling of the term “arrythmia” where it is presumed to be “arrhythmia” such as seen in claim 52.
Maintained Rejections
Claim Rejections - 35 USC §102, Anticipation
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1 and 52 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Jia (Stimulating Cardiac Muscle by Light Cardiac Optogenetics by Cell Delivery, 2011 - cited by the ISA and in the IDS filed on 05/30/2023).
Jia’s general disclosure relates to the field of “optogenetics” which is the precise interrogation, stimulation, and control by light of excitable tissue, genetically altered to become light-sensitive (see page 753, left col.).
Regarding claim 1, Jia teaches “we exploit the heart’s high coupling aspect to develop and validate a non-viral cell delivery system for expression of light-sensitive ion channels. Figure 1 illustrates the concept of a tandem cell unit (TCU), formed by a host cardiomyocyte and a non-excitable donor cell, carrying exogenous ion channels, for example, ChR2. Biophysically, for this unit to be functional (to fire an action potential on light excitation), low-resistance coupling is needed for closing the local electric circuits. Our group has previously validated this concept for generation of a 2-cell pace-making unit using cardiomyocytes and stem cells expressing a pace-making ion channel” wherein the “functional tandem cell unit (TCU) concept of donor-host cells. Non-excitable cells (e.g., HEK cells) are transfected to express a light-sensitive ion channel (ChR2). When coupled through gap junctions to excitable cardiomyocytes (CM), they form an optically controllable functional TCU, that is, the cardiomyocytes will generate an action potential on light-triggered opening of the depolarizing ChR2 in the HEK cell” (see page 754, left col.) and performing electric and optical stimulation illumination (see page 754: Methods section). Jia teaches “we developed a stable HEK cell line expressing ChR2 and capable of Cx43-mediated coupling to cardiomyocytes to generate optically excitable cardiac tissue. The ChR2 plasmid … transfection of the HEK293 cells was done with the use of Lipofectamine and Geneticin selection to achieve >98% expression (see pages 754-755: Methods & Results Discussion section).
Regarding claim 52, Jia teaches using the TCU approach to control excitation and
contraction in cardiac muscle by light which can serve as a tool in arrhythmia research (see abstract) and further teaches the cell delivery platform for in vivo applications (see page 760: Conclusion).
Maintained Rejections
Claim Rejections - 35 USC §103, Obviousness
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 2-3 and 42 are rejected under 35 U.S.C. 103 as being unpatentable over Jia as applied to claims 1 and 52 above, and in view of Wondergem (Lipopolysaccharide Prolongs Action Potential Duration in HL-1 Mouse Cardiomyocytes, 2012) - both references cited by the ISA and in the IDS filed on 05/30/2023.
Jia’s teachings are discussed above as it pertains to modulating action potential properties of cardiac tissue cells.
However, Jia does not teach: modulating or elongating the action potential duration to improve contraction (claims 2-3 and 42).
Wondergem teaches a method of modulating the action potential duration wherein lipopolysaccharides decreased rate of firing of spontaneous action potentials in HL-1 cardiac myocyte cells, and it increased their pacemaker potential durations and decreased their rates of depolarization (see abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modulate the action potential duration in cardiac tissue cells such as taught by Wondergem in the method of Jia. The ordinary artisan would have been motivated to do so is because it would allow for control or improvement of heart contraction rate for the purpose of preventing or treating the cardiac arrythmia in Jia. The ordinary artisan would have had a reasonable expectation of success is because both of the cited references are directed to the modulation of an action potential of cardiac myocytes cells.
Claims 2-3, 42-50, and 55-58 are rejected under 35 U.S.C. 103 as being unpatentable over Jia as applied to claims 1 and 52 above, and in view of Quach (US 2022/0010279 A1).
Jia’s teachings are discussed above as it pertains to modulating action potential properties of cardiac tissue cells.
However, Jia does not teach: modulating via elongating or shortening the action potential duration (APD) (claims 2-3 and 45); or the specific illumination parameters to affect the contraction or electrical activity by depolarization, repolarization, or hyperpolarization of the cardiac tissue cells (such as required by claims 42-50); or the light-sensitive ion channels, pump, or signaling receptor (such as required by claims 55-57).
Quach’s general disclosure relates to kits and methods for performing optical dynamic clamping on an excitable cell (see abstract). Quach’s methodology is “directed to a method for modulating the electrophysiology of a cell comprising: (i) providing an excitable cell, an electrode, and a light source with a controllable light intensity or a controllable light wavelength” (see ¶ [0034]-[0043]).
Quach discloses “optogenetic tools are typically used to generate a static current to stimulate action potentials or completely inhibit electrical activity (claims 42 and 46). An optical action potential clamp has been used to uncover the dynamic contribution of Channelrhodopsin-2 (ChR2), a depolarizing opsin, during the cardiac action potential. Several computational and experimental studies have used depolarizing and hyperpolarizing opsin to modulate the cardiac action potential morphology. For example, activation of ChR2 by static light pulses delivered during different action potential phases (claims 44 and 49) extended the action potential duration (APD) (claims 2-3) in neonatal rat ventricular myocytes (NRVM). Hyperpolarizing anion Channelrhodopsin 1 from Guillardia theta (GtACRl) was optically activated by static pulses to shorten the APD (claim 45) in NRVMs via forced hyperpolarization (claim 48). Static optogenetic manipulation can yield a range of AP responses depending on pulse timing, strength and duration” (see ¶ [0003]).
Regarding claims 55-56 and 58, Quach teaches “an excitable cell expressing at least one light-sensitive protein from an exogenous nucleic acid, wherein the light sensitive protein is selected from the group consisting of a light-sensitive ion channel and a light-sensitive ion pump” (see ¶ [0027]-[0029]) wherein the excitable cell is selected from a muscle cell being a cardiomyocyte (see ¶ [0030], [0069]-[0071]).
Regarding claim 57, Quach further teaches “wherein the at least one light-sensitive protein is a channelrhodopsin, an anion conducting channelrhodopsin, or a chimeric channelrhodopsin. In some embodiments, the channelrhodopsin is selected from the group consisting of Channelrhodopsin 1 (ChR1), Channelrhodopsin (ChR2), Volvox channelrhodopsin (VChR1), and Step function or bi-stable opsins (SFOs). In some embodiments, the light-sensitive protein is selected from a halorhodopsin (NpHR), an enhanced halorhodopsin eNpHR2.0, an enhanced halorhodopsin eNpHR3.0, an archaerhodopsin (Arch), the fungal opsin Mac and an enhanced bacteriorhodopsin (eBR)” (see ¶ [0031]-[0033], [0112]). Quach discloses that “the term ‘channelrhodopsin’ refers to a cation channel that depolarizes a cell upon light illumination. In some embodiments, the channelrhodopsin is activated by blue light. In some embodiments, the channelrhodopsin is activated by red light” (see ¶ [0072]-[0082]).
It would have been obvious to one of ordinary skill in the art before the filing date of the claimed invention to modulate the action potential duration (APD) of an excitable cardiomyocyte such as taught by Quach in the method of Jia. The ordinary artisan would have been motivated to do so is because Quach allows for a methodology of modulating the action potential morphology via controllable light illumination with calculated precision which an objective of Jia. The ordinary artisan would have had a reasonable expectation of success is because both of the cited references are in the same field of endeavor related to optogenetic of cardiomyocytes comprising light-sensitive proteins.
Furthermore, regarding claims 43-50 pertaining to the illumination parameters for modulating the action potential duration (APD), Quach discloses that “optogenetic manipulation can yield a range of AP [action potential] responses depending on pulse timing, strength and duration” (see Quach at ¶ [0003]) and further teaches dynamic clamp experiments and mathematical models for action potential modulation using various parameters including msec, current, voltage, wavelengths, et. al. (see, e.g., Quach at ¶ [0114]-[0118] & Figures 16-17). Therefore, one of ordinary skill in the art following the guidance of Quach would recognize that the claimed illumination parameters are experimental variables that are considered to be routine optimization. This is motivation for someone of ordinary skill in the art to practice or test the parameter widely to find those that are functional or optimal which then would be inclusive or cover the steps as instantly claimed. Absent any teaching of criticality by the Applicant concerning the illumination parameters for modulating the APD, it would be prima facie obvious that one of ordinary skill in the art would recognize these limitations are result effective variable which can be met as a matter of routine optimization.
Claims 51 and 53-54 are rejected under 35 U.S.C. 103 as being unpatentable over Jia as applied to claims 1 and 52 above, and in view of Trayanova (US 2013/0102912 A1).
Jia’s teachings are discussed above as it pertains to modulating action potential properties of cardiac tissue cells with for arrhythmia research and in vivo applications.
However, Jia does not teach: for preventing or treating Short/Long QT Syndrome (claims 51 and 54); or wherein the arrhythmia is Torsade-de-Pointe (claim 53).
Trayanova’s general disclosure relates to systems and methods of predicting risk of ventricular arrhythmias (see abstract & ¶ [0004]). Trayanova discloses “instability in the QT interval is a manifestation of instability in repolarization in the heart. At the cellular level, instability in myocyte repolarization is assessed from the dynamics of its action potential duration (APD) … It is thus reasonable to expect that concepts developed to determine instability in APD could be translated to the clinic and applied in the evaluation of the patient’s QT interval instability” (see ¶ [0009]-[0010]) and may lead to an event of Torsade de Pointes during QT prolongation (see ¶ [0013]).
Trayanova discloses that “the QT interval of the ECG (interval between Q and T deflections, FIG. 1A) has been found to be unstable in the diseased heart (FIG. 1B). QT interval instability has been reported in long QT syndrome patients” (see ¶ [0008]). Trayanova discloses “unstable APD dynamics results in spatial gradients in APD, leads to ventricular tachycardia (VT) following PA, and causes the transition from VT to ventricular fibrillation (VF)” (see ¶ [0048]).
It would have been obvious to one of ordinary skill in the art to envisage the preventing or treating of cardiac arrhythmic conditions including long QT syndrome, ventricular tachycardia, Torsade de Pointe, et. al. such as taught by Trayanova in the method of Jia. The ordinary artisan would have been motivated to consider other types of arrhythmic conditions because these are conditions affected by instability in action potential duration.
Examiner’s Response to Arguments
Applicant’s amendments and arguments filed on 07/13/2026 have been fully considered but they are not persuasive and deemed insufficient to overcome the prior arts of record.
In response to Applicant’s argument (addressing pages 7-8 of the remarks) that “claim 1 specifically requires that the illuminating occur ‘during’ the action potential. This claim limitation requires that illumination occurs while an actional potential is already in progress … Jia, however teaches using light to initiate or trigger action potentials”: the Examiner is not certain or clear how the action potential of the claimed invention is initiated or started based on the language of claim 1. Clarification is requested. Nevertheless, Applicant’s argument is not persuasive because the prior art of Jia still reads on independent claim 1 under the broadest reasonable interpretation (BRI) standard (MPEP 2111). Assuming arguendo, Jia’s use of light to initiate or trigger action potential would read on ‘during’ under BRI because this would be phase 0 of the action potential where the instant specification discloses “in certain embodiments, the method comprises illuminating the cardiac tissue cells in phase 0, phase 1, phase 2, or phase 3 of the AP” (see pre-grant specification at ¶ [0029]). Moreover, the claim’s transitional phrase of “comprising” does not exclude Jia’s initiation step. Alternatively, since Jia teaches a tandem unit of host cardiomyocyte and donor cell carrying exogenous ion channels, the optical illumination would occur during the host cardiomyocyte’s action potential. Thus, at least base claim 1 is broad to encompass the teachings of the prior art under BRI. Furthermore, Jia concludes with “finer control of excitation and repolarization in shaping cardiac action potentials and potentially in terminating arrhythmias” which is an objective the claimed invention (see, e.g., claim 52).
In response to Applicant’s argument (addressing page 9 of the remarks) that “Wondergem relates to the effects of lipopolysaccharides on action potential duration in cardiac myocytes and does not involve optogenetics illumination of cardiac tissue cells at all”: this argument is not persuasive because, as noted above, the claim’s transitional phrase of “comprising” does not exclude additional steps or elements such as the lipopolysaccharides of Wondergem. The use of lipopolysaccharides would allow for control or improvement of heart contraction rate for the purpose of preventing or treating the cardiac arrythmia in Jia. The ordinary artisan would have had a reasonable expectation of success is because both of the cited references are directed to the modulation of an action potential of cardiac myocytes cells.
In response to Applicant’s argument (addressing page 9 of the remarks) that “Trayanova relates to systems and methods for predicting risk of ventricular arrhythmias by assessing QT interval instability and similarly does not teach illuminating cardiac tissue cells during an action potential”: this argument is not persuasive because Trayanova was relied upon to address the pathophysiological conditions or disorders relates to ventricular arrhythmias or QT syndrome as they are related to cardiac arrhythmias.
In response to Applicant’s argument (addressing page 9 of the remarks) that Quach is directed to optical dynamic clamping which is a fundamentally different technique from the claimed method: this argument is not persuasive because the primary reference of Jia already taught the in vivo optogenetic illumination methodology. Quach allows for a methodology of modulating the action potential morphology via controllable light illumination with calculated precision which an objective of Jia. Quach teaches modulating during an action potential at different phases to affect its duration. Quach then goes on to teach optogenetic manipulation can yield a range of AP responses depending on pulse timing, strength and duration (see Quach at ¶ [0003]).
In response to Applicant’s argument (addressing page 10 of the remarks) that the claimed illumination parameters are not result-effective variables: this argument is not persuasive because Quach discloses that “optogenetic manipulation can yield a range of AP [action potential] responses depending on pulse timing, strength and duration” (see Quach at ¶ [0003]) and further teaches dynamic clamp experiments and mathematical models for action potential modulation using various parameters including msec, current, voltage, wavelengths, et. al. (see, e.g., Quach at ¶ [0114]-[0118] & Figures 16-17).
Conclusion
No claims were allowed.
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.
Correspondence Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NGHI V NGUYEN whose telephone number is (571)270-3055. The examiner can normally be reached Mon-Fri: 9 - 3 pm (EST).
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/NGHI V NGUYEN/Primary Examiner, Art Unit 1653
