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 42-57 are pending (claim set as filed on 05/30/2023).
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.
Information Disclosure Statement
The Information Disclosure Statement (IDS) submitted on 05/30/2023 is acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the Examiner.
Drawings
The drawings filed on 01/25/2024 have been accepted.
Abstract Objection
The abstract of the disclosure is objected to because it does not comply with the proper language and format (see MPEP 608.01(b)). Appropriate correction is required.
Applicant is reminded of the proper language and format for an abstract of the disclosure. The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words. It is important that the abstract not exceed 150 words in length since the space provided for the abstract on the computer tape used by the printer is limited. The form and legal phraseology often used in patent claims, such as “means” and “said” should be avoided. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details. The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns”, “The disclosure defined by this invention”, or “The disclosure describes”, etc.
Claim Objection
Claim 54 is objected to for minor misspellings of the term “Syndrom” where it is presumed to be “Syndrome” such as seen in claim 51.
Claim Rejections - 35 USC §102, Anticipation
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
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).
Claim Rejections - 35 USC §103, Obviousness
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 non-obviousness.
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 55-57 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, 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.
Conclusion
No claims were allowed.
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/NGHI V NGUYEN/Primary Examiner, Art Unit 1653