Patent Application
20210379557
Some embodiments are directed to the field of systems and methods for promoting selected chemical interactions and relates in particular to techniques for promoting enantio-specific reactions of chiral molecules having selected handedness thereby allowing separation of chiral molecules and selection of molecules of desired handedness.
Chiral molecules are molecules having non-supposable mirror reflection, generally allowing two non-identical enantiomers which are mirror reflections of each other. Biological systems are typically based on molecules with specific chiral properties. More specifically, in many cases, enantiomers of one handedness interact in biological systems with specific receptors, while the other handedness may not interact, or interact with receptors to provide undesired outcome.
General chemical processes, performed outside of biological systems, are often non-selective to chirality. Thus, reactants in a chemical reaction may include all or most enantiomers of chiral molecules, or the reaction forms both enantiomers of molecules without selectivity to handedness of the products.
Generally, promoting enantio-specific chemical processes, may require either enantio-pure reagent or an environment that has a specific handedness (mainly chiral environment with a specific chirality). Accordingly, the conventional techniques for producing chiral molecules of selected handedness rely on either applying chiral specific catalyst or reaction with an enantio-pure reagent.
It was recently found that when chiral molecules are electrically polarized by electric field, the electric polarization is accompanied by spin polarization. Forming a state where at each electric pole there is an unpaired electron, or part of an electron, which for some finite time has a specific spin orientation that depends on the specific chirality of the molecule. In addition, it was found that when chiral molecules are adsorbed on a ferromagnetic substrate, which is initially not magnetized, the substrate tends to magnetize, and the direction of the magnetic dipole depends on the specific chirality. Namely, one enantiomer will cause the substrate to be magnetized with the magnetic dipole pointing up, whereas the other enantiomer will cause the dipole to point down.
There is a need in the art for a novel technique for use in chemical and molecular synthesis, allowing chirality selective synthesis. Generally, the present technique enables chemical synthesis using chiral reactants of specific handedness (specific enantiomer) and/or achiral molecules with a chiral catalyst.
Spin polarized electrons can be characterized by helicity property. The helicity of a particle relates to relations between the angular momentum (spin) and linear momentum. Moving spin polarized electrons have well defined helicity that depends on the sign of the spin. The helicity of electrons has similar symmetry as that of a chiral molecule with corresponding handedness. This effect indicates that based on symmetry considerations the spin polarized electron can provide “chiral environment” that can promote interaction or production of one enantiomer versus the other. More specifically, the spin polarized electrons are used as chiral reagents for enantiospecific reactions. This omits the need for using enantio-pure chiral catalysts.
To this end, the present technique provides an interaction container configured for containing one or more reactant molecules and including at least one magnetized surface having magnetization in direction perpendicular to the surface. Location and shape of the surface with respect to regions where the interaction takes place, as well as chemical or electrical properties thereof are selected to bring the reactant molecules to interact at the vicinity of the surface. The magnetization of the at least one magnetized surface affects spin distribution of the electrons participating in the chemical interaction, resulting in interaction preference toward selected handedness of chiral reactants.
To this end, in some embodiments of the technique, the at least one magnetized surface is configured as electrically conducting surface connected to an electrical power supply unit, and the container includes at least one additional electrode providing opposite electrical potential. In this configuration, electrochemical interactions of reactant molecules involve donating or receiving electrons from the at least one magnetized surface. Due to perpendicular magnetization of the surface, such interaction is specific to electrons having spins that are in-line with magnetization of the surface, providing selectivity to chiral reactants of corresponding handedness.
In some other configurations, selected reactants are pre-adsorbed onto the at least one magnetizes surface. Magnetization of the at least one magnetized surface induces spin polarization on electrons at interacting ends of the adsorbed reactants, thereby promoting interaction forming chiral products of specific chiral handedness. Generally, to maintain spin polarization at the interacting ends of the adsorbed reactants, location of the interacting ends of the adsorbed reactant is desired to be no more than several angstroms away from the magnetized surface.
Generally, the electron spin providing the fermionic nature of electrons, is key to the Pauli Exclusion principle and hence the stability of matter. Because of its spin, the electron has a magnetic moment, and a magnetic field is usually required to separate (or split) the energies of its two possible spin states (quantum numbers of ½ or −½). However, this splitting energy is typically small compared to the ambient thermal energies (about 0.025 eV). In contrast, the interaction energy between two electrons occupying the same volume can be large, on the order of an eV (about 20 kJ/mole) and it arises from the exchange/correlation energy, not the magnetic interactions. A manifestation of this energy is the energy gap between singlet and triplet states, in which the spins are antiparallel for the singlet and parallel for the triplet.
The electron's spin is considered as an one of the important venues for transferring information, replacing the electron's charge. In addition, the spin serves in memory applications and is a candidate as one of the important tools to introduce quantum mechanics into computation. Any attempt to utilize spin dynamics may require material through which the spin information can be transferred. In most cases, the spin transport was attempted by transferring electron that carries a pre-defined spin through a conductor or semiconducting materials. In another approach, no charge is actually transferred but the spin information is transferred by exchange interaction through the system. Organic molecules are not generally considered as a good medium for transferring neither charge nor spin information. However, the present technique utilizes spin polarization and transfer properties of electrons in organic molecules, being either achiral or chiral molecules, to utilize relation between spin polarization and chirality for promoting reaction of the molecules with, or near, one or more magnetic surfaces. For example, the technique may utilize interaction between chiral or achiral molecules adsorbed on the surface and one or more types of chiral molecule in a racemic mixture in contact with the adsorbed molecules.
Because of the significant exchange energy differences associated with the relative spin alignment of electrons, the interaction energy between the electrons might be considered to be useful for controlling chemical reactions. However, it has been demonstrated that except for photochemical and some enzymatic reactions, the interaction energy between the electrons cannot be used for controlling chemical reactions. The reason is that the direction of a spin is typically not defined in the molecular frame and is well defined with respect to external magnetic field. When the magnetic field's direction changes, the same electron's spin may be defined again irrespective of its direction relative to previous magnetic field. Thus, the spin direction is generally not defined in the molecular frame. The exception is the case when unpaired electrons reside on the same molecule. Then, the relative spin directions are defined in the context of the unpaired electrons giving rise to a singlet, a triplet, or a higher multiplet states.
This difficulty in relating spin orientation to the molecular frame generally limits the ability to exploit spin polarization for controlling reactions between two molecules or between molecules and a surface. The recently discovered chiral induced spin selectivity (CISS) effect implies that chiral molecules (or moieties) have a preferred orientation of the electron spin in the molecular frame, having significant implications for controlling chemical processes, enantiomer separations, and bio-recognition processes.
When a chiral molecule interacts with another molecule or with a surface, the charge reorganization associated with this reorganization results in a transient spin polarization in the molecule, because the electronic redistribution in the molecule is spin dependent. In this connection, it should be understood that when a molecule approaches a surface, the molecule is charge polarized. For chiral molecules, this charge polarization is accompanied by transient spin polarization. The spin direction associated with each electric pole depends on the handedness of the molecule. If the substrate is a ferromagnet, magnetized perpendicular to its surface, only one enantiomer is able to bind to the surface or to accept electron from the surface. Hence the interaction with the surface is enantio-selective. This effect results in the ability to separate enantiomers from racemic mixture, using ferromagnetic surfaces as described for example in K. Banerjee-Ghosh et al “Separation of enantiomers by their enantiospecific interaction with achiral magnetic substrates”, Science 360, 1331-1334 (2018) and in WO 2019/043,693 describing aspects use of a relation between spin polarization and adsorption selectivity. The racemic mixture can thus be separated to its two different enantiomers by adsorbing preferentially one enantiomer on the substrate magnetized perpendicular to its surface.
For having enantio-specific chemical process, at least one pure enantiomer of a chiral molecule, or enantio-pure chiral catalyst need to be involved. It was shown that photoelectrons transmitted through chiral monolayer of double stranded DNA, induce manner dissociation of chiral molecules in enantio-selective. As described above, it has been shown that enantio-selective adsorption on an achiral substrate can be controlled by the substrate being magnetic with magnetization perpendicular to its surface. The presently disclosed subject matter utilizes the CISS effects for inducing enantio-specific reactions (e.g. redox reactions) in a racemic mixture of chiral molecules in an electrochemical cell.
It is known that electrode coated with chiral molecules or films may show enantio-specific interaction with the redox couple in solution. This is viewed as a result from the common chiral-recognition properties that result from spatial preferred interaction between the chiral molecules on the electrode and the chiral redox couple. It is therefore expected, that for each specific chiral molecule, a specific chiral coating on the electrode will result in enantio-selectivity.
The presently disclosed subject matter provides a system and method enabling carrying out a chemical reaction while promoting reactions of enantiomers of certain handedness over enantiomers of the opposite handedness. More specifically, in some configurations, the reactants include at least one chiral molecule and the technique promotes the reaction with one enantiomer of the molecule over the other. In some other configurations, the products include achiral molecules and the technique promotes reaction toward selected handedness of the product.
The technique is based on providing reactants in a container having at least one magnetic surface (surface including ferromagnetic or paramagnetic material) having magnetization in a direction perpendicular to the surface. The container is configured to allow the chemical reaction to occur at a distance that does not exceed several angstroms from the surface, effectively allowing transmission of electrons with one spin orientation (with respect to the direction of magnetization). This may be used in electrochemical reactions where the spin polarized electrons can promote reaction selectively with one enantiomer or produce chiral product from achiral reactant or in a case that no current is flowing, and achiral or chiral molecules are adsorbed on a substrate magnetized perpendicular to the surface and the adsorbed molecules react spontaneously in enantio-specific manner with chiral molecules in the solution.
Moreover, the inventors have demonstrated that organic molecules can serve for transferring spin information with high reliability and the transferred information can be utilized to control the interaction of the molecule with chiral molecules. Hence, the system of the presently disclosed subject matter provides a mean for controlling chemical interaction, using the electron's spin. In this connection, it should be understood that magnetic proximity effects can transform a given material to become magnetic through its adjustment to a magnet. In bulk materials, the sample size exceeds significantly the characteristic lengths of proximity effects, allowing their neglect. However, in the case of monolayers even short-range magnetic proximity effects may have a range comparable with their thickness. The inventors have shown that in the case of self-assembled organic monolayers, the magnetic proximity effect may induce selectivity in their reactions with chiral molecules. The selectivity means that for magnetic field pointing perpendicular to the surface and away from it, the reaction will occur with one enantiomer while if the magnetic field is pointing to the opposite direction, the other enantiomer will react. The selectivity depends on the thickness of the organic monolayer. Interestingly, the extend of control on the achiral-chiral interaction does not depend on the nature of the bond formed and it is shown up when the bonds are covalent, π-π interaction, or hydrogen bond.
Thus, according to one broad aspect, the presently disclosed subject matter provides a system for use in synthesis of molecules, including: a container configured for containing fluid mixture including one or more reactant molecules, and at least one surface including ferromagnetic or paramagnetic material, located to be in at least partial contact with reactants in said container, said ferromagnetic or paramagnetic material being magnetized with magnetization direction perpendicular to said at least one surface, thereby providing chiral selective synthesis from said one or more reactant molecules.
Generally, the at least one surface may include structured substrate including at least one layer of ferromagnetic or paramagnetic material. The structured substrate may further include at least one surface layer having affinity for adsorption with one or more selected reactants, thereby enabling molecular interactions between reactants at vicinity of the at least one surface.
According to some embodiments, the system may further include at least one type of reactant molecules pre-adsorbed on said at least one surface, said pre-adsorbed reactant molecules selectively interacting with molecules of selected handedness in said fluid mixture. The at least one type of reactant molecules pre-adsorbed on said at least one surface includes molecules having length that does not exceed certain length (e.g. corresponding to a few carbon link length).
According to some embodiments, the system may further include one or more additional types of reactant molecules being adsorbed in corresponding one or more additional layers associated with enantiospecific interactions. In some cases, each of the additional layers adds certain thickness, while maintaining spin polarization properties.
According to some embodiments, the at least one surface may be associated with an electrode providing electrical contact with said fluid mixture, thereby promoting electro-chemical reaction at the vicinity of the at least one surface.
According to some embodiments, the at least one surface including ferromagnetic or paramagnetic material is mounted to be selectively placed to be in contact with reactants in said container, and to be placed out of contact with said reactants.
According to some embodiments, the system may be configured for selectively promoting chemical reactions for enantiomers of selected handedness of chiral molecules in accordance with direction of magnetization perpendicular to said at least one surface being up or down with respect to said at least one surface.
According to one other broad aspect, the presently disclosed subject matter provides a system for use in synthesis of molecules, the system including:
According to some embodiments, the first electrode may include at least one ferromagnetic or paramagnetic material, said system further includes at least one field generating unit configured to selectively apply magnetic field onto said first electrode providing selected magnetization direction of said first electrode.
Generally, the system may be configured for synthesis or separation of chiral molecules. For example, the system may be configured for enantiospecific reactions such of selected enantiomer from racemic mixture. Such enantiospecific reaction may be electrochemical oxidation or reduction reactions.
According to some embodiments, the at least said first electrode is mounted to be selectively insert into said container for selectively start and stop said interaction with reactants in said fluid mixture.
According to yet another broad aspect, the presently disclosed subject matter provides a method for use in molecular synthesis, the method including: providing at least one substrate having magnetization perpendicular to surface of said substrate; bringing said substrate in contact with one or more types of reactant molecules for promoting one or more molecular reactions on or in vicinity of surface of said substrate; wherein magnetization direction of said at least one substrate provides spin selectivity of electrons participating in said one or more molecular reactions resulting in enantioselective reactions.
According to some embodiments, said one or more molecular reactions may include electro-chemical reaction, the method further includes applying selected electrical voltage on said at least one substrate thereby receiving or donating electrons of selected spin polarization to perform said one or more molecular reactions.
According to some embodiments, the method may further include adsorbing one or more selected reactants onto said surface of said at least one substrate prior to bringing said substrate in contact with one or more types of reactant molecules, thereby providing enantioselective interactions between said one or more types of reactant molecules and said one or more selected reactants adsorbed on said surface.
According to some embodiments, said one or more types of reactant molecules may include chiral molecules, said enantioselective reactions provide reactions of enantiomers of one handedness selected in accordance with direction of magnetization of said at least one substrate.
According to some embodiments, said one or more types of reactant molecules may include a-chiral molecules, said enantioselective reactions provide formation of chiral products having handedness selected in accordance with direction of magnetization of said at least one substrate.
According to some embodiments, the method may be configured for enantiomer separation by physical adsorption enantiomers of selected handedness.
Generally, according to some embodiments, the method may include transferring said least one substrate to container including buffer solution for removing molecules of said selected handedness from said least one substrate.
According to yet another broad aspect, the presently disclosed subject matter provides a method for use in separation of chiral molecules, the method including: providing at least one substrate having magnetization perpendicular to surface of said substrate; bringing said substrate in contact with mixture of chiral molecules for a selected time and removing said substrate from said mixture to remove the adsorbed molecules therefrom; wherein magnetization direction of said at least one substrate provides preferred adsorption of molecules of one enantiomer over molecules of the opposite enantiomer thereby removing molecules of a selected enantiomer from said mixture.
According to some embodiments, the method may further include, washing adsorbed molecules from said substrate in a second container, thereby providing a solution of substantially enantiomer pure mixture.
According to some embodiments, the method may further include, repeatedly bring said substrate into contact with said mixture of chiral molecules for selected time and washing said substrate in a second container to thereby provide a continuous separation process.
According to some embodiments, the method may further include, using a plurality of substrates and repeating said separation process with each of said substrates.
In order to better understand the subject matter that is disclosed herein and to exemplify how it may be carried out in practice, embodiments will now be described, by way of non-limiting example only, with reference to the accompanying drawings, in which:
Reference is made to
The obtained CD signals indicate that after the electrochemical reaction, one enantiomer remains in the solution, while the molecules of the other enantiomer have been reduced, providing increase CD signal with respect to the racemic mixture. This result demonstrates enantioselective electrochemical redox process of camphor sulfonic acid, so that one enantiomer was reduced and the other remain mainly unaffected. It should be noted that the enantioselectivity in electrochemical reaction (e.g. electro-oxidization, electro-hydrogenation) is not specific to camphor sulfonic acid and may be used with various other molecules.
As described above, when a molecule approaches a substrate (being a surface or other molecules), charge rearrangement occurs, and an induced dipole is formed, in which fractions of an electron or hole is located at the negative and positive poles respectively. A moving electron with its spin has a certain helicity, i.e. relation between the spin and the linear momentum of the electron. The similarity between the electron helicity and chirality of a molecules is exemplified in
Typically, if the ground state of the electron is a singlet state, the spins at the electric poles will be anticorrelated, so that the total spin of the molecule remains zero. As described above, this effect varies with the adsorption of molecules on the magnetized substrates depending on the spin of the electron pointing towards the surface. Accordingly, for a chemical bond to be formed between the molecule and the substrate, the electron that is donated by the molecule and the one donated by the magnetized substrate to the bond formation, should be of opposite spins. This effect is similar upon interaction between two molecules. The electrons in the magnetized substrate that can participate in the bond with the molecule, have a well-defined spin due to magnetization of the substrate. Therefore, the electron donated by the molecule must or should have the opposite spin. This leaves the molecule with (partially) unpaired electron in the electric pole farther away from the substrate and this electron has the same spin as the ferromagnetic layer, as long as the system is coherent.
The present technique utilizes such spin preference in interaction between molecules and magnetized substrates (or between molecules in the vicinity of magnetized substrates). Such spin preference holds not only for covalent bonding but for any strength of interaction between the molecules and the ferromagnetic substrate, being adsorption, electron exchange, etc. More specifically, magnetized surface/substrate can donate or receive electron of a selected spin. Additionally, when molecules are adsorbed on the surface, the unpaired electron located on the opposite pole of the molecule, away from the surface, is generally similarly spin polarized. This extends the effect of the surface magnetization and resulting chiral selectivity to molecule-molecule interaction. More specifically, such unpaired, spin polarized electron of molecules may interact in enantio-specific manner with additional chiral molecules, as well as with non-chiral molecules. This enables promoting chiral selective interactions, where chiral molecules of selected handedness participate in the interaction, while same molecules with opposite handedness do not take part in the reaction. Additionally, such spin selectivity of the electrons facilitating chemical reaction, may lead to selected chiral symmetry of reaction products, even if the initial reactants are non-chiral.
Reference is made to
As exemplified in
To remove the reaction products from the magnetized substrate 50, it may be transferred to a third container 76 including solvent material. The A-B product molecules are removed from the magnetized structure 50 and can be moved for further processing or use. At this stage, the A-B reaction products generally contain a high ratio of one enantiomer (e.g. concentration ratio of 0.8 to 1 of a selected enantiomer). The process may be repeated for production of further complex molecules and it may include additional stages such as washing the magnetized structure. It should also be noted that the magnetized structure may be used as electrode for one or more electrochemical reactions with reactants of selected handedness. This is exemplified in
The system 100 exemplified in
Reference is made to
The distance between the magnetized ferromagnetic substrate and the chiral molecules was achieved and controlled by selecting the length of the linker molecules. More specifically, the linker molecules, forming a monolayer of stationary phase, were composed of molecules with the general structure HS—(CH2)X-1—COO−, where the thiol group acts to link the molecules to the substrate and the number X of carbon groups determined length of the linker. The tests were conducted several times using linker molecules of different lengths, i.e. different numbers X of carbon groups. The easy axis in this ferromagnetic Ni layer is set to be perpendicular to the substrate and it can be magnetized at the up direction (+) or down direction (−). The interaction of the chiral molecules with the stationary monolayer is based on electrostatic bonds. Two enantiomers of R or S 1-amino-2-propanol were prepared in ethanol (pH˜7) solvent for all or most experiments. In this situation of about pH-7, both the carboxyl group and the amine group are charged, so that an electrostatic interaction between them is possible. The hydroxyl group, apart from defining the chiral center, acts as an Fourier-transform infrared spectroscopy (FTIR) marker for stretch modes in the wavenumber range of 3200-3500 cm−1.
The OH stretch signals appears in S enantiomer under down (−) magnetization direction at about 3300-3450 cm−1 after 2-minute interaction in
By changing the linker length, location of the interacting ends of the molecules with respect to the magnetized surface changes. Increased linker lengths results in decay of spin polarization of the electrons participating in the interaction, reducing selectivity of the interaction. The use of linker molecules of varying lengths enables to monitor this effect. The inventors have found that the decay of the selectivity is clearly noticed with linker length of more than 3 carbons (X=3), which relates to linker length of 6.3 Å under assumption of tetrahedral angle and 0.77 Å covalent radius of carbon in c-c bonding. Thus, the selectivity decays at distances larger than 6.3 Å. With any longer linkers, the interaction does not show selectivity with respect to chirality of the molecules and magnetization of the substrate. Thus, the adsorption rate, using linkers longer than 6.3 Å is similar for up or down magnetization and R or S enantiomers. At this case, the interaction shows similar characteristics to the case where no magnetization is applied on the surface. The system was verified also for mercaptohexanoic acid (with X=6) and mercaptooctanoic acid (with X=8). Both did not show any qualitative difference, there was no selective adsorption and the analyte adsorbed in the same rate under up or down or without magnetization. These results suggest that the length dependence decay is due to losing the electron spin coherency in the linker molecules biased by the magnetic field on the ferromagnet.
As indicated, at large distance (longer than length of 3 carbons' covalent bonds) electrostatic bonds may be created at the same rate with and without magnetic field for the two enantiomers. At these conditions the OH stretch signal appears after 30 minutes, indicating time of interaction between the 1-amino-2-propanol molecules and the linker molecules. Generally, if the interaction with the substrate is stronger, the first signal of the OH stretch is expected to appear faster, while if it is weaker the signal is expected to appear after longer interaction time. Table 1 exemplifies minimal absorption durations for different linker lengths and magnetizations, normalized by the time of adsorption with long linkers where enantioselectivity vanishes. More specifically, the time of the appearance of the OH stretch signal in FTIR measurements for interaction with short linkers is normalized by the time of appearance of the OH stretch signal after interaction with long linkers where the substrate magnetization does not play a role. In table 1, the first and the second rows are the normalized times relevant to reaction of R 1-amino-2-propanol, and the third and fourth last rows are the normalized times relevant to reaction of S 1-amino-2-propanol. The interaction rates were correlated to the first appearance of the OH stretch signal, defined by integrating the peak area having a signal that is two folds higher than that shown in FTIR of the TGA monomers. The measured time was measured and averaged over 5 samples. The time under up (+) magnetization direction for the R enantiomer is faster than under down (−) magnetization direction. The S enantiomer displays the opposite trend. When 4 carbons (7.5 Å) are used, no selective absorbance is achieved.
As shown in table 1, the use of short linking layers to magnetized surface provide enantioselective interactions. As indicated above, this is considered to be associated with the CISS exchange interactions being stronger due to spin polarization of interacting electrons. For enantiomers of selected handedness, weaker interaction is shown as well as longer adsorption rates for one magnetization direction, while in the opposite magnetization direction, shorter adsorption rates are shown. The enantiomers of opposite handedness behave similarly for opposite magnetization directions. The shorter the linkers the selectivity becomes stronger. For linkers having length associated with 2 carbon bonds, the selectivity reaches a factor of 9 for the R enantiomer and a factor of 30 for the S enantiomer. For linker length of 3 carbons, the selectivity reaches a factor of 3 for the R enantiomer and a factor of 9 for the S enantiomer. With 4 carbons linkers, the selectivity disappears.
To relate the asymmetrical electrostatic adsorption properties to magnetic spin, the same chemical layout was deposited on sensitive Hall devices based on GaAs/AlGaAs heterostructure with shallow 2D electron gas. Reference is made to
The results above indicate stereo-chemistry and enantioselective reactions provided by promoting physical and chemical molecular interactions at the vicinity of magnetized surfaces. More specifically, the present technique provides enantioselective interactions on, or at selected distances (generally not exceeding 0.7 nm) from magnetized surface (being ferromagnetic or paramagnetic surface). Furthermore, the enantio-selective interactions are stable for relatively long period of time, in response to adsorption onto the magnetized surface.
Thus, the present technique provides for promoting enantioselective interaction between selected chiral molecules. Generally, unlike the conventional techniques using chromatographic systems with selected lock and key features that are specific for selected molecules. The present technique enables the use of physical bonds and CISS controlled reaction that provide generic differentiation between enantiomers, where similar system configuration provides enantioselective interactions to various reactants. Further, the present technique is also relevant for selective interactions using chiral, helical as well as non-chiral and non-helical molecules, where in the later cases, the selectivity is manifested in chirality of the reaction products. Accordingly, the present technique demonstrates spin-based chemistry, exemplifying selected enantioselective interactions where the interaction centers are on, or in vicinity of a surface having magnetization perpendicular to the surface.
This application is a national phase filing under 35 C.F.R. § 371 of and claims priority to PCT Patent Application No. PCT/IL2019/051143, filed on Oct. 23, 2019, which claims the priority benefit under 35 U.S.C. § 119 of U.S. Provisional Application No. 62/749,271 filed on Oct. 23, 2018, the contents of each of which are hereby incorporated by reference in their entireties.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/IL2019/051143 | 10/23/2019 | WO | 00 |
| Number | Date | Country | |
|---|---|---|---|
| 62749271 | Oct 2018 | US |
