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 .
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 01/02/2026 has been entered.
Applicant Response
Applicant's response, filed 01/02/2026, has been fully considered. Rejections and/or objections not reiterated from previous Office Actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Terminal Disclaimer
The terminal disclaimer filed on 01/02/2026 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of prior patent No. 11,441,994 B2 has been reviewed and is accepted. The terminal disclaimer has been recorded.
The terminal disclaimer filed on 01/02/2026 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of prior patent No. 11,488,686 B2 has been reviewed and is accepted. The terminal disclaimer has been recorded.
Claim Status
Claims 2-5, 8-11, and 14-17 are cancelled.
Claims 19-20 are newly added.
Claims 1, 3-4, 6-7, 9-10, 12-13, 15-16 and 18 are pending and under examination herein.
Claims 7 and 13 are objected to.
Claims 1, 6-7, 12-13 and 18-20 are rejected.
Priority
The instant application claims the benefit of foreign priority to 202021007335, filed 02/20/2020. As such, the effective filing date assigned to each of claims 1, 6-7, 12-13 and 18-20 is 02/20/2020. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Drawings
The drawings filed 12/29/2020 were accepted by the examiner in the office action mailed 02/19/2025.
Claim Interpretation
Under the broadest reasonable interpretation of the claims based on the title, abstract, drawings and specification, the steps in the claims are interpreted to be a simulation.
Claim Objections
The objections to claims 3 and 15 are withdrawn in view of cancelation of the claims in the claim amendment filed 01/02/2026.
The objections to claims 1 are withdrawn in view of the claim amendment filed 01/02/2026.
Claims 7 and 13 remain objected to because of the following informalities: “in presence of external electric field is performed” should be “in presence of an external electric field is performed”. Appropriate correction is required.
Response to Applicant’s Arguments
Applicant’s arguments have been fully considered, but they do not address the issues discussed above.
Claim Rejections - 35 USC § 112
The rejections of claims 3-4 and 9-10 under 35 U.S.C. 112(b) are withdrawn in view of cancelation of the claims in the claim amendment filed 01/02/2026.
The rejections of claims 1, 6-7 and 12 under 35 U.S.C. 112(b) are withdrawn in view of the claim amendment filed 01/02/2026.
Claim Rejections - 35 USC § 101
The rejections of claims 3-4, 9-10, and 15-16 under 35 U.S.C. 101 are withdrawn in view of cancelation of the claims in the claim amendments filed 01/02/2026.
The rejections of claims , 6-7, 12-13, and 18 are withdrawn in view of the claim amendments filed 01/02/2026, as it does not appear that the combination of additional elements recited in the independent claims was well-known, routine or conventional (WURC) in the art at the effective filing date of the instant application. Specifically, it was not WURC to calculate both an active and passive diffusion coefficient using a MD technique which integrates simulations at molecular and macroscopic levels and test the electroporation model against data on fentanyl permeation under the applied electric field, wherein in a virtual testing of active permeation through skin in the presence of an external electric field is performed as described in the instant claims. Furthermore, with respect to claim 13 and 19-20, it is further not WURC to perform full factorial design simulation for four different voltages and three pulse durations for the given number of pulses, as disclosed in the instant claims.
.
Claim Rejections - 35 USC § 103
The rejections of claims 3-4, 9-10 and 15-16 under 35 U.S.C. 103 are withdrawn in view of cancelation of the claims in the claim amendment filed 01/02/2026.
The rejection of claims 13 and 18 under 35 U.S.C. 103 as being unpatentable over Gupta and Rai (Langmuir 2018 34 (20), 5860-5870; ; previously cited; hereafter referred to as Gupta), and further in view of Gupta et al. (US20180253525A1; previously cited) and Becker (International journal of thermal sciences 2012, 54, pp.48-61; previously cited) is withdrawn in view of claim amendments filed 01/02/2026, as the cited art does not appear to suggest, teach or provide motivation for
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3-4, 6-7, 9-10, 12-13, 15-16 and 18-20 remain rejected under 35 U.S.C. 103 as being unpatentable over Gupta and Rai (Langmuir 2018 34 (20), 5860-5870; ; previously cited; hereafter referred to as Gupta), and further in view of Gupta et al. (US20180253525A1; previously cited) and Becker (International journal of thermal sciences 2012, 54, pp.48-61; previously cited). Newly recited portions are necessitated by claim amendments.
With respect to claims 1, 7, 13 and 19-20, Gupta discloses molecular dynamics simulation, in which they obtain an equimolar model to mimic the skin Stratum Corneum (SC) lipid bilayer (p 5861, col 2, para 4).
Gupta further discloses direct application of the electric field along the lipid bilayer method to capture the electroporation of the skin SC lipid bilayer, and that pore formation occurs after a certain critical electric field, also known as the threshold field (p 5862, col 1, para 4-col 2, para 1).
Gupta also discloses water pore stabilization and that to stabilize the water pore, the electric field was reduced significantly, once the pore radius almost reached to ∼3−4nm (p 5863, col 2, para 2).
Gupta also discloses performing simulation of drug molecule permeation in the presence of an external electric field by manually inserting four benzoic acid (drug) molecules into a lipid bilayer with a stable pore (p 5866, col 2, para 2-p 5867, col 1, [para 1; fig 6).
Gupta further discloses using the obtained model to simulate the structure of the SC layer, comprising corneocytes interconnected by a lipid lamellar bilayer structure in a crystalline−gel phase at both a molecular and coarse-grained, in which the corneocytes and lipid matrix are arranged in a brick and mortar fashion, respectively (i.e. micro- and macroscopic level) (p 5861, col 2, para 4). Gupta also discloses performing the extensive atomistic MD simulation of the skin lipid bilayer in the presence of varying external electric fields (p 5861, col 2, para 4-p 5868, col 1, para 1).
Gupta discloses performing four separate electroporation simulations were performed at each electric field at different durations to tune the parameters (p 5862, col 1, para 4-p 5867, col 2, para 3; Table S1-S3). It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have performed full factorial design simulation for four different voltages and three pulse durations for the given number of pulses through routine experimentation of the voltage and pulse durations within the prior art conditions of tuning the parameters through the performance of electroporation simulations. See MPEP 2144.05 II. A..
Gupta further suggests the use of simulations with experiments, such as full-factorial design simulations with different voltages and varying pulse durations could be used for better design of experiments, and that for a given skin composition and size of the drug molecule, the combination of pore formation time and pore growth rate can be used to know a priori the desired electric field and time for the application of the electric field (p 5866, col 2, para 2-p5867, col 2, para 3).
Gupta further discloses the provided molecular mechanism could help in optimizing/designing the electroporation experiments for better drug delivery (p 5868, col 1, para 2). Therefore, Gupta suggests selecting one or more electroporation protocols.
However, with respect to claims 1, 7 and 13, Gupta does not disclose calculating passive and active diffusion coefficients of drug molecules through the stable pore, calculating the concentration gradient of the drug molecules in the presence of the electric potential using a FEA technique and the diffusion coefficients, calculating the drug profiles or drug release profiles using the concentration coefficient, testing the molecular electroporation model against data on fentanyl permeation under the applied electric field, tuning one or more pre-defined pulse parameters based on the calculated flux profile and the calculated cumulative release profile.
However, with respect to claims 1, 7 and 13, the prior art to Gupta et al., in the same field of endeavor, discloses method and system for in-silico testing of actives on human skin, in which a micro and macroscopic level model of the structure of the skin’s upper layer (i.e. SC layer) is provided and used in a multi-scale modeling framework for the calculation of diffusion and release profile of different actives like drugs, particles and cosmetics through developed skin model using molecular dynamics simulations and computational fluid dynamics approach (abstract; claim 1l para 0027).
Gupta et al. discloses constrained molecular dynamics simulation is used for the calculation of diffusion coefficient or diffusivity of the active molecule (i.e. passive diffusion coefficient of one or more drug molecules) (para 0033).
Gupta et al. discloses calculated diffusion coefficient can further be used to predict the dermal uptake/ cumulative release through the stratum corneum using computational fluid dynamics techniques (para 0007).
Gupta et al. discloses the averaged diffusion coefficient along the bilayer normal is further used as an input to the transport model, which is configured to generate the release profile of the actives, and that a finite element technique (FBM) is used to solve the transport model (para 0034).
Gupta et al. further discloses the flux across the SC is measured and integrated with respect to time to calculate the dermal uptake/cumulative release of permeate through SC (para 0035)
Gupta et al. further discloses the measurement of the diffusion coefficient of the molecules in stratum corneum is very important in order to predict the transport mechanism and that studying the transport mechanism of molecules through skin is necessary in order to design a new molecule/drugs/cosmetic (para 0004).
Gupta et al. also discloses performing simulations to test the model using experimental data on fentanyl permeation (para 0058-0067).
However, Gupta et al. does not disclose calculating the active diffusion coefficient (i.e. the diffusion coefficient across the stable pore), calculating the diffusion coefficient of a drug molecule in the presence of an electric potential, using this gradient to determine the drug flux and cumulative release profiled, or tuning the parameters to obtain a desired release profile.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the molecular dynamics simulation described by Gupta with the steps of determining a passive diffusion coefficient and calculating the drug flux, release profile and testing the simulation against experimental data as described by Gupta et al., because the measurement of the diffusion coefficient of the molecules in stratum corneum is very important in order to predict the transport mechanism and that studying the transport mechanism of molecules through skin is necessary in order to design a new molecule/drugs/cosmetic, as disclosed by Gupta. There would be a reasonable expectation of success because determining the diffusion coefficient of molecules would not impede the simulation of Gupta.
With respect to claims 1, 7 and 13, the prior art to Becker, in the same field of endeavor, discloses computationally modeling and treatment of mass transport associated with electroporation of the skin, which is computer implemented (as evidenced by the use of programming language Fortran (abstract; p 54, col 2, para 3; p 59, col 2, para 2).
Becker discloses, modeling a composite description of skin including the lipid bilayer of a SC layer (fig 1; p 50, col 2, para 4; fig 3).
Becker discloses applying an electric pulse, which results in the development of Local Transport Regions (LTR) (i.e. pore) and determining the electric field required for (LTR (p 48, col 2, para 1; p 50, col 1, para 3-col 2, para 2; p 51, col 2, para 1-3).
Becker further discloses estimating transport coefficients, such as the diffusion coefficient, and modeling the transient transport of a large charged solute in the presence of an electric field (i.e. active diffusion through a pore) (abstract; sections 2.2 and 2.6). Becker discloses considering both passive and active diffusion models (p 50, col 2, para 2; section 2.5).
Becker also discloses the model of the SC includes the macroscopic structure, which includes the understanding that that the SC is composed of lamellar lipid sheets set between corneocytes (p 50, col 1, para 2-col 2, para 2).
Becker discloses modeling calculating a transient transport of a charged solute in the presence of an electric field in the LTR (i.e. concentration gradient), using transport coefficients, such as the diffusion coefficient and electrophoretic mobility, porosity, lipid melt fraction, etc., using the Laplace equation and modified Nernst-Planck equation (i.e. uses a finite element analysis (FEA) technique) (sections 2.1-2.2, 2.4 and 2.6; equation 1-7). Becker discloses the transport model is derived from both a Laplace equation and Nernst-Planck equation (sections 2.2-2.5). Becker discloses the equations are used based on the understanding of the skin used by the molecular electroporation model, including the macroscopic structure and pre-defined pulse/temperature parameters and boundaries of the SC layer (p 50, col 1, para 3-col 2, para 2). Becker further discloses the modified Nernst-Planck equation makes use of solute concentration, effective electrophoretic mobility and effective diffusion coefficient, and further discloses using the electrical conductivity as described by the instant specification in para 0071 (p 51, col 1, para 2-col 2, para 2).
Becker further discloses estimating the solute flux and total solute deposition and transportation (i.e. cumulative release profile) using the concentration gradient equations (p 54, col 1, para 2; fig 5-11; section 4).
Becker discloses further performing a parametric investigation (i.e. tuning) based on the solute flux and total solute deposition and transportation (section 4).
With respect to claims 6, 12 and 18, Becker discloses a pre-defined pulse parameter of a pulse type (p 50, col 2, para 1).
It would also have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the molecular dynamics simulation described by Gupta with the steps of determining an active diffusion coefficient which takes into account passive diffusion, model the transport of solutes across the SC layer through a pore and calculate the drug flux and release profile in the presence of an electric potential as described by Becker, because skin electroporation has been shown to greatly increase the success of transdermal delivery through the SC, as disclosed by Becker, and the measurement of the diffusion coefficient of the molecules in stratum corneum is very important in order to predict the transport mechanism and that studying the transport mechanism of molecules through skin is necessary in order to design a new molecule/drugs/cosmetic, as disclosed by Gupta et al.. There would be a reasonable expectation of success because determining the transport mechanisms of electroporation to determine the drug flux and release profiles would not impede the simulation of Gupta.
Therefore, the invention is prima facie obvious.
Response to Applicant’s Arguments
Applicant states the prior art to Gupta and Becker do not disclose the amended subject matter (Applicant’s Arguments, p 18, para 4). Applicant states Becker does not discloses the amended limitations related to the calculating the concentration gradient and the variables used in the Nernst-Planck, or the use of the active and passive diffusion coefficients that are incorporated into the multiscale model and developing a multiscale model that can be used as a tool to plan and design electroporation protocols (Applicant’s Arguments, p 19, para 2-p 20, para 5). Applicant further states Gupta does not disclose calculating an active and passive diffusion coefficient or selecting electroporation protocol to get desired release profile, and that Gupta and Becker do not disclose calculating the MD simulation integrates simulations at molecular and macroscopic levels, and requests withdrawal of the rejections (Applicant’s Arguments, p 20, para 7-p 21, para 5).
It is respectfully submitted that this is not persuasive. As discussed above, Gupta discloses molecular dynamics simulation, in which they obtain an equimolar model to mimic the skin Stratum Corneum (SC) lipid bilayer (p 5861, col 2, para 4). Gupta further discloses using the obtained model to simulate the structure of the SC layer, comprising corneocytes interconnected by a lipid lamellar bilayer structure in a crystalline−gel phase at both a molecular and coarse-grained, in which the corneocytes and lipid matrix are arranged in a brick and mortar fashion, respectively (i.e. micro- and macroscopic level) (p 5861, col 2, para 4). Gupta also discloses performing the extensive atomistic MD simulation of the skin lipid bilayer in the presence of varying external electric fields (p 5861, col 2, para 4-p 5868, col 1, para 1).
Gupta et al. discloses constrained molecular dynamics simulation is used for the calculation of diffusion coefficient or diffusivity of the active molecule (i.e. passive diffusion coefficient of one or more drug molecules) (para 0033). Gupta et al. discloses calculated diffusion coefficient can further be used to predict the dermal uptake/ cumulative release through the stratum corneum using computational fluid dynamics techniques (para 0007). And, Becker further discloses estimating transport coefficients, such as the diffusion coefficient, and modeling the transient transport of a large charged solute in the presence of an electric field (i.e. active diffusion through a pore) (abstract; sections 2.2 and 2.6). Becker discloses considering both passive and active diffusion models (p 50, col 2, para 2; section 2.5).
Becker also discloses the model of the SC includes the macroscopic structure, which includes the understanding that that the SC is composed of lamellar lipid sheets set between corneocytes, and modeling and calculating a transient transport of a charged solute in the presence of an electric field in the LTR (i.e. concentration gradient), using transport coefficients, such as the diffusion coefficient and electrophoretic mobility, porosity, lipid melt fraction, etc., using the Laplace equation and modified Nernst-Planck equation (i.e. uses a finite element analysis (FEA) technique) (i.e. simulation techniques takes into account both micro- and macroscopic level) (p 50, col 1, para 2-col 2, para 2; sections 2.1-2.2, 2.4 and 2.6; equation 1-7). Becker discloses the transport model is derived from both a Laplace equation and Nernst-Planck equation (sections 2.2-2.5). Becker discloses the equations are used based on the understanding of the skin used by the molecular electroporation model, including the macroscopic structure and pre-defined pulse/temperature parameters and boundaries of the SC layer (p 50, col 1, para 3-col 2, para 2). Becker further discloses the modified Nernst-Planck equation makes use of solute concentration, effective electrophoretic mobility and effective diffusion coefficient, and further discloses using the electrical conductivity as described by the instant specification in para 0071 (p 51, col 1, para 2-col 2, para 2). Becker further discloses estimating the solute flux and total solute deposition and transportation (i.e. cumulative release profile) using the concentration gradient equations (p 54, col 1, para 2; fig 5-11; section 4).
Gupta et al. discloses constrained molecular dynamics simulation is used for the calculation of diffusion coefficient or diffusivity of the active molecule (i.e. passive diffusion coefficient of one or more drug molecules) (para 0033). Gupta et al. discloses calculated diffusion coefficient can further be used to predict the dermal uptake/ cumulative release through the stratum corneum using computational fluid dynamics techniques (para 0007). And, Becker further discloses estimating transport coefficients, such as the diffusion coefficient, and modeling the transient transport of a large charged solute in the presence of an electric field (i.e. active diffusion through a pore) (abstract; sections 2.2 and 2.6). Becker discloses considering both passive and active diffusion models (p 50, col 2, para 2; section 2.5).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the molecular dynamics simulation described by Gupta with the steps of determining a passive diffusion coefficient and calculating the drug flux, release profile and testing the simulation against experimental data as described by Gupta et al., because the measurement of the diffusion coefficient of the molecules in stratum corneum is very important in order to predict the transport mechanism and that studying the transport mechanism of molecules through skin is necessary in order to design a new molecule/drugs/cosmetic, as disclosed by Gupta.
It would also have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the molecular dynamics simulation described by Gupta with the steps of determining an active diffusion coefficient which takes into account passive diffusion, model the transport of solutes across the SC layer through a pore and calculate the drug flux and release profile in the presence of an electric potential as described by Becker, because skin electroporation has been shown to greatly increase the success of transdermal delivery through the SC, as disclosed by Becker, and the measurement of the diffusion coefficient of the molecules in stratum corneum is very important in order to predict the transport mechanism and that studying the transport mechanism of molecules through skin is necessary in order to design a new molecule/drugs/cosmetic, as disclosed by Gupta et al.
Gupta discloses performing four separate electroporation simulations were performed at each electric field at different durations to tune the parameters (p 5862, col 1, para 4-p 5867, col 2, para 3; Table S1-S3). It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to have performed full factorial design simulation for four different voltages and three pulse durations for the given number of pulses through routine experimentation of the voltage and pulse durations within the prior art conditions of tuning the parameters through the performance of electroporation simulations. See MPEP 2144.05 II. A..
Gupta further suggests the use of simulations with experiments, such as full-factorial design simulations with different voltages and varying pulse durations could be used for better design of experiments, and that for a given skin composition and size of the drug molecule, the combination of pore formation time and pore growth rate can be used to know a priori the desired electric field and time for the application of the electric field (p 5866, col 2, para 2-p5867, col 2, para 3). Gupta further discloses the provided molecular mechanism could help in optimizing/designing the electroporation experiments for better drug delivery (p 5868, col 1, para 2). Therefore, Gupta suggests selecting one or more electroporation protocols.
Therefore, the invention is prima facie obvious, and the rejection is maintained.
Double Patenting
The rejections of claims 3-4, 9-10, and 15-16 on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of U.S. Patent No. US11441994B2 in view of Gupta et al. (US20180253525A1) and Becker (International journal of thermal sciences 2012, 54, pp.48-61) is withdrawn in view of cancelation of the claims in the claim amendments filed 01/02/2025.
The rejections of claims 3-4, 9-10, and 15-16 on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of US11488686B2, in view of Becker (International journal of thermal sciences 2012, 54, pp.48-61) is withdrawn in view of cancelation of the claims in the claim amendments filed 01/02/2025.
The rejections of claims 1, 6-7, 12-13, and 18 on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of U.S. Patent No. US11441994B2 in view of Gupta et al. (US20180253525A1) and Becker (International journal of thermal sciences 2012, 54, pp.48-61) is withdrawn in view of the terminal disclaimer filed 01/02/2025.
The rejections of claims 1, 6-7, 12-13, and 18 on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of US11488686B2, in view of Becker (International journal of thermal sciences 2012, 54, pp.48-61) is withdrawn in view of the terminal disclaimer filed 01/02/2025.
Conclusion
No claims allowed.
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/N.D./ Examiner, Art Unit 1686
/Karlheinz R. Skowronek/ Supervisory Patent Examiner, Art Unit 1687