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 .
Applicant’s response filed 11/10/2025 has been received and entered into the case. All arguments and amendments have been considered.
Claims 1-20 are pending and have been considered on the merits herein.
The previous rejections of record have been withdrawn in light of applicants claim amendments.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more. The claim(s) recite(s) a method and system for evaluating test-drug induces fatter liver based upon evaluating resistance and capacitance measures compared to a control and determining if the drug has toxicity causing fatty liver based upon resistance and capacitance measures. The steps of evaluating, comparing and determining are considered to be mental steps or basic critical thinking and thus an abstract idea, i.e. the judicial exception. This judicial exception is not integrated into a practical application because the steps of placing a liver cell spheroid treated with a test drug in a system to not impose a meaningful limit of the judicial exception because they are considered to be extra-solution activity, i.e. is performed to gather data for the mental step analysis in the claims and thus are a necessary precursor for uses of the recited exception. Additionally, the comparing and determining steps are recited a high level of generality that merely requires a comparison of two pieces of information and a critical thinking step. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because steps of treating cells with a drug and measuring impedance are routine and conventional in art, see Atienzar and Gamal, for example (previously cited). Thus, the claims elements recited well-understood, routine and conventional activity which add insignificant extra-solution activity to the judicial exception.
The claimed invention is not directed to patent eligible subject matter. Based upon an analysis with respect to the claim as a whole, claim(s) 1-20 is/are determined to be directed to a judicial exception.
For these reasons the claims are rejected under section 101 as being directed tonon-statutory subject matter.
Claim Rejections - 35 USC § 103
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 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.
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.
Claim(s) 1-11,13-20 is/are rejected under 35 U.S.C. 103 as being unpatentable over the combination of Thielecke et al. (US2006/0199173, IDS), Larsen (US6959618 B1, IDS) Park et al., (Biomed. Res. Int., 2016, p. 1-10, IDS) and Thielecke et al. (Biosensors and Bioelectron., 2001) in view of Kozyra et al. (Sci. Reports, Sept. 2018, p. 1-12), Bhati et al. (Transp. Proceed., 2009, IDS), Atienzar et al. (Biosensors, 2013, vol. 3, p. 132-156).
Regarding claims 1, Thielecke teach a device and method for characterizing spheroids comprising a tube, i.e. a strain generating part, wherein the tube has an inner diameter smaller than a spheroid (labeled 1 in Fig. 1-3), and an impedance measuring part (0009-0015). The reference teaches that the device can be used in methods of testing therapeutics (pharmacology, pharmakinetics) and their effect mechanisms (0025). Spheroids are introduced into the tube and because of the inner diameter of the tube, the spheroid is in contact with the inner walls of the tube (0010) and electrode materials are positioned on each end of the tube (each side having an inner and outer electrode (0013)) and a current flow is generated through the spheroid and impedance is measured as well as current resistance (abstract, Fig. 1, 2, 0009-0018, 0020). The method produces an impedance spectrum of spheroids (abstract, 0009-0012).
Regarding the use of a first and second tube, the reference suggests that multiple tubes or an array-like arrangement having different diameters can be used (0022, 0024). In addition, they teach that the middle of the tube (labeled 1 in Fig. 1 and 2) has a smaller diameter than the two outer attached tubes (labeled 2 in Fig. 1 and 2, 0030-0032, 0035). While the second tube (labeled 1) is not inserted into the first tube, but rather connected to the “first” tubes having diameters larger than the second tube, the insertion versus the connection appears to be a design choice which would be an obvious variation of the device of Thielecke, still allowing for said first tube to have an inner diameter which is the same as the outer diameter of the second tube and wherein the second tube has a smaller diameter of a spheroid cell. Thus, the design choice of the claimed invention is obvious in view of Thielecke.
Regarding claims 7, 8, 16, 17, and the limitation of controlling the position of the spheroid by applying pressure, the spheroids are positioned within the tube via a pump, moveable piston or pressure (0019, 0036). Further, regarding claims 7, 8, 10, 16, 17, 19, the device comprises a third and fourth tube (labeled 7 and 9) connected to the ends of the outer tubes, wherein tube 7 is connected to a control valve (labeled 8) which applies pressure and tube 9 is connected to a moveable piston which positions the spheroid (labeled 10) along with the pressure applied from 8 (0036). It is also disclosed that the spheroids are pressed into or drawn into the tubes via a pump. While a syringe or syringe pump is not specifically disclosed by Thielecke, syringe pumps for use with impedance analyzers which apply pressure and position cells to be analyzed were known at the time of the claimed invention, see Park et al., p. 4, whole page, section 2.3 and Fig. 3, who teach syringe pumps to adjust cell positioning and applying pressure to cells when measuring impedance using an impedance analyzer. Therefore, it would have been obvious to use a syringe pump as the pump in the system of Thielecke, which they teach positions the cells by applying a pressure.
Regarding claims 9, 11, 18, 20, the reference teaches 4 platinum electrode wires (labeled 3, 4 of Fig. 2) on the ends of the outer tubes for receiving impedance measurements (0033) which are connected to an impedance analyzer (0037). While Thielecke does not teach the wire electrodes to be in the form of a coil-shaped wire within the tube, Larsen teaches that electrodes for use in measuring impedance can be electrodes having a coil-shaped wire within tubular electrodes (col. 9, lines 25-45). Therefore, it is the Examiners position that the placement of the coiled-wire electrode material within the tube instead of positioned at the ends of the tubes would be an obvious design choice modification to the system of Thielecke given the teachings of Larsen because the placement and design of the wire inside the tube does not change the operation of the electrode and thus is an obvious matter of design choice.
Regarding claims 2 and 14, Thielecke teach the tube (strain generating part) to be filled with a culture medium (0010), while a buffer is not specifically disclosed, Park teaches the cells in PBS which are injected into the “channel”, i.e. the strain generating part of Park (p. 4, 1st col, 1st parag.). Thus, it would have been obvious to pursue known option within his or her technical grasp for use within the system of Thielecke with a reasonable expectation of successfully obtaining impedance measurements of spheroids within the system.
While Thielecke teaches measuring resistance, they do not specifically disclose interior and exterior resistance and capacitance measurements.
Thielecke (biosensors and bioelec.) teach the use of an impedance analyzer to measure Rint, the interior resistance of 3D spheroids (intracellular space), Rext, the exterior resistance of the extracellular space of the spheroid, and Cmem capacitance to measure the capacitive component of the cell membranes of the spheroids (p. 263-264, section 2.3, Fig. 3). Thielecke teach using the same analyzer system as Thielecke (US173) see Fig. 2 and Fig. 1 and 2 of US173. Thielecke teach that 3D spheroids mimic the physiological behaviors of tissues and tumors and impedance analysis can be used for diagnostic and therapeutic screenings of spheroid models (introd., p. 269, whole page).
Thus, before the effective filing date of the claimed invention, a posita would have had a reasonable expectation of successfully using the impedance analysis/system (of Thielecke) to measure interior and exterior resistance and capacitance of spheroids in response to drugs/therapeutics.
The above references do not teach evaluating a test drug-induced fatty liver using the impedance system as claimed.
Kozyra teaches using hepatic 3D spheroids as models for steatosis, i.e. excessive accumulation of lipids. 3D spheroids closely mimic human liver function in vitro. To model steatosis, the 3D spheroids are exposed to excessive free fatty acids, carbohydrate and insulin levels (p. 2, 3rd and 4th parag., last parag.-p. 3). Kozyra teaches measuring lipid accumulation and distribution in the 3D spheroids promoting steatosis and comparing to controls (p. 4, Results Modelling of hepatic and Hepatic spheroids sections, Fig. 1).
Bhati teaches measuring resistance, capacitance and impedance of the liver to determine levels of steatosis when compared to normal livers (p. 1678-1679, . Bhati teaches that impedance measurements accurately diagnose the grade of donor hepatic steatosis to estimate liver functional reserve (intro.). The reference teaches that electrical current flows through an organ more easily if the water content is high versus if the organ has a higher fat content because adipose tissue is a poor conductor of current, and bioelectrical impedance analysis (BIA) allows one to evaluate changes in body composition (p. 1678, 1st col, 1st full parag., p. 1680-1681 Discussion section). Bhati also teaches that drugs like chemotherapy can induce histological changes including steatosis, sinusoidal dilation, fibrosis, and necrosis which can influence the results of BIA (p. 1681, 1st full parag.).
Atienzar teach electrical impedance technology to assess toxicology of 50 compounds on liver cells (abstract). Atienzar also generate cellular models having profile signatures when liver cells are exposed to calcium modulators, antimitotics, DNA damaging and nuclear receptor agents to predict genotoxic and non-genotoxic compounds (abstract). Atienzar teaches that impedance-based-time-dependent-cell response profiles (TCRP) has and can be used to produce profiles measuring and profiling cellular responses and cytotoxic effects of drugs/compounds (p. 133, whole page-p. 134, 1st parag., Fig. 1, 2, section 3.1-3.5, Table 3). The reference teaches obtaining impedance measurements from a “normalized cell index” and those of cells treated with different concentrations of compounds (section 2.4, 2.7).
Therefore, before the effective filing date of the claimed invention, it would have been obvious to use the system of Thielecke taken with Larsen and Park which is disclosed to measure impedance of spheroids to evaluate test drug effects, on the spheroids of Kozyra who teach 3D liver spheroids as models for steatosis which closely mimic human liver function in vitro. The 3D spheroids are exposed to excessive free fatty acids, carbohydrate and insulin levels and lipid accumulation and distribution in the 3D spheroids promoting steatosis are measured and comparing to controls. Further, Bhati and Atienzar teach that impedance systems are easy-to-use systems having high specificity and sensitivity for detecting structural liver alterations as well as detecting said alterations as an effect of cytotoxic compound exposure/administration. Therefore, before the effective filing date of the claimed invention, 3D liver spheroids were used to study a test drugs ability to induce fatty liver, i.e. steatosis by contacting the spheroids with excessive free fatty acids, carbohydrate and insulin levels, additionally impedance analyzers were used to effective measure resistance and capacitance as a result of a test drugs effect on spheroids, livers and liver cells. Thus, a posita would have had a reasonable expectation of successfully evaluating a test drugs ability to induce fatty liver in a 3D spheroid system which mimics human liver function in vitro using an impedance system in view of the teachings of the prior art of record.
Claim(s) 12 is/are rejected under 35 U.S.C. 103 as being unpatentable over the combination of Thielecke et al. (US2006/0199173, IDS), Larsen (US6959618 B1, IDS) Park et al., (Biomed. Res. Int., 2016, p. 1-10, IDS) and Thielecke et al. (Biosensors and Bioelectron., 2001) in view of Kozyra et al. (Sci. Reports, Sept. 2018, p. 1-12), Bhati et al. (Transp. Proceed., 2009, IDS), Atienzar et al. (Biosensors, 2013, vol. 3, p. 132-156) as applied to claims 1-11,13-20 above, and further in view of KR2011-0001405 (IDS).
The teachings of Thielecke et al. (US2006/0199173, IDS), Larsen (US6959618 B1, IDS) Park et al., (Biomed. Res. Int., 2016, p. 1-10, IDS) and Thielecke et al. (Biosensors and Bioelectron., 2001) in view of Kozyra et al. (Sci. Reports, Sept. 2018, p. 1-12), Bhati et al. (Transp. Proceed., 2009, IDS), Atienzar et al. (Biosensors, 2013, vol. 3, p. 132-156) are found above.
The references do not teach measuring stiffness of the liver cell spheroid from pressure changes according to claim 12.
KR405 teaches using an impedance analyzer system to detect the level of deformation/stiffness of a cell within the impedance systems strain generating part (abstract), wherein the strain generating part is a suction channel (having a buffer/electrolyte solution therein) into which the cells are sucked into which is located between electrodes (p. 1, 1st whole parag., p. 3rd -6th parag.) and impedance is measured (p. 4, 2nd full parag.. p. 5, 6th , 7th parag.). KR405 teaches that the apparatus measures the shape of the cells before and after applying force/pressure. The force modifies the shape of cells by stretching the cells longer, thus allowing one to determine the degree of deformation of cells based upon impedance values which increase in proportion to the length of cells having force applied thereto (p. 5, 6-8th full parag.).
Thus, before the effective filing date of the claimed invention, a posita would have had a reasonable expectation of successfully using an impedance analyzer to measure stiffness in the systems and method of the art of record in light of KR405, who teach that a cells deformation/stiffness can be measured using impedance values based upon pressure changes to evaluate whether cells are normal or modified.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of copending Application No. 18003757 (reference application) in view of Kozyra et al. (Sci. Reports, Sept. 2018, p. 1-12) supported by Pei et al. (Biomed. Res. Int, 2020, p. 1-12).
The claimed inventions are drawn to impedance-based evaluation systems (and methods for using) comprising a deformation/strain generating part including a first tube, a second tube having a diameter smaller than the first tube, wherein the second tube is inserted into the first tube. The evaluation systems also comprise an impedance analyzer connected to the deformation/strain generating part for measuring impedance of an organoid/spheroid. The deformation/strain generating parts include additional (3rd and 4th) tubes connected to the first tube. The first tube contains a buffer, saline solution, culture solution, membrane function impairment solution. The third tubes contain electrode material within and the electrodes are claimed to be in the form of a coil-shaped wire. The fourth tubes comprise a syringe pump. The inventions are also drawn to methods for using the evaluation systems comprising evaluating barrier integrity of the organoid/spheroid comprising testing a substance that induced membrane function damage and obtaining impedance measurements including resistance.
While the instant examined claims include evaluating a test drug and the reference claims are generically drawn to a substance that induces membrane function damage, Kozyra teaches using hepatic 3D spheroids as models for steatosis, i.e. excessive accumulation of lipids. 3D spheroids closely mimic human liver function in vitro. To model steatosis, the 3D spheroids are exposed to excessive free fatty acids, carbohydrate and insulin levels (p. 2, 3rd and 4th parag., last parag.-p. 3). Kozyra teaches measuring lipid accumulation and distribution in the 3D spheroids promoting steatosis and comparing to controls (p. 4, Results Modelling of hepatic and Hepatic spheroids sections, Fig. 1).
Steatosis and fat accumulation are known to damage liver cells membrane function and damage and thus, the fatty acids of Kozyra would be substances which induce membrane function damage. Support is further provided by Pei who teach fatty acid accumulations and toxicity cause liver cell damage (section 4.1)
Therefore, before the effective filing date of the claimed invention, it would have been obvious that fatty acids would be substances which induce membrane function damage. Thus, a posita would have had a reasonable expectation of successfully evaluating a test drug on liver cells using an impedance system in view of the teachings of the prior art of record.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant's arguments filed 11/10/2025 have been fully considered but they are not persuasive. While new reference of record have been applied, the Examiner will address applicants arguments directed at the limitations regarding the diameters of the first and second tubes and the Examiners position of being an obvious design choice.
Applicant argues that second tube is separate and insertable so as to be positioned within the first tube (made from different materials) to facilitate the handling of the spheroid and having inner diameters to accommodate different spheroid sizes, without remaking the first tube.
Applicants arguments directed to a tubes of different materials is not commensurate in scope with the claims. The tube of Thielecke was made using a capillary which on both ends are funnel shaped and bonded to glass tubes. The glass capillary has an inner diameter of 400-300 µm and a length of 8 mm and the glass tubes on both sides of the capillary have an inner diameter of 4 mm and length of 40 mm (see Thielecke Biosensors section 2.3, Fig. 2). Thielecke teaches that spheroids of different diameters can be placed in the analyzer and impedance measured because large and smaller spheroids have the same cross-sectional area in a capillary (p. 264-p.2665, section 2.4 and section 3.1.1, 3.2), thus the analyzer of Thielecke can accommodate spheroids of different sizes.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to TIFFANY MAUREEN GOUGH whose telephone number is (571)272-0697. The examiner can normally be reached M-Thu 8-5.
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/TIFFANY M GOUGH/ Examiner, Art Unit 1651
/DAVID W BERKE-SCHLESSEL/ Primary Examiner, Art Unit 1651