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 .
Claims 1-18 are pending and under examination in the instant application.
Priority
The instant application, filed 06/07/2024 is a 35 U.S.C. 371 national stage filing of PCT/US2022/051504, filed 12/01/2022, which claims priority to US Provisional Application No. 63287382, filed 12/08/2021. Thus, the earliest possible priority for the instant Application is 12/08/2021.
Claim Rejections - 35 USC § 102
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 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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 15 is/are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Clavien et al. (WO2021047947A1, filed 09/01/2020, and published on 03/18/2021).
Regarding claim 15, Clavien et al. teaches a method for assessing a health of a tissue, comprising: measuring a first level of a first marker in the tissue whose distribution within the tissue changes based on the tissue being damaged; measuring a second level of a second marker in the tissue whose distribution within the tissue does not change based on the tissue being damaged; generating an index based on the first level and the second level; and determining the health of the tissue based on the index (Abstract, claims 1, page 3, lines 21-26).
Claim Rejections - 35 USC § 103
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.
Claim(s) 1, 3, 4, 7, 8, 10, 11, and 14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Clavien et al. (WO2021047947A1, filed 09/01/2020, and published on 03/18/2021), in view of Freyer et al. (the US Patent Application Publication US20160178618A1, filed on 12/17/2015, and published on 06/23/2016).
Regarding claim 1, 4, 8, and 11 Clavien et al. teaches a method for evaluating damage of an organ tissue, in particular ischemic damage/injury of an organ tissue (Abstract and claim 1). Clavien et al. teaches a machine perfusion technology is used to preserve human organs (e.g. ex vivo) by perfusing the organ/tissue with perfusate for a certain time period (page 1, lines 18-19). Clavien et al. teaches that the method can be carried out in vitro (page 12, lines 11-13). Clavien et al. further teaches identifying and testing the predictive value of perfusate markers of organ tissues analyzed during machine perfusion (page 2, lines 16-20). This is comparable to the instantly claimed product a system for monitoring an organ in vitro, comprising a machine perfusion apparatus for perfusing the organ with a perfusate comprising an indicator. Clavien et al. further teaches a spectroscopic analysis unit for use in the method (page 1, lines 4-5). Clavien et al. further teaches that the continuous measurement during organ perfusion is done by means of a flow cell (flow-through cell, flow-through cuvette) integrated into the spectroscopic analysis unit. Permanent and stable flow has to be established through the flow cell to get reliable measurements. This can be realized by means of a suitable pressure difference between inlet and outlet of the flow cell given by the different pressure levels in the perfusion loop (page 11, lines 14-23). This reads on a spectrometer coupled to an input flow cell and an output flow cell, the input flow cell fluidically coupled to a perfusate recirculation input to the machine perfusion apparatus, and the output flow cell fluidically coupled to a physiological fluid output from the organ. Clavien et al. further teaches that further parts of the spectroscopic analysis unit are a data acquisition, processing and storage unit as well as a controlling unit that switches, synchronizes and controls light sources, bandpass filters, optical filters, shutters and spectrometers (page 15, lines 1-3). This reads on a controller comprising a processor coupled to the input flow cell, the output flow cell, and the spectrometer. Also, Clavien et al. teaches using a spectroscopic analysis unit comprising at least one spectrometer and at least one computer processor for carrying out the at least one prediction algorithm for predicting the at least one success score (page 8, lines 16-18). Measurements in the perfusate in a continuous or non-continuous manner are done by the spectroscopic analysis unit by detecting fluorescence and absorption spectra (page 11, lines 9-11). This reads on the processor being configured to: obtain a first-time course of optical measurements from the input flow cell, analyze the first time course of optical measurements. Clavien et al. teaches that the amount of marker molecule (predictive target molecule) in the perfusate, i.e. the fluid that is used to flush and/or perfuse solid organ tissue during explantation, harvesting, during in-vivo, or during ex-vivo preservation, correlates positively with the degree of injury or damage of the solid organ (page. 9, lines. 4-7). This reads on determining an integrity of the organ in vitro based on identifying the levels of the indicator in the first-time course of optical measurements.
However, Clavien et al. fails to explicitly teach obtaining a second time course of optical measurements from the output flow cell, analyzing the second time course of optical measurements to identify levels of the indicator, and determining an integrity of the organ in vitro based on identifying the levels of the indicator in the second time course of optical measurements.
However, Freyer et al. teaches a novel, three-dimensional (3D), in vitro tissue model that allows
measurement of spatial distributions of microenvironmental parameters and directly correlates these with alterations in cellular physiology, metabolism and functional genomics. The design further comprises in-line chemical monitoring of the input and output perfusate, providing data on the bulk metabolism within the culture (paragraph 0012). Freyer et al. further teaches that electrodes positioned at the input and output can measure the concentration of a compound and by comparing the measurements at the input and output, detect an overall change in the parameter (paragraph 0020). Through direct optical observation, a user can measure, for example, cell number, cell proliferation, mitochondrial activity, cell viability (paragraph 0072). The perfusion and external monitoring system comprise a perfusion input and output equipped with in-line sensors for continuous monitoring of medium composition (paragraph 0065).
Therefore, it would have been prima facie obvious to one of the ordinary skills in the art before the effective filing date of the claimed invention to have modified the computer processor of Clavien et al. to further include monitoring of the output perfusate by measuring the concentration of a compound and by comparing the optical measurements at the input and output, detect an overall change in the parameter with a reasonable expectation of success. One would have been motivated to have done so in order to provide a system that measures the initial input of an indicator, its concentration in an output perfusate, compare the two levels to determine
changes in the indicator, and determine organ integrity based on the change in concentration of said indicator.
Regarding claims 3 and 10: Following discussion of claim 1 above, Freyer et al. further teaches that the perfusion and external monitoring system comprise a perfusion input and output equipped with in-line sensors for continuous monitoring of medium composition (paragraph 0065). Various molecular dye probes include fluorescein (paragraph 0105). Optical signals are collected by an epi-fluorescence microscope or other optical system that collects light from a defined volume within the chamber (paragraph 0068). This reads on that the indicator comprises fluorescein and wherein the first-time course of optical measurements and the second time course of optical measurements comprise fluorescence measurements.
Regarding claims 7 and 14: Following discussion of claim 1 above, Clavien et al. further teaches that the available information used to decide whether solid organ tissue is transplanted into a recipient, or to predict any other post-transplant parameter, is comprised of the continuous and/or point measurements of any or a combination of marker molecules (or predictive target molecules), in particular a spectroscopic measurement (page 4, lines 18-22). This reads on each of the first-time course of optical measurements and the second time course of optical measurements comprises at least two measurements.
Claim(s) 1, 2 and 8-9 is/are rejected under 35 U.S.C. 103 as being unpatentable over Clavien et al. (WO2021047947A1, filed 09/01/2020, and published on 03/18/2021), in view of Freyer et al. (the US Patent Application Publication US20160178618A1, filed on 12/17/2015, and published on 06/23/2016) as applied to claims 1 and 8 above, and further in view of Chapman et al. (US20170188571A1, filed on 01/06/2017, and published on 07/06/2017).
Regarding claims 1 and 8, the teachings of Clavien et al. and Freyer et al. are set forth in detail above.
Regarding claims 2 and 9: Following discussion of claim 1 above, Clavien et al. teaches that the organ is liver (page 1, line 33 and page 13, lines 22-23).
However, Clavien et al. in view of Freyer et al. fails to teach that the output flow cell is fluidically coupled to a bile duct of the liver.
However, Chapman et al. teaches a normothermic extracorporeal organ perfusion system (paragraph 0006), the liver is an organ of dual circulation, the liver for perfusion may be connected to a dual input circuit. One input may be connected to the hepatic artery, and another input may be connected to the portal vein. A bile output unit connected to the bile duct may be included in the circuit (paragraph 0012), bile production was assessed every hour (paragraph 0124).
Therefore, it would have been prima facie obvious to one of the ordinary skills in the art before the effective filing date of the claimed invention to have modified the outlet of the flow cell in the system of Clavien et al. to have fluidically coupled it to a bile duct of the liver with a reasonable expectation of success. One would have been motivated to have done so in order to place an output flow cell in a position where the perfusate has perfused through the liver and is capable of being analyzed upon exiting of the liver as taught by Chapman et al.
Claim(s) 1, 5, 6, 8, 12, 13 is/are rejected under 35 U.S.C. 103 as being unpatentable over Clavien et al. (WO2021047947A1, filed 09/01/2020, and published on 03/18/2021), in view of Freyer et al. (the US Patent Application Publication US20160178618A1, filed on 12/17/2015, and published on 06/23/2016) as applied to claims 1 and 8 above, and further in view of Edelman et al. (the US Patent Application Publication US20160121023A1, filed on 10/29/2015, and published on 05/05/2016).
Regarding claims 1 and 8, the teachings of Clavien et al. and Freyer et al. are set forth in detail above.
Regarding claims 5, 6, 12, and 13: Following discussion of claims 1 and 8 above, Clavien et al. in view of Freyer et al. fails to teach that the system further comprises an imaging system optically coupled to the organ to obtain structural information from the organ.
However, Edelman et al. teaches an intravital multiphoton microscopy system optically coupled to the organ to obtain structural information from the organ (Analysis of vascularity in the interface between median liver lobe and autologous graft by angiography using intravital multiphoton microscopy (paragraph 0045).
Therefore, it would have been prima facie obvious to one of the ordinary skills in the art before the effective filing date of the claimed invention to have modified the system of Clavien et al. to further include an imaging system comprising intravital multiphoton microscopy optically coupled to the organ with a reasonable expectation of success. One would have been motivated to have done so as the multiphoton microscopy system is capable of assessing the structure of the organ, which is useful for monitoring the organ and determining its integrity.
Claim(s) 15-18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Clavien et al. (WO2021047947A1, filed 09/01/2020, and published on 03/18/2021), in view of Hu et al. CD13 promotes hepatocellular carcinogenesis and sorafenib resistance by activating HDAC5-LSD1-NF-κB oncogenic signaling. Clin Transl Med. 2020;10:e233 and Li et al. "NHERF-1 binds to Mrp2 and regulates hepatic Mrp2 expression and function". J Biol Chem. 2010 Jun 18;285(25):19299-307.
Regarding claim 15, the teachings of Clavien et al. are set forth in detail above.
Regarding claims 16-18, Clavien et al. teaches that the organ is liver (page 1, line 33 and page 13, lines 22-23).
However, Clavien et al. fails to teach that the first marker is a transporter molecule comprising MRP2 and the second marker comprises a molecule that localizes to the canalicular membrane comprising CD13.
However, Hu et al. teaches that CD13 is a new marker for liver cancer stem cells (CSCs) that contributes to sorafenib resistance in hepatocellular carcinoma (HCC) (Abstract).
Also, Li et al. teaches that in the liver, canalicular Mrp2 plays an important role in bile formation and detoxification by transporting a wide variety of organic anions, including divalent bile salt conjugates, bilirubin-glucuronides, and drug conjugates, into bile (page 19299, column 2, paragraph 1)
Therefore, it would have been prima facie obvious to one of the ordinary skills in the art before the effective filing date of the claimed invention to have modified the method for assessing a health of a tissue of Clavien et al. such that the first marker is MRP2 and measure its level in a first area in the liver and the second marker is CD13 and measure its level in a second area of the liver with a reasonable expectation of success. One would have been motivated to have done so since MRP2 is a transporter molecule that plays an important role in bile formation and detoxification as taught by Li et al. and CD13 is a marker for liver cancer stem cells as taught by Hu et al., which make them both great markers to be used in order to assess the health of the liver tissue.
Conclusion
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Hanan Isam Abuzeineh
/H.I.A./Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633
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