DETAILED ACTION
Preliminary Amendment filed on 03/29/2024 is acknowledged. Claims 1-17 are pending in the application and are considered on merits.
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 .
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, 8, 13, 15, and 16 are rejected under 35 U.S.C. §101 because the claimed invention is directed to a judicial exception without significantly more. The USPTO eligibility analysis first determines whether the claim recites a judicial exception, including a law of nature, natural phenomenon, or abstract idea, and then determines whether any additional elements integrate the exception into a practical application or amount to significantly more than the exception. (USPTO)
Regarding claim 1, the claim recites “[a] method to determine a homeostatic steady-state of a biological entity.” The homeostatic steady-state of a biological entity is a naturally occurring biological condition or state. The claim is therefore directed to the natural phenomenon of biological homeostasis and/or the abstract idea of determining information about such a natural biological state. The claim does not recite any specific measurement step, machine, transformation, treatment step, or other practical application that integrates the judicial exception into patent-eligible subject matter. Rather, the claim merely recites the desired result of determining the natural state.
Regarding claim 8, the claim recites “[a] method to quantify an exchange rate between at least two compartments in a biological system.” The exchange rate between compartments in a biological system, such as exchange across biological membranes or between biological compartments, is a naturally occurring biological property. The act of “quantify[ing]” the exchange rate also encompasses mathematical calculation or mental evaluation of the natural property. The claim does not recite how the exchange rate is measured or quantified, nor does it require a particular machine or practical application. Thus, the claim is directed to a natural phenomenon and/or abstract idea without additional elements that integrate the exception into a practical application.
Regarding claim 13, the claim recites “[a] Nuclear Magnetic Resonance (NMR) method to characterize physiological water transport.” Physiological water transport is a naturally occurring biological process. Although the claim recites “NMR,” the claim does not recite any particular NMR pulse sequence, signal acquisition step, data-processing technique, hardware configuration, treatment step, or transformation of matter. The mere recitation of NMR at this level of generality is no more than an instruction to observe or characterize the natural biological process using a generic measurement environment. Therefore, the claim does not integrate the judicial exception into a practical application.
Regarding claim 15, the claim recites “non-invasively measuring transmembrane exchange rates of endogenous water in a biological system under steady-state or non-steady-state conditions in near-real time.” Transmembrane exchange of endogenous water and its exchange rate are naturally occurring biological processes/properties. The claim broadly recites measuring that natural property, but does not recite a specific measurement technique, particular machine, particular signal acquisition protocol, or technological improvement. The recitations of “non-invasively,” “endogenous water,” “steady-state or non-steady-state,” and “near-real time” merely describe the natural subject matter and desired measurement result, and do not add significantly more than the judicial exception.
Regarding claim 16, the claim depends from claim 15 and further recites that the detected exchange rate is “an intrinsic metric or an absolute value” used as “a quantitative imaging biomarker to measure the physiological or pathological state of the biological system.” The physiological or pathological state of a biological system is a natural biological state, and the relationship between an exchange rate and such a state is a natural correlation. Using the detected exchange rate as a biomarker merely applies or interprets the natural correlation and does not add a specific practical application, treatment step, or technological improvement.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 8, 13, 15, 16, and 17 are rejected under 35 U.S.C. §112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor regards as the invention.
Regarding claim 1, the claim recites “[a] method to determine a homeostatic steady-state of a biological entity.” However, the claim does not recite any affirmative method step for performing the determination, any measurement technique, any data acquisition step, any analysis step, or any criteria for determining that a homeostatic steady-state has been determined. The claim merely recites an intended result or objective. Therefore, the metes and bounds of the claimed method are unclear.
Regarding claim 8, the claim recites “[a] method to quantify an exchange rate between at least two compartments in a biological system.” However, the claim does not identify what compartments are being used, what is being exchanged, how the exchange rate is measured or quantified, or what method steps are required to perform the quantification. Thus, the claim merely recites a desired result without distinctly claiming the method by which the result is achieved. Therefore, the metes and bounds of the claim are unclear.
Regarding claim 13, the claim recites “[a] Nuclear Magnetic Resonance (NMR) method to characterize physiological water transport.” However, the claim does not recite any NMR pulse sequence, signal acquisition step, processing step, measurement parameter, or characterization criterion. The phrase “characterize physiological water transport” is functional/result-oriented language that does not reasonably apprise one of ordinary skill in the art of the scope of the claimed method. Therefore, the claim is indefinite.
Regarding claim 15, the claim recites “non-invasively measuring transmembrane exchange rates of endogenous water in a biological system under steady-state or non-steady-state conditions in near-real time.” However, the claim does not recite how the transmembrane exchange rates are measured, what structure or technique performs the measurement, or what objective boundary defines “near-real time.” The term “near-real time” is relative and subjective because the claim and specification do not provide an objective standard for determining how close to real time a measurement must be to fall within the scope of the claim. Therefore, the scope of claim 15 is unclear.
Regarding claim 16, the claim recites that the exchange rate is “an intrinsic metric or an absolute value” used as “a quantitative imaging biomarker.” However, it is unclear what makes the detected exchange rate an “intrinsic metric,” what is meant by “absolute value” in this context, and how the claimed exchange rate must be used to qualify as a “quantitative imaging biomarker.” The claim does not provide objective boundaries for these terms, and therefore one of ordinary skill in the art would not be reasonably apprised of the scope of the claim.
Regarding claim 17, the claim recites “utilizing a existing MRI device or a existing NMR device to measure the physiological or pathological state in vivo.” The term “existing” is indefinite because it is unclear whether the device must have existed at the time of filing, at the time of infringement, at the time of examination, or at some other time. In addition, the phrase “the physiological or pathological state” lacks clear antecedent basis in claim 15, from which claim 17 depends. Therefore, the scope of claim 17 is unclear.
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.
Claim(s) 1-6, 8-9 and 14 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Williamson et al. (Journal of Magnetic Resonance, 2020, IDS) (Williamson).
Regarding claim 1, Williamson teaches a method to determine a homeostatic steady-state of a biological entity (page 1, par 2). Williamson teaches that “DEXSY-based exchange measurements in biological tissue are very powerful because they can measure permeability of lipid membranes to water without injecting a contrast agent,” (page 1, par 2), that “DEXSY is well-suited for studying cellular physiology because it can measure exchange of water when the sample is at steady state,” (page 1, par 2), and that “[r]eal-time measurements of the apparent exchange rate may provide observations of transmembrane water cycling associated with homeostasis.” (page 1, par 2). Therefore, Williamson’s DEXSY measurement of steady-state transmembrane water exchange in biological tissue corresponds to determining a homeostatic steady-state of a biological entity.
Regarding claim 2, Williamson teaches a method to determine a homeostatic steady-state of a biological entity, the method comprising a magnetic resonance (MR) system (page 1, par 2). Williamson teaches NMR measurements performed on biological tissue using an NMR MOUSE system and DEXSY-based apparent exchange-rate measurements (page 2, par 1). Williamson teaches that DEXSY measures exchange of water when the sample is at steady state and may provide observations of water cycling associated with homeostasis (page 1, par 2).
Williamson teaches
a. a means to create a static or pulsed magnetic field gradient (page 4, par 5);
b. a means to create a constant magnetic field (page 4, par 5).
Williamson teaches that “NMR measurements were performed using a PM-10 NMR MOUSE single-sided permanent magnet” and that “[t]he magnetic field decays rapidly and linearly with distance from the magnet, producing a strong static gradient in the magnetic field.” Williamson further teaches experiments performed at “B0 = 0.3239 T” and gradient “g = 15.3 T/m.” (page 4, par 5).
The permanent magnet/B0 corresponds to the constant magnetic field, and the strong static gradient corresponds to the static magnetic field gradient.
Williamson teaches
c. a means to hold a biological entity within the constant magnetic field and the static or pulsed magnetic field gradient (page 5, par 1).
Williamson teaches “a test chamber and a 13 × 2 mm solenoid radiofrequency (RF) coil and RF circuit” for use with the NMR MOUSE, and further teaches that the RF coil was selected to maximize the active region filled by a spinal cord sample (page 4, par 6). Williamson also teaches that, prior to an experiment, “a sample was threaded through the RF coil and a bath of aCSF.” (page 5, par 1). The test chamber/RF coil arrangement corresponds to the claimed means for holding the biological entity.
Williamson teaches
d. a radiofrequency transmitter (page 5, par 3);
e. a radiofrequency receiver that measures radiofrequency electromagnetic fields (page 5, par 3); and
f. a radiofrequency transmit amplifier (page 5, par 3).
Williamson teaches use of a “Kea 2 spectrometer,” a “solenoid radiofrequency (RF) coil and RF circuit,” and RF pulse operation using “90/180 pulse times = 2 µs and amplitudes = 22/16 dB.” Williamson further teaches CPMG acquisition blocks with “2000 echoes,” echo time, acquisition time, and dwell time (page 5, par 3).
The spectrometer/RF coil/RF circuit is interpreted as the RF transmitter, RF receiver, and RF transmit amplifier because the system transmits RF pulses and receives/acquires MR echo signals.
Williamson teaches
g. a MR radiofrequency pulse sequence generator that sends signals to the radiofrequency transmit amplifier to acquire Diffusion Exchange Spectroscopy (DEXSY) data (page 5, par 4).
Williamson teaches that “[t]he DEXSY pulse sequence is shown in Fig. 1 and was modified from a standard spin echo diffusion sequence,” and that “Four DEXSY data points were acquired at every tm.” (page 5, par 4).
The spectrometer executing the DEXSY pulse sequence corresponds to the claimed MR radiofrequency pulse sequence generator.
Williamson teaches
h. a recording device to sample and store a MR magnetization signal detected by the radiofrequency receiver (page 5, par 3).
Williamson teaches CPMG acquisition blocks using “2000 echoes,” “acquisition time,” and “dwell time,” and teaches collecting DEXSY signal/data points at mixing times (page 5, par 3).
The acquisition system of the spectrometer corresponds to the recording device because it samples and records MR echo/magnetization signals detected by the RF receiver.
Williamson teaches
i. a mathematical modeling framework to transform the recorded magnetization signal DEXSY data (page 3, par 6).
Williamson teaches that “[t]he exchange rate can be estimated by fitting a diffusion exchange model to signals acquired with variable mixing times.” (abstract) Williamson also teaches mathematical DEXSY signal models and explains that apparent exchange rate is estimated by fitting signal combinations as a function of mixing time (page 3, par 6). This corresponds to transforming recorded DEXSY magnetization-signal data using a mathematical modeling framework.
Williamson teaches
wherein interpretation of the DEXSY data provides a homeostatic steady-state of a biological entity (page 1, par 2).
Williamson teaches DEXSY measurements in biological tissue at steady state and states that real-time apparent exchange-rate measurements may provide observations of transmembrane water cycling associated with homeostasis (page 1, par 2).
Regarding claim 3, Williamson teaches placing a biological entity in the means to hold the biological entity (page 5, par 1). Williamson teaches that spinal cord samples were prepared and, prior to the experiment, “threaded through the RF coil and a bath of aCSF.” (page 5, par 1). The spinal cord sample corresponds to the biological entity, and threading the sample through the RF coil/test chamber corresponds to placing the biological entity in the means to hold the biological entity.
Regarding claim 4, Williamson teaches that wherein the MR system is a Nuclear Magnetic Resonance (NMR) system or a Magnetic Resonance Imaging (MRI) system (page 5, par 3)
Regarding claim 5, Williamson teaches that wherein the biological entity is a cell (page 5, par 1).
Regarding claim 6, Williamson teaches that wherein the biological entity is an organelle (page 5, par 1).
Regarding claim 8, Williamson teaches a method to quantify an exchange rate between at least two compartments in a biological system (page 1, par 2).
Regarding claim 9, Williamson teaches the claimed MR system for the same reasons discussed above regarding claim 2. Williamson teaches the NMR MOUSE permanent magnet/static gradient, B0 field, RF coil/test chamber for holding the spinal cord sample, RF coil/RF circuit/Kea 2 spectrometer, DEXSY pulse sequence, DEXSY data acquisition, and mathematical modeling/fitting of the DEXSY signals to estimate apparent exchange rate. Therefore, Williamson anticipates claim 9.
Regarding claim 14, Williamson teaches that wherein the method does not require exogenous contrast agents (page 1, par 2).
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 (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.
Claim(s) 7, 12 and 15-17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Williamson et al. (Journal of Magnetic Resonance, 2020, IDS) (Williamson) in view of Breen-Norris et al. (Magnetic Resonance in Medicine, 2020) (Norris).
Regarding claim 7, Williamson teaches the method of claim 3, as set forth above, but does not expressly perform the method on a living biological entity. However, Williamson teaches that its reduced acquisition method overcomes a barrier that limited use of DEXSY on “living specimen.” (abstract). Norris teaches in vivo DEXSY measurements in mouse tumor xenograft models and concludes that DEXSY can make in vivo measurements of diffusion exchange and cell membrane permeability (abstract). Therefore, it would have been obvious for the biological entity in Williamson to be living.
Regarding claim 12, Norris teaches that cell membrane permeability and water exchange can be modified in diseases and that cell-membrane disruption causes permeability changes during “apoptosis, oncosis, and necrosis.” (page 1543, par 1). Therefore, it would have been obvious that the homeostatic non-steady state is a pathological state.
Regarding claim 15, Williamson teaches measuring exchange rates of water across lipid membranes in biological tissue using DEXSY and teaches an 80-second reduced acquisition method for real-time exchange-rate measurement (page 10, par 6). Norris teaches measuring diffusion exchange “across the cell membrane” with DEXSY, including intracellular/extracellular exchange and in vivo DEXSY measurements (abstract). Therefore, the combination teaches or suggests non-invasively measuring transmembrane exchange rates of endogenous water in a biological system under steady-state or non-steady-state conditions in near-real time.
Regarding claim 16, Williamson teaches that the exchange rate is a measured quantitative value obtained by fitting a diffusion exchange model to DEXSY signals acquired at variable mixing times (page 3, par 6). Norris teaches that water-exchange measurements can provide biomarkers of disease progression and response to treatment (page 1543, par 1). Therefore, it would have been obvious to use the detected exchange rate as an intrinsic metric or absolute value and as a quantitative imaging biomarker to measure the physiological or pathological state of the biological system.
Regarding claim 17, Williamson teaches use of an existing NMR device, namely an NMR MOUSE single-sided permanent magnet system, to acquire DEXSY exchange-rate measurements in biological tissue (page 6, par 3). Norris teaches in vivo DEXSY measurements using a 9.4 T MRI scanner and a slice-selective DEXSY sequence (abstract). Therefore, it would have been obvious to utilize an existing MRI device or existing NMR device to measure the physiological or pathological state in vivo.
Claim(s) 10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Williamson et al. (Journal of Magnetic Resonance, 2020, IDS) (Williamson) in view of Schwartz et al. (NeuroReport 2005) (Schwartz).
Regarding claim 10, Williamson teaches the method of claim 8, as set forth above, but does not expressly state that the exchange rate is used to determine neuroprotectant efficacy. Schwartz teaches diffusion MRI detection of neuroprotection following treatment and estimation of the degree of neuroprotection (abstract). Therefore, it would have been obvious to use the exchange rate in Williamson, as modified by the teachings of Springer and Breen-Norris, to determine neuroprotectant efficacy.
Claim(s) 11 and 13 is/are rejected under 35 U.S.C. 103 as being unpatentable over Williamson et al. (Journal of Magnetic Resonance, 2020, IDS) (Williamson) in view of Springer (Journal of Magnetic Resonance, 2018, IDS).
Regarding claim 11, Williamson teaches that DEXSY measures exchange of water when the sample is at steady state and that real-time apparent exchange-rate measurements may provide observations of transmembrane water cycling associated with homeostasis (page 1, par 2). Springer teaches that active transmembrane water cycling is associated with “cellular homeostatic NKA activity in vivo” and includes steady-state water efflux and influx rate constants (abstract). Therefore, the exchange rate is used to determine a homeostatic steady-state and a homeostatic non-steady state of the biological entity.
Regarding claim 13, Williamson teaches an NMR method to characterize physiological water transport because Williamson teaches NMR/DEXSY measurement of water exchange across lipid membranes in biological tissue and teaches that such measurements may observe transmembrane water cycling associated with homeostasis (page 1, par 2). Springer teaches that ¹H₂O NMR can measure net and steady-state water molecule transport kinetics and teaches active transmembrane water cycling (abstract). Therefore, the combination teaches or suggests a Nuclear Magnetic Resonance method to characterize physiological water transport.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to XIAOYUN R XU, Ph. D. whose telephone number is (571)270-5560. The examiner can normally be reached M-F 8am-5pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lyle Alexander can be reached at 571-272-1254. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/XIAOYUN R XU, Ph.D./ Primary Examiner, Art Unit 1797
Prosecution Insights