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 .
Response to Amendment
The amendment filed on 01/20/2026 has been entered. Claims 1-2, 9-10 and 15-16 have been amended. Claims 1-20 remain pending.
Response to Arguments
On Pages 7-10 of Remarks, with regard to amended Claims 9, 15 and 1, Applicant argues that reference Kovtunov I (US 9702946 B1) or the combination of Kovtunov I and Waddell (US 20140034481 A1) does not disclose a “non-magnetic breathing-actuated valve” that can be “actuated by a breath-hold from a subject”, and does not disclose a “non-magnetic mouthpiece”.
For the limitation of “non-magnetic valve”, Kovtunov I discloses a valve. Please see the cited Fig. 1C below. The arrow-pointed symbol is annotated as “valve” in the figure (see the dashed-line box). Further, as discussed in previous office action, Waddell teaches a non-magnetic valve (Waddell, Para 0035, the valve assembly 20).
Fig. 1C of Kovtunov I
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For the limitation of “non-magnetic mouthpiece”, Examiner identifies the following disclosures in the specification of Application: “the mouthpiece 114 may be placed in the mouth of the subject 118” (Para 0018), “the mouthpiece 210 or some other component that allows HP gas 220 to leave the system” (Para 0030), “the mouthpiece can be placed in a subject’s mouth” (Para 0041), and “the mouthpiece or some other type of exit for the HP gas” (Para 0046). Based on these disclosures, the claimed “mouthpiece” can be interpreted as some apparatus (e.g. tube as one simple example) for HP gas to exit the system and enter either a living subject (animal or human) or any container for phantom scans. To one of ordinary skill in the art of magnetic resonance imaging and spectroscopy, such mouthpiece is well known as being widely used in experiments such as brain MRI scan stimulated by CO2 inhalation, inhalation anesthesia (with mixture of O2 and isoflurane) for pre-clinical scans, and lung MRI enhanced with hyper-polarized gas. Kovtunov I focuses on inhalable MRI contrast agents, and discloses a “Teflon tubing” (Column 12), which is non-magnetic and can be used to transfer gas from the system to either subject or phantom. Examiner agrees that the “NMR” system in Fig. 4a of Kovtunov I is of course not a mouthpiece, but whether the gas is delivered to a phantom inside an NMR system (as in Fig. 4a) or an MRI scanner (Fig. 1C), some apparatus (such as the Teflon tubing discussed above) is inherently needed to allow the gas to enter the region of interest.
For the limitation of breathing-actuated valve that is actuated by a breath-hold from a subject, the argument is moot in view of the new grounds of rejection which relies on McKinnon et al (US 8936023 B2) to disclose the limitation in the claims.
On Pages 11-12 of Remarks, with regard to Claims 2-8, 11-12, 16-18 and 20, Applicant argues that, besides the issues of “non-magnetic breathing-actuated valve” and “non-magnetic mouthpiece”, Fig. 4a of Kovtunov I shows an NMR system, which is not a mouthpiece, and the reference does not explicitly state that the figure contains a valve. All these arguments have been discussed above.
Claim Objections
Claims 1 and 6 are objected to because of the following informalities:
Claim 1, Line 3, “a non-magnetic configured to” should be changed to “a non-magnetic container configured to”.
Claim 6, Line 1, “non-metallic reactor” should be changed to “the non-magnetic reactor”.
Appropriate correction is required.
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.
Claims 1-4, 6, 8-11, 13-17 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Kovtunov et al (US 9702946 B1; hereafter Kovtunov), in view of Waddell (US 20140034481 A1; hereafter Waddell) and McKinnon et al (US 8936023 B2; hereafter McKinnon).
With regard to Claim 1, Kovtunov discloses a magnetic resonance (MR) contrast agent system (Kovtunov, Fig. 1C discloses a system for making contrast agent for MRI imaging. Details are in Kovtunov, Column 12, Para 2-3.) comprising:
a non-magnetic (“a custom mixing chamber … polysulfone”. The material of “polysulfone” is non-magnetic) configured to house a propylene-parahydrogen gas mixture therein (Kovtunov, Column 12, Lines 16-25; “… para-state parahydrogen gas … Propene … Gases were mixed … in a custom mixing chamber, which represented a previously described (23, 24) high-pressure ~60 mL polysulfone reactor ...”);
a valve couplable to the non-magnetic container (Kovtunov, Fig. 1C shows a volve between the mixing chamber and the reactor);
a non-magnetic reactor couplable to the valve (Kovtunov, Column 12, Lines 33-36; “Approximately 50 mg of this catalyst was packed inside an 1/8 in. OD copper tubing representing variable-temperature (VT) reaction chamber.” The material of “copper” is non-magnetic), wherein the nonmagnetic reactor is configured to convert the propylene-parahydrogen gas mixture to a hyperpolarized gas as the propylene-parahydrogen gas mixture passes through the non-magnetic reactor via the valve (Kovtunov, Column 13, Lines 31-38; “… propene (PHIP precursor) was mixed with parahydrogen in 1:2 molar ratio (40 psi propene and 80 psi parahydrogen) to yield a mixture of hyperpolarized propane … after passing it through over a solid supported metal nanoparticles (used as a catalyst for molecular addition of parahydrogen) placed inside 1/8 in. copper tubing heated to ~100°C.”; as shown in Fig. 1C, the gas enters the reactor via a valve); and
a non-magnetic mouthpiece couplable to the non-magnetic reactor (Kovtunov, Column 12, Lines 37-40; “The hydrogenation reaction was performed in a temperature controlled reaction chamber …, and the resulting gas was transferred … via 1/16 in. OD ( 1/32 in. ID) Teflon tubing …”), wherein the non-magnetic mouthpiece is configured to allow passage of the hyperpolarized gas into a subject (Kovtunov, Column 12, Lines 41-43; “HP gas was delivered to the bottom of a standard 5 mm NMR tube via 1/16 in. OD Teflon flexible tubing.” Here the Teflon tubing can be used as a mouthpiece for potential animal or human experiment, and is non-magnetic), and wherein when actuated, the valve is configured to allow passage of the parahydrogen-propylene gas mixture through the non-magnetic reactor (Kovtunov, Fig. 1C shows that the valve on the left side of the reactor would allow passage of gas to enter the reactor).
Kovtunov does not clearly and explicitly disclose
the valve being non-magnetic;
the valve being a breathing-actuated valve that is actuated by a breath-hold from a subject; and
wherein the MR contrast agent system is configured to be usable within a magnetic resonance imaging (MRI) system as the MRI system is scanning.
Waddell in the same field of endeavor discloses a valve being non-magnetic (Waddell, Para 0035; “the components of the valve assembly 20 may be made entirely of non-magnetic materials …”); and
wherein the MR contrast agent system is configured to be usable within a magnetic resonance imaging (MRI) system as the MRI system is scanning (Waddell, Para 0035; “the components of the valve assembly 20 may be made entirely of non-magnetic materials, so that the valve assembly 20 may be safely positioned within the static (B0) and/or applied (B1) magnetic field(s).” As suggested by the disclosures, with all the components being made of non-magnetic materials, the system would be usable within magnetic field B0 and B1 (in other words, within an MRI system as it is scanning)).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Kovtunov, as suggested by Waddell, in order to use a non-magnetic valve and to make the system usable within an MRI system as the MRI is scanning. One of ordinary skill in the art would have been motivated to make the modification of using non-magnetic valve for the benefit of rapid delivery of hyperpolarized contrast agent into MRI scanner, therefore stronger strength of generated signals, by allowing the polarization apparatus to locate close to MRI scanner (Waddell, Para 0039; “Valve assemblies 20 formed of nonmagnetic materials, which would permit users to position the valve assembly within a magnetic field to reduce dead-volume”), and making the system usable within MRI system for the benefit of maximally enhancing MRI signals using hyperpolarized contrast agent made on-site, with unnecessary T1 relaxation in the process of transportation (Waddell, Para 0057; “hyperpolarized contrast agents can be produced in close proximity to their biological targets, which may result in decreased transfer times from contrast agent production to infusion”).
Kovtunov and Waddell do not clearly and explicitly disclose the valve being a breathing-actuated valve that is actuated by a breath-hold from a subject.
McKinnon in the same field of endeavor discloses a valve being a breathing-actuated valve (a pulmonary drug delivery system 30 as shown in Figs. 9-10, or more specifically the combination of main housing 32 and valve 50) that is actuated by a breath-hold from a subject (McKinnon, Column 10, Lines 7-9; “During exhalation and the dwell period, gas will be prevented from reaching the patient by the inlet check valve 50 and the reservoir 100 will fill …”. The disclosed “dwell period” is defined as “the time between inhalation and exhalation” (Column 1, Lines 53-54), i.e. breath-hold period). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Kovtunov and Waddell, as suggested by McKinnon, in order to use a valve that can be actuated by a breath-hold from a subject. One of ordinary skill in the art would have been motivated to make the modification for the benefit of improved flexibility of utilizing the subject’s respiration to control the delivery of a gas and thus improving accuracy of dosage and reducing waste.
With regard to Claim 2, Kovtunov, Waddell and McKinnon disclose all the limitations of Claim 1 as discussed above, including a non-magnetic valve. Kovtunov further discloses comprising a gas flow valve between the non-magnetic mouthpiece and the non-magnetic reactor (Kovtunov, Fig. 4a shows an experimental setup, wherein a gas valve is included between the reactor and MR system; for proper delivery of the produced gas into the MR system, some type of mouthpiece, e.g. Teflon tubing in Column 12, Lines 37-40, is intrinsically used (i.e. mouthpiece)).
Kovtunov, Waddell and McKinnon as discussed above do not clearly and explicitly disclose wherein the non-magnetic gas flow valve is configured to be actuated by a technician.
Waddell further discloses wherein the non-magnetic gas flow valve is configured to be actuated by a technician (Waddell, Para 0036; “… a controller may be used to selectively actuate and/or control one or more of the magnet 12, the RF Pulse generator 14, the reservoir 16, the reaction chamber 18 and the valve assembly 20. The controller may be manually or automatically operated …”; the disclosed manual operation of the controller is intrinsically by a technician who performs the experimental procedure). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Kovtunov, Waddell and McKinnon, as further suggested by Waddell, in order to include a manually operated valve. One of ordinary skill in the art would have been motivated to make the modification for the benefit of ensuring the safety of the subject by manually controlling the initiation and termination of contrast delivery.
With regard to Claim 3, Kovtunov, Waddell and McKinnon disclose all the limitations of Claim 1 as discussed above. Kovtunov further discloses wherein the non-magnetic reactor comprises a parahydrogen-Induced Polarization (PHIP) catalyst (Kovtunov, Column 12, Lines 20-22; “Supported metal nanoparticles (e.g., Rh on TiO2) were used as a catalyst for molecular addition of parahydrogen to propene”.).
With regard to Claim 4, Kovtunov, Waddell and McKinnon disclose all the limitations of Claim 3 as discussed above. Kovtunov further discloses wherein the PHIP catalyst comprises Rh/TiO2, and wherein the hyperpolarized gas is a hyperpolarized propane gas (Kovtunov, Column 12, Lines 20-22; “Supported metal nanoparticles (e.g., Rh on TiO2) were used as a catalyst for molecular addition of parahydrogen to propene”; Lines 31-32; “the resulting gas mixture consists of propane-d6:parahydrogen in ~1:1 ratio”.).
With regard to Claim 6, Kovtunov, Waddell and McKinnon disclose all the limitations of Claim 3 as discussed above. Kovtunov further discloses wherein non-metallic reactor comprises copper (as pointed out in Objection, the claimed “non-metallic reactor” should be changed to “the non-magnetic reactor”. Kovtunov, Column 12, Lines 33-36; “Approximately 50 mg of this catalyst was packed inside an 1/8 in. OD copper tubing representing variable-temperature (VT) reaction chamber.”).
With regard to Claim 8, Kovtunov, Waddell and McKinnon disclose all the limitations of Claim 1 as discussed above. Kovtunov further discloses wherein the propylene-parahydrogen gas is free of paramagnetic impurities (Kovtunov, Column 19, Lines 44-45; “mixing parahydrogen gas with an unsaturated precursor in an absence of paramagnetic gases and impurities”).
With regard to Claim 9, Kovtunov discloses a method of administering a magnetic resonance imaging (MRI) contrast agent (Kovtunov, Fig. 1C demonstrates a method of administering an MRI contrast agent) comprising:
coupling a non-magnetic reactor (Kovtunov, Column 12, Lines 33-36; “Approximately 50 mg of this catalyst was packed inside an 1/8 in. OD copper tubing representing variable-temperature (VT) reaction chamber.” The material of “copper” is non-magnetic) to a valve (Kovtunov, Fig. 1C shows that a valve (denoted as [Wingdings 2 font/0x55]) is disposed between the reactor and the mixing chamber) coupled to a non-magnetic container, wherein the nonmagnetic container has a parahydrogen-propylene gas mixture therein (Kovtunov, Column 12, Lines 16-25; “… para-state parahydrogen gas … Propene … Gases were mixed … in a custom mixing chamber, which represented a previously described (23, 24) high-pressure ~60 mL polysulfone reactor ...”. The material of “polysulfone” is non-magnetic);
coupling the non-magnetic reactor to a non-magnetic mouthpiece (Kovtunov, Column 12, Lines 37-40; “The hydrogenation reaction was performed in a temperature controlled reaction chamber …, and the resulting gas was transferred … via 1/16 in. OD ( 1/32 in. ID) Teflon tubing …”. The material of Teflon is non-magnetic. The Teflon tubing acts as a mouthpiece for delivering the gas into MR system);
passing the parahydrogen-propylene gas mixture through the non-magnetic reactor such that parahydrogen pairwise addition to propylene occurs to produce a hyperpolarized gas (Kovtunov, Column 13, Lines 31-38; “… propene (PHIP precursor) was mixed with parahydrogen in 1:2 molar ratio (40 psi propene and 80 psi parahydrogen) to yield a mixture of hyperpolarized propane … after passing it through over a solid supported metal nanoparticles (used as a catalyst for molecular addition of parahydrogen) placed inside 1/8 in. copper tubing heated to ~100°C.”); and
directing the hyperpolarized gas that exits the non-magnetic reactor to a mouthpiece coupled to a subject that is inside an MRI scanner (Kovtunov, Column 12, Lines 41-43; “HP gas was delivered to the bottom of a standard 5 mm NMR tube via 1/16 in. OD Teflon flexible tubing.”. To one of ordinary skill in the art, the phantom scans in the reference aim to simulate experiment with living subjects such as animal or human) such that MRI scanning occurs while the hyperpolarized gas is within the subject (Kovtunov; Column 4, Lines 45-47; “Fig. 1 … Part (D) shows a 3D gradient echo (GRE) imaging of HP propane in continuous flow at 4.7 T”), wherein the valve can be opened to enable the passing of the parahydrogen-propylene gas mixture through the non-magnetic reactor (Kovtunov, Fig. 1C shows that opening of the valve would allow the passing of gas through the reactor).
Kovtunov does not clearly and explicitly disclose
the valve being non-magnetic; and
the valve being a breathing-actuated valve that is actuated by a breath-hold from a subject.
Waddell in the same field of endeavor discloses a valve being non-magnetic (Waddell, Para 0035; “the components of the valve assembly 20 may be made entirely of non-magnetic materials …”).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Kovtunov, as suggested by Waddell, in order to use a non-magnetic valve. One of ordinary skill in the art would have been motivated to make the modification of rapid delivery of hyperpolarized contrast agent into MRI scanner, therefore stronger strength of generated signals, by allowing the polarization apparatus to locate close to MRI scanner (Waddell, Para 0039; “Valve assemblies 20 formed of nonmagnetic materials, which would permit users to position the valve assembly within a magnetic field to reduce dead-volume”).
Kovtunov and Waddell do not clearly and explicitly disclose the valve being a breathing-actuated valve that is actuated by a breath-hold from a subject.
McKinnon in the same field of endeavor discloses a valve being a breathing-actuated valve (a pulmonary drug delivery system 30 as shown in Figs. 9-10, or more specifically the combination of main housing 32 and valve 50) that is actuated by a breath-hold from a subject (McKinnon, Column 10, Lines 7-9; “During exhalation and the dwell period, gas will be prevented from reaching the patient by the inlet check valve 50 and the reservoir 100 will fill …”. The disclosed “dwell period” is defined as “the time between inhalation and exhalation” (Column 1, Lines 53-54), i.e. breath-hold period). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Kovtunov and Waddell, as suggested by McKinnon, in order to use a valve that can be actuated by a breath-hold from a subject. One of ordinary skill in the art would have been motivated to make the modification for the benefit of improved flexibility of utilizing the subject’s respiration to control the delivery of a gas and thus improving accuracy of dosage and reducing waste.
With regard to Claim 10, Kovtunov, Waddell and McKinnon disclose the method of Claim 9, including a non-magnetic valve and a valve that can be actuated by a breath-hold from a subject. Kovtunov further discloses wherein the non-magnetic gas flow valve is positioned between the non-magnetic reactor and the non-magnetic mouthpiece (Kovtunov, Fig. 4a shows an experimental setup, wherein a gas valve is included between the reactor and a MR system. Actuation of the gas valve would intrinsically allow passage of gas to be delivered into the MR system).
With regard to Claim 11, Kovtunov, Waddell and McKinnon disclose all the limitations of Claim 10 as discussed above. Kovtunov further discloses wherein the PHIP catalyst comprises Rh/TiO2 (Kovtunov, Column 12, Lines 20-22; “Supported metal nanoparticles (e.g., Rh on TiO2) were used as a catalyst for molecular addition of parahydrogen to propene”). Kovtunov, Waddell and McKinnon as discussed above do not explicitly and clearly disclose comprising placing the non-magnetic reactor and the non-magnetic container in the MRI scanner such that the MRI scanning occurs while the non-magnetic reactor and the non-magnetic container are in the MRI scanner.
Waddell further discloses comprising placing the non-magnetic reactor and the non-magnetic container in the MRI scanner such that the MRI scanning occurs while the non-magnetic reactor and the non-magnetic container are in the MRI scanner (Waddell, Para 0032; “The RF pulse generator 14 may be adapted to provide an applied magnetic field (B1) within an area 24 … may be any known or hereinafter devised RF pulse generator capable of producing applied magnetic fields suitable for use in nuclear magnetic resonance experiments, or in pre-clinical or clinical imaging systems … area 24 is only shown as being sufficient to encompass the reaction chamber 18, it should be appreciated that the applied magnetic field (B1) also may encompass some or all of a reactant reservoir 16 and/or a valve assembly 20”. As suggested by the disclosures, all the non-magnetic components can be encompassed in an MRI system with magnetic field B0 and B1 (note that magnetic field B1 is typically only on when MR scan occurs)). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Kovtunov, Waddell and McKinnon, as further suggested by Waddell, in order to place the non-magnetic reactor and the non-magnetic container in an MRI scanner. One of ordinary skill in the art would have been motivated to make the modification for the benefit of maximally enhancing MRI signals using hyperpolarized contrast agent made on-site, with unnecessary T1 relaxation in the process of transportation (Waddell, Para 0057; “hyperpolarized contrast agents can be produced in close proximity to their biological targets, which may result in decreased transfer times from contrast agent production to infusion”).
With regard to Claim 13, Kovtunov, Waddell and McKinnon disclose the method of Claim 10. Kovtunov further discloses wherein the parahydrogen-propylene gas mixture in the non-magnetic container is substantially free of air and molecular oxygen (Kovtunov, Column 19, Lines 44-45; “mixing parahydrogen gas with an unsaturated precursor in an absence of paramagnetic gases and impurities”; Column 20, Lines 21-22; “… wherein the paramagnetic gas is O2”. The disclosed gas mixture is free of O2, so inherently is free of air that contains O2).
With regard to Claim 14, Kovtunov, Waddell and McKinnon disclose the method of Claim 10. Kovtunov further discloses wherein the MRI scanner has proton-only detection capabilities (Kovtunov, Column 13 and 14; all the MR scanners listed here, e.g. 9.4T Bruker scanner and Varian 4.7 T preclinical scanner, when not being equipped with non-proton RF coils, provide proton-only detection capabilities).
With regard to Claim 15, Kovtunov discloses a method of manufacturing a magnetic resonance imaging (MRI) contrast agent system (Kovtunov, Fig. 1C demonstrates a method of setting up an MRI contrast agent system) comprising:
mixing parahydrogen gas with propylene gas to create a parahydrogen-propylene gas mixture (Kovtunov, Column 12, Lines 16-23; “… para-state parahydrogen gas … Propene … Gases were mixed … in a custom mixing chamber”);
filling a non-magnetic container with the parahydrogen-propylene gas mixture (Kovtunov, Column 12, Lines 22-25; “Gases were mixed … in a custom mixing chamber, which represented a previously described (23, 24) high-pressure ~60 mL polysulfone reactor ...”);
providing a valve for the MRI contrast agent system (Kovtunov, Fig. 1C shows a valve (denoted by symbol [Wingdings 2 font/0x55]) between the mixing chamber and the reactor); and
creating a non-magnetic reactor to convert the parahydrogen-propylene gas mixture to a hyperpolarized gas as the parahydrogen-propylene gas mixture passes through the non-magnetic reactor (Kovtunov, Column 12, Lines 33-36; “Approximately 50 mg of this catalyst was packed inside an 1/8 in. OD copper tubing representing variable-temperature (VT) reaction chamber.” Column 13, Lines 31-38; “… propene (PHIP precursor) was mixed with parahydrogen in 1:2 molar ratio (40 psi propene and 80 psi parahydrogen) to yield a mixture of hyperpolarized propane … after passing it through over a solid supported metal nanoparticles (used as a catalyst for molecular addition of parahydrogen) placed inside 1/8 in. copper tubing heated to ~100°C.”) from the valve (Kovtunov, Fig. 1C shows a valve in the upstream of the reactor), wherein the hyperpolarized gas is an MRI contrast agent that enhance images from an MRI scan (Kovtunov, Column 10, Lines 47-49; “The level of signal enhancement (ε~6000) enabled higher SNR in the images of HP propane compared to that of thermally polarized water, see FIG. 8”).
Kovtunov does not clearly and explicitly disclose
the valve being non-magnetic; and
the valve being a breathing-actuated valve that is actuated by a breath-hold from a subject.
Waddell in the same field of endeavor discloses a valve being non-magnetic (Waddell, Para 0035; “the components of the valve assembly 20 may be made entirely of non-magnetic materials …”).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Kovtunov, as suggested by Waddell, in order to use a non-magnetic valve. One of ordinary skill in the art would have been motivated to make the modification of rapid delivery of hyperpolarized contrast agent into MRI scanner, therefore stronger strength of generated signals, by allowing the polarization apparatus to locate close to MRI scanner (Waddell, Para 0039; “Valve assemblies 20 formed of nonmagnetic materials, which would permit users to position the valve assembly within a magnetic field to reduce dead-volume”).
Kovtunov and Waddell do not clearly and explicitly disclose the valve being a breathing-actuated valve that is actuated by a breath-hold from a subject.
McKinnon in the same field of endeavor discloses a valve being a breathing-actuated valve (a pulmonary drug delivery system 30 as shown in Figs. 9-10, or more specifically the combination of main housing 32 and valve 50) that is actuated by a breath-hold from a subject (McKinnon, Column 10, Lines 7-9; “During exhalation and the dwell period, gas will be prevented from reaching the patient by the inlet check valve 50 and the reservoir 100 will fill …”. The disclosed “dwell period” is defined as “the time between inhalation and exhalation” (Column 1, Lines 53-54), i.e. breath-hold period). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Kovtunov and Waddell, as suggested by McKinnon, in order to use a valve that can be actuated by a breath-hold from a subject. One of ordinary skill in the art would have been motivated to make the modification for the benefit of improved flexibility of utilizing the subject’s respiration to control the delivery of a gas and thus improving accuracy of dosage and reducing waste.
With regard to Claim 16, Kovtunov, Waddell and McKinnon disclose all the limitations of Claim 15 as discussed above, including a non-magnetic valve and a valve that can be actuated by a breath-hold from a subject. Kovtunov further discloses a gas flow valve couplable between the non-magnetic reactor and the non-magnetic mouthpiece (Kovtunov, Fig. 4a shows an experimental setup, wherein a gas valve is included between the reactor and a MR system).
With regard to Claim 17, Kovtunov, Waddell and McKinnon disclose all the limitations of Claim 16 as discussed above. Kovtunov further discloses wherein filling the non-magnetic container includes pressurizing the parahydrogen-propylene gas mixture inside the non-magnetic container to 50 bar or less (Kovtunov, Column 12, Lines 27-29; “… the chamber was then filled with parahydrogen gas with ~9.5 bar total pressure …”), and wherein the parahydrogen-propylene gas mixture is free of paramagnetic impurities (Kovtunov, Column 19, Lines 44-45; “mixing parahydrogen gas with an unsaturated precursor in an absence of paramagnetic gases and impurities”).
With regard to Claim 19, Kovtunov, Waddell and McKinnon disclose the method of Claim 15. Kovtunov further discloses wherein the non-magnetic reactor comprises rhodium (Rh) nanoparticles on titanium oxide (IV) support (Kovtunov, Column 12, Lines 20-22; “Supported metal nanoparticles (e.g., Rh on TiO2) were used as a catalyst for molecular addition of parahydrogen to propene”).
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Kovtunov, Waddell and McKinnon, further in view of Salnikov et al (Anal. Chem. 2019, 91, 4741 - 4746; hereafter Salnikov).
With regard to Claim 5, Kovtunov, Waddell and McKinnon disclose all the limitations of Claim 3 as discussed above, but do not clearly and explicitly disclose wherein the non-magnetic reactor further comprises non-magnetic metallic beads configured to dissipate heat as the propylene-parahydrogen gas mixture reacts with the PHIP catalyst.
Salnikov in the same field of endeavor discloses wherein the non-magnetic reactor further comprises non-magnetic metallic beads configured to dissipate heat as the propylene-parahydrogen gas mixture reacts with the PHIP catalyst (Salnikov, Page 4742, Para 4; “The second zone was filled with ~12 g of copper beads and a small quantity (60−280 mg) of 1 wt % Rh/TiO2 catalyst.”). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Kovtunov, Waddell and McKinnon, as suggested by Salnikov, in order to include non-magnetic metallic beads in the reactor. One of ordinary skill in the art would have been motivated to make the modification for the benefit of rapidly dissipating the heat generated in the process of hyperpolarization so that the generated contrast agent can be safely used for clinical MRI scans.
Claims 7 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Kovtunov, Waddell and McKinnon, further in view of Goldman et al (US 20060127313 A1; hereafter Goldman).
With regard to Claim 7, Kovtunov, Waddell and McKinnon disclose all the limitations of Claim 1 as discussed above, but do not clearly and explicitly disclose wherein the non-magnetic container is free of paramagnetic impurities.
Goldman in the same field of endeavor discloses wherein the non-magnetic container is free of paramagnetic impurities (Goldman, Para 0032; “The enriched hydrogen is transferred to and stored in gas cylinders made of inert material. Inert in this context should be understood as made up by material essentially free from paramagnetic materials (primarily iron) and other para-hydrogen relaxing compounds (e.g. palladium).”). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Kovtunov, Waddell and McKinnon, as suggested by Goldman, in order to use a container free of paramagnetic impurities. One of ordinary skill in the art would have been motivated to make the modification for the benefit of increased storage time by slowing down relaxation of parahydrogen.
With regard to Claim 12, Kovtunov, Waddell and McKinnon disclose all the limitations of Claim 10 as discussed above. Kovtunov further discloses wherein a magnetic field of the MRI scanner is in a range from 1 milli-Tesla to 10 Tesla (Kovtunov, Column 13 and 14 discloses multiple MRI scanners with magnetic field strength in a range between 0.0475 and 9.4 T). Kovtunov, Waddell and McKinnon as discussed above do not clearly and explicitly disclose wherein at least the non-magnetic container is substantially free of paramagnetic impurities.
Goldman in the same field of endeavor discloses wherein at least the non-magnetic container is substantially free of paramagnetic impurities (Goldman, Para 0032; “The enriched hydrogen is transferred to and stored in gas cylinders made of inert material. Inert in this context should be understood as made up by material essentially free from paramagnetic materials (primarily iron) and other para-hydrogen relaxing compounds (e.g. palladium).”). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Kovtunov, Waddell and McKinnon, as suggested by Goldman, in order to make the container to be free of paramagnetic impurities. One of ordinary skill in the art would have been motivated to make the modification for the benefit of increased storage time by slowing down relaxation of parahydrogen.
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Kovtunov, Waddell and McKinnon, further in view of Salnikov and Wagner (Magn Reson Mater Phy (2014) 27:195-199; hereafter Wagner).
With regard to Claim 18, Kovtunov, Waddell and McKinnon disclose all the limitations of Claim 15 as discussed above, but do not clearly and explicitly disclose wherein the non-magnetic container has a valve coupled thereto that is configured to allow gas flow in a range of 10 - 10,000 standard cubic centimeters per second, and wherein the parahydrogen-propylene gas mixture in the nonmagnetic container has a usable shelf-life of 365 days or less.
Salnikov in the same field of endeavor discloses wherein the non-magnetic container has a valve coupled thereto that is configured to allow gas flow in a range of 10 - 10,000 standard cubic centimeters per second (Salnikov, Page 4744, Para 3; “We demonstrate the utility of the batch-mode production approach of the HP propane gas for high-resolution MR imaging on the example of the HP propane production using the setup presented in Figure 1a at an average flow rate of ∼18 sLm …”. Here HP propane flow rate of 18 sLm, which is 300 standard cubic centimeters per second, falls within the gas flow of the container of 10-10000 sccs.). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Kovtunov, Waddell and McKinnon, as suggested by Salnikov, in order to have a valve that allows gas flow of the abovementioned range. One of ordinary skill in the art would have been motivated to make the modification for the benefit of improved signal to noise ratio in the generated images by administering adequate amount of contrast agent with high hyperpolarized state (Salnikov, Page 4742, Para 3; “we show that the clinically relevant quantity (∼0.3 standard liters)39−44 of HP propane gas can be produced in approximately 2 s, i.e., sufficiently fast to retain its hyperpolarized state.”).
Kovtunov, Waddell, McKinnon and Salnikov do not explicitly and clearly disclose wherein the parahydrogen-propylene gas mixture in the nonmagnetic container has a usable shelf-life of 365 days or less.
Wagner in the same field of endeavor discloses wherein the parahydrogen-propylene gas mixture in the nonmagnetic container has a usable shelf-life of 365 days or less (Wagner, Page 199, Conclusion; “Storage can be effective for weeks or months, provided storage is done in a paramagnetic free storage tank.” The disclosure discloses that when properly stored, parahydrogen can have usable shelf life of “weeks or months”. For a mixture of parahydrogen and propylene, propylene has shelf life of years when properly stored, and without catalyst, the two gases do not react, so the gas mixture can have usable shelf life of weeks or months.). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Kovtunov, Waddell, McKinnon and Salnikov, as suggested by Wagner, in order to have the gas mixture to have a usable shelf-life of 365 days or less. One of ordinary skill in the art would have been motivated to make the modification for the benefit of storing the gas mixture on site (such as hospitals) for immediate usage when needed.
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Kovtunov, Waddell and McKinnon, further in view of Kovtunov et al (Top Catal (2016) 59:1686-1699; hereafter Kovtunov 2).
With regard to Claim 20, Kovtunov, Waddell and McKinnon disclose all the limitations of Claim 15 as discussed above, but do not clearly and explicitly disclose wherein the non-magnetic reactor comprises rhodium (Rh) nanoparticles on aluminum oxide support.
Kovtunov 2 in the same field of endeavor discloses wherein the non-magnetic reactor comprises rhodium (Rh) nanoparticles on aluminum oxide support (Kovtunov-2, Page 1691, Para 5; “PHIP effects were successfully observed for different metals (Pt, Pd, Rh, Ir, Ru, Au, Ag) supported on a variety of metal oxides and other types of support (SiO2, ZrO2, Al2O3, TiO2, …”). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Kovtunov, Waddell and McKinnon, as suggested by Kovtunov 2, in order to use rhodium (Rh) nanoparticles on aluminum oxide support in the reactor. One of ordinary skill in the art would have been motivated to make the modification for the benefit of achieving PHIP-type hyperpolarization using a support based on more abundant aluminum.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/L.Z./ Examiner, Art Unit 3798
/PASCAL M BUI PHO/ Supervisory Patent Examiner, Art Unit 3798
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