Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Detailed Action
2. This office action is in response to the filing with the office dated 08/22/2022.
Claim Rejections – 35 U.S.C. 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.
3. Claims 1-9, 11-17 are rejected under 35 U.S.C. 102 (a) (1) as being anticipated by Roy et al (US 2022/0009854 A1).
Regarding independent claim 1, Roy et al (US 2022/0009854 A1) teaches, A method for measuring interactions between a ligand and a protein (paragraph [0053]), the method comprising: hyperpolarizing a ligand in a solvent using para-hydrogen to form a first solution (method steps in paragraphs [0020]-[0026], [0077], [0079]); transferring the first solution to a detector (paragraph [0053]); mixing the first solution with a protein solution, the protein solution having one or more ligands of interest therein (paragraphs [0053], [0109], [0140]; and determining interactions of the hyperpolarized ligand with the one or more ligands of interest by observing a change in an NMR signal of the hyperpolarized ligand (paragraph [0109]), wherein the ligand includes one or more sites for hyperpolarization by parahydrogen, and one or more binding sites for interaction with the protein (paragraph [0109], [0155], [0163]).
Regarding dependent claim 2, Roy et al (US 2022/0009854 A1) teaches the method of claim 1.
Roy et al further teaches, wherein the ligand is hyperpolarized by signal amplification by reversible exchange (SABRE) to transfer nuclear spin polarization from para- hydrogen (paragraphs [0011], [0012]).
Regarding dependent claim 3, Roy et al (US 2022/0009854 A1) teaches the method of claim 2.
Roy et al further teaches, wherein the nuclear spin polarization is transferred from para-hydrogen to molecules of interest (paragraphs [0102], [0103]).
Regarding dependent claim 4, Roy et al (US 2022/0009854 A1) teaches the method of claim 1.
Roy et al further teaches, wherein determining interactions of the hyperpolarized ligand is performed in the absence of superconducting magnets (Figure 2, paragraphs [0151]-[0155], [0169]).
Regarding dependent claim 5, Roy et al (US 2022/0009854 A1) teaches the method of claim 1.
Roy et al further teaches, wherein determining interactions of the hyperpolarized ligand is performed in the absence of high field NMR (Figure 2, paragraphs [0151]-[0155], [0169]).
Regarding dependent claim 6, Roy et al (US 2022/0009854 A1) teaches the method of claim 1.
Roy et al further teaches, wherein hyperpolarization of the ligand in the solvent is performed in an organic solvent (paragraph [0044]).
Regarding dependent claim 7, Roy et al (US 2022/0009854 A1) teaches the method of claim 6.
Roy et al further teaches, wherein the hyperpolarization of the ligand further comprises using a hydrogenative catalyst for producing parahydrogen derived polarization (paragraph [0028]).
Regarding dependent claim 8, Roy et al (US 2022/0009854 A1) teaches the method of claim 6.
Roy et al further teaches, wherein the organic solvent further comprises one or more of methanol, ethanol, chloroform, dichloromethane, or any combination thereof (paragraph [0044]).
Regarding dependent claim 9, Roy et al (US 2022/0009854 A1) teaches the method of claim 1.
Roy et al further teaches, further comprising diluting the solvent to minimize a concentration of organic solvent therein (paragraphs [0077]-[0082]).
Regarding dependent claim 11, Roy et al (US 2022/0009854 A1) teaches the method of claim 1.
Roy et al further teaches, wherein transferring the first solution to the detector further comprises injecting the hyperpolarized molecule into an NMR spectrometer (paragraphs [0116]-[0118]).
Regarding dependent claim 12, Roy et al (US 2022/0009854 A1) teaches the method of claim 11.
Roy et al further teaches, wherein the injecting is automated (paragraphs [0116]-[0118]).
Regarding dependent claim 13, Roy et al (US 2022/0009854 A1) teaches the method of claim 1.
Roy et al further teaches, wherein observing a change in the NMR signal of the hyperpolarized ligand further comprises measuring a change in spin rate of the hydrogens in the ligand (Figure 2, paragraph [0169]).
Regarding independent claim 14, Roy et al (US 2022/0009854 A1) teaches, A method for creating a polarizable ligand for use in detecting the interaction of a protein with competitively binding ligands (paragraphs [0053], [0109], [0140], the method comprising: introducing a signal amplification by reversible exchange (SABRE) catalyst (paragraphs [0011], [0012]) or a reaction site for a hydrogenative polarization transfer catalyst to a first ligand in a solvent to produce hyperpolarization of the first ligand (paragraphs [0020]-[0026], [0077], [0079]); and mixing hyperpolarized first ligand with a protein solution having a second ligand admixed therein to form a solution (paragraphs [0053], [0109], [0140], such that a signal of the first ligand in the presence of the second ligand differs from a signal of the first ligand in the absence of the second ligand (paragraph [0109], [0155], [0163]).
Regarding dependent claim 15, Roy et al (US 2022/0009854 A1) teaches the method of claim 14.
Roy et al further teaches, wherein further comprising injecting the solution into an NMR spectrometer (paragraphs [0116]-[0118]).
Regarding dependent claim 16, Roy et al (US 2022/0009854 A1) teaches the method of claim 14.
Roy et al further teaches, further comprising adjusting a concentration of one or more of the second ligand, the polarization transfer catalyst, or an exchange rate in the catalyst-ligand complex (paragraphs [0088], [0093]).
Regarding dependent claim 17, Roy et al (US 2022/0009854 A1) teaches the method of claim 14.
Roy et al further teaches, wherein introducing the transfer catalyst further comprises bubbling a para-enriched hydrogen gas into the organic solvent (paragraph [0039]).
Regarding dependent claim 20, Roy et al (US 2022/0009854 A1) teaches the method of claim 14.
Roy et al further teaches, further comprising adjusting a concentration of the second ligand in the protein solution in response to expected binding affinities ([0016], [0017], [0020]-[0026]).
Claim Rejections – 35 U.S.C. 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.
4. Claims 10, 18 and 19 are rejected as being obvious over Roy et al (US 2022/0009854 A1).
Regarding dependent claim 10, Roy et al (US 2022/0009854 A1) teaches the method of claim 9.
Roy et al further teaches, wherein the solvent is diluted at a ratio approximately in a range of about 1:10 to about 1:100 ([0079] The ratio of solvent phases can be selected to: [0080] (i) maximise the degree of target hyperpolarisation; and/or [0081] (ii) maximise the speed of phase separation. [0082] When required an aqueous solvent mixture combination may be used to maximise the relaxation time of the hyperpolarised target molecule in the solution by: [0083] (i) employing D.sub.2O; [0084] (ii) employing a D.sub.2O/H.sub.2O mixture of suitable proportion e.g. 1:1; and/or [0085] (iii) adding a further co-solvent to an appropriate aqueous phase such as ethanol or d.sub.6-ethanol. [0086] When SABRE hyperpolarisation is used, a SABRE hyperpolarisation transfer catalyst (e.g. [Ir(Cl(COD)(IMes)] or a .sup.2H-labelled counterpart or one containing L or a catalyst optimised to work in the polar phase with the selected singlet state derived substrate).[0087] When a mixed solvent system is used a solvent phase-separation promoter e.g. NaCl or NaO.sub.2CCH.sub.3 or NaOH or NaHCO.sub.3 or Na.sub.2CO.sub.3 or ethanol, at a suitable concentration may be added to the system, please see paragarphs [0088]- and [0095] for further details).
Roy et al does not explicitly teach the solvent dilution ratio approximately in a range of about 1:10 to about 1:100.
It would have been obvious to one of the ordinary skill in the art at the time of the filing of the invention to have modified the teachings of Roy et al to arrive at the claimed range of dilution, "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
One of the ordinary skill in the art would have been motivated to make this modification to optimize the solvent concentration maximize the degree of target hyperpolarization, as taught by Roy et al (paragraph [0081]).
Regarding dependent claim 18, Roy et al (US 2022/0009854 A1) teaches the method of claim 17.
Roy et al further teaches, wherein the para-enriched hydrogen gas is delivered at a pressure of about 10 bar ([0018] It is also possible to use, temperature, the polarisation transfer-field, .sup.2H labelled versions of these co-ligands and the NHC's, alongside their concentrations and those of the precatalyst, and the para-H.sub.2 pressure, to improve the efficiency of the hyperpolarisation process.[0110] The use of L (e.g. DMSO, diethylsulfoxide, (etc.)) and their .sup.2H or .sup.13C labelled counterparts can be used to control the efficiency of hyperpolarisation transfer in the first step. This is a result of the metal complexes reactivity which can be optimised for specific solvent, cost, pressure of p-H.sub.2 and time of activation. [0152] the p-H.sub.2 pressure 3 bar used).
Roy et al does not explicitly teach the pressure of about 10 bar.
It would have been obvious to one of the ordinary skill in the art at the time of the filing of the invention to have modified the teachings of Roy et al to arrive at the claimed value of pressure, since it has been held that discovering an optimum value of a result effective variable involves only routine skill in the art. In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980).
One of the ordinary skill in the art would have been motivated to make this modification to optimize the para-H.sub.2 pressure to improve the efficiency of the hyperpolarisation process, as taught by Roy et al (paragraph [0018]).
Regarding dependent claim 19, Roy et al (US 2022/0009854 A1) teaches the method of claim 14.
Roy et al further teaches, wherein a concentration of the second ligand in the protein solution is approximately in a range of about 10 micromolars to about 500 micromolars ([0018] It is also possible to use, temperature, the polarisation transfer-field, .sup.2H labelled versions of these co-ligands and the NHC's, alongside their concentrations and those of the precatalyst, and the para-H.sub.2 pressure, to improve the efficiency of the hyperpolarisation process).
Roy et al does not explicitly teach the range of about 10 micromolars to about 500 micromolars.
It would have been obvious to one of the ordinary skill in the art at the time of the filing of the invention to have modified the teachings of Roy et al to arrive at the claimed range of concentration, "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
One of the ordinary skill in the art would have been motivated to make this modification to improve the efficiency of the hyperpolarisation process, as taught by Roy et al (paragraph [0081]).
Closest Prior art
5. The following relevant prior art of record is not cited in the office action.
Chekmenev et al (US 2020/0132788 A1) teaches, methods for nuclear spin polarization enhancement via signal amplification by reversible exchange at very low magnetic fields. The spin polarization is hyperpolarization of isotopically enriched heteronuclei by using a catalyst and parahydrogen to create a complex using iridium and applying magnetic fields in the microtesia range to transfer the spin order from parahydrogen to the complex.
Ducket (US 2021/0154333 A1) teaches, a method for preparation of an imaging medium via transfer from a hyperpolarised singlet state that is not parahydrogen, said method comprising the steps of: (i) preparing a system containing: parahydrogen; a magnetisation transfer complex, with a molecular symmetry that allows the creation of a singlet state between spin pairs within it, said complex including a reversibly bound small molecule transference substrate; applying a magnetic field such that hyperpolarisation is transferred into the transfer complex, including the reversibly bound small molecule transference substrate; (ii) introducing a recipient complex capable of binding the small molecule transference substrate, said recipient complex including a recipient substrate, such that the recipient complex and recipient substrate, including the bound transference substrate, is hyperpolarised.
Goodson (US 2020/0172493 A1) teaches, a cleavable agent for enhanced magnetic resonance generally corresponding to the formula Y-L-R, wherein Y represents a catalyst-binding moiety having at least one isotopically labeled heteroatom, L represents a cleavable bond, and R represents a hyperpolarized payload having at least one isotopically labeled carbon. Also disclosed herein is a method of cleaving the cleavable agent for enhanced magnetic resonance.
Goodson et al (US 2021/0252493 A1) teaches, a method that embodies a simple and effective route to remove homogeneous catalysts from solutions wherein NMR/MRI signal amplification by reversible exchange (SABRE) or parahydrogen-induced polarization (PHIP) is performed. A method for recovering a homogeneous SABRE/PHIP catalyst for reuse is also described.
Warren et al (US 2016/0169998 A1) teaches, methods for nuclear spin polarization enhancement via signal amplification by reversible exchange at very low magnetic fields.
Bowers et al (US 2020/0261606 A1) teaches, Methods of and systems for making a hyperpolarized fluid are provided, which include exposing a fluid and parahydrogen to a catalyst. The hyperpolarized fluid can be introduced to a subject. The hyperpolarized fluid can be included in methods of imaging a subject. Also provided are methods that use the hyperpolarized fluids for detecting protein ligand interactions and for enhancing the NMR signals of biopolymers having chemically exchangeable protons.
Tang et al (US 2013/0267036 A1) teaches, A method and system for providing an article of manufacture with increased longevity of hyperpolarized .sup.1H signals (and other species) for NMR spectroscopy and MRI. The method involves providing a material including a molecular species susceptible of NMR spectroscopy, by providing parahydrogen (and other appropriate species) to disperse within the material/solvent to establish increased longevity of the NMR signals. The material can be in a solution with a surfactant and catalysts added to enhance the persistence of parahydrogen (or other species) in the form of enhanced solubility, microbubbles or micelles and resultant hydrogenation (or other species) of the material.
Ducket et al (US 8154284 B2) teaches, An NMR method is presented having enhanced sensitivity on a compound comprising hyperpolarizable nuclei, in particular applying enhanced PHIP. Polarization is thereby transferred from a prepared fluid, which is enriched with symmetric molecules of a particular spin state (e.g. para-hydrogen enriched), directly to the hyperpolarizable nuclei of a compound, without altering the chemical identity of the compound in this process. Spin transfer is achieved using a template having sites of ordered environment, and the fluid and the compound are brought together in the presence of the template. Polarization transfer to the hyperpolarizable nuclei of the compound is thereby easier to perform and can be applied to a broader scope of compounds.
Conclusion
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/SURESH K RAJAPUTRA/Examiner, Art Unit 2858
/EMAN A ALKAFAWI/Supervisory Patent Examiner, Art Unit 2858 6/3/2025