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 .
Information Disclosure Statement
The information disclosure statements filed on February 16, 2024 and January 7, 2025 are acknowledged and have been considered by the examiner.
Drawings
The drawings are objected to for the following informalities:
Figures 1-3 are provided with inadequate resolution. In the depicted chemical structures, it is difficult to clearly discern the identities of several atoms depicted by letters and to understand the bonding between atoms.
Figure 4 also lacks adequate resolution. The words in the flowchart and the axes labels on the provided graph are difficult to clearly read.
Figure 7 provides a graph with four curves on it. Even considering the inset legend and numbered arrows, it is difficult to distinguish each curve from each other. The curves are very similar to each other in color and shape. Therefore, it is difficult to clearly interpret the drawing.
Appropriate correction is required.
Specification
The disclosure is objected to because of the following informality.
On page 22, the last paragraph states that the GB1T53C protein was obtained “by replacing the 53rd threonine residue of the B1 domain of protein G expressed from E. coli with cysteine.” However, the examiner notes that in the field of biochemistry, a T53C mutation would typically represent replacing the 53rd residue, which is threonine in the wild-type sequence, with cysteine; rather than replacement of the 53rd occurrence of threonine, which is the meaning of the current language. Considering the broader context provided, the standard biochemical interpretation of T53C appears to be what is meant by the statement in the specification.
Appropriate correction is required.
Claim Interpretation
In claim 1, “for use in a DNP-NMR method” is interpreted to be a recitation of an intended use (MPEP § 2111.02(II)). As the preamble already requires the claimed composition of matter to be “a DNP-NMR polarizing agent,” this “for use” statement is considered to not further limit the scope of the structure of the composition. Art that reads on the structural limitations of this claim and is capable of this function will read on the claim.
In claim 3, the language “further modified” is interpreted to require that the charged group and the functional group capable of interacting/covalently binding with proteins, drugs, or organic molecules are different in identity from each other.
Claims 4, 7, and 8 require a protein to be bonded to the functional group capable of covalently binding to proteins, drugs, or organic molecules. It is understood that the act of forming a covalent bond changes the structure of functional groups. Therefore, it is interpreted that after covalently bonding a protein to the functional group, the functional group may change in identity from the form that is capable of covalently binding to a protein, drug, or organic molecule to its associated product in the reacted/bound state.
Claim Rejections - 35 USC § 112(b)
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 2, 6-7, 9, and 11-12 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 2, the phrase “a group derived from biotin” is unclear in scope. Biotin can be chemically modified in many ways that alter its structure and functions. It is not clear to what extent of modification the biotin compound may be modified while still qualifying as such a derivative. Therefore, the scope of this limitation, and therefore the claim, is considered indefinite. Furthermore, claims 7, 9, and 11 are rejected due to dependence on claim 2.
Claims 6, 11, and 12 are methods of use including the step of “binding a target protein to a functional group capable of covalently binding to proteins.” However, this limitation is unclear in scope. It is not clear whether the functional group belongs to the DNP-NMR polarizing agent or if the functional group may be any functional group on any molecule. Therefore, these claims are rendered indefinite. For the purpose of examination, the examiner will interpret these claims to be referring to the functional group capable of covalently binding to proteins present on the DNP-NMR polarizing agent compositions in the claims from which these depend.
Claims 6, 11, and 12 are methods of using the DNP-NMR polarizing agents according to claims 1, 2, and 3, respectively. These methods require binding a target protein to a functional group. These claims further recite “thereby enhancing an NMR signal.” This limitation is not clear in meaning or scope. The property of being “enhanced” implies an enhancement relative to something else. However, the comparison for the claimed enhanced NMR signal to be produced by the recited method is not specified in the claim. Furthermore, the only provided structural step required by the claimed method is the binding of the protein to a functional group. It is not apparent how the action of binding a protein to a functional group results in an enhanced NMR signal in the absence of additional procedural steps being provided. It is not clear what additional steps need to be performed to achieve this intended result. For these reasons, the claims are considered indefinite. The examiner notes that in the art of DNP-NMR polarizing agents, enhanced NMR signal is generally used to describe the comparison on NMR signals acquired for a sample in the presence of a polarizing agent with and without additional microwave radiation being applied (see Voinov, (Voinov, M. A.; et al., J. Phys. Chem. B, 2015), Abstract Image), wherein an enhanced signal is observed in the presence of the microwaves. Such data provide evidence that the agent possesses the desired polarizing properties. For the purpose of compact prosecution, the examiner will interpret “enhancing an NMR signal” to relate to this property.
Claim Rejections - 35 USC § 102
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.
Claims 1-12 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zhang (Zhang, X. Q.; et al., Adv. Mater., 2011) as evidenced by Dutta (Dutta, P.; et al., J. Phys. Chem. Lett., 2014 – provided by applicant in IDS filed January 7, 2025).
Zhang teaches bifunctionalized nanodiamond particles (pg. 4771, Figure 1a). To prepare these nanodiamond particles, the nanodiamond particles were first functionalized with amines (Supporting Information pg. 1, Synthesis of ND-SPDP). Then, the surfaces was modified with sulfosuccinimidyl 6-(3’-[2-pyridyldithio]propionamido)hexanoate (sulfo-LC-SPDP) (pg. 4771, left column, last paragraph). Then, these particles were further modified with a thiolated antibody and a fluorescently labeled drug-oligonucleotide conjugate (pg. 4771, right column, second paragraph). The oligonucleotide was poly-dT, or poly-deoxythymidine (pg. 4771, right column, second paragraph).
Dutta characterizes the polarization and related properties of nanodiamond material (pg. 598, Figures 1 and 2; and pg. 599, Figure 3), including DNP-NMR signal (pg. 598, figure 2A). Dutta concludes that nanodiamond particles can be used as DNP-NMR hyperpolarizing agents (pg. 599, right column, third paragraph).
Regarding claim 1, Zhang teaches nanodiamond particles possessing a surface modified with a functional group capable of covalently binding to proteins (ND-SPDP) (pg. 4771, Figure 1a). As evidenced by Dutta, nanodiamond particles are DNP-NMR polarizing agents (pg. 599, right column, third paragraph).
Regarding claim 2, Zhang teaches nanodiamond particles wherein the functional group includes a group that reads on “-S-S-Py wherein Py represents a pyridine ring” (ND-SPDP) (pg. 4771, Figure 1a).
Regarding claim 3, Zhang teaches modifying the nanodiamond particles with a fluorescently labeled drug-oligonucleotide conjugate (pg. 4771, Figure 1a; and pg. 4771, right column, second paragraph). This drug-oligonucleotide conjugate is poly-deoxythymidine (pg. 4771, right column, second paragraph), which contains a backbone comprising phosphate groups, which are negatively charged. Therefore, the oligonucleotide conjugate is a charged group.
Regarding claim 4, Zhang teaches modifying the nanodiamond particles with an antibody (pg. 4771, Figure 1a; and pg. 4771, right column, second paragraph), which is a protein.
Regarding claim 5, Zhang teaches a method for producing a product that reads on that of claim 1 comprising modifying the nanodiamond particle modified to be amine functionalized (Supplemental Information pg. 1, Synthesis of ND-SPDP) with sulfo-LC-SPDP to generate ND-SPDP (pg. 4771, Figure 1a and left column last paragraph). The SPDP group is capable of covalently binding to proteins.
Regarding claim 6, as described above, Zhang, as evidenced by Dutta, anticipates the DNP-NMR polarizing agent of claim 1. Zhang teaches using the ND-SPDP particle (nanodiamond particle modified with a functional group that can covalently bind to proteins) to covalently modify thiol containing proteins (pg. 4771, right column, second paragraph and Figure 1a). The only required structural step of claim 6 is the binding of a target protein to a functional group capable of covalently binding to proteins. The aforementioned method of Zhang reads on this process. Additionally, insofar as the “thereby” statement is a necessary outcome of the binding process, it is met as nanodiamond particles are known to be DNP-NMR polarizing agents (Dutta, pg. 599, right column, third paragraph). In the interest of compact prosecution, the reference that meets the clearly stated process limitation is applied. Therefore, as Zhang teaches the limitation of binding a target protein to a functional group capable of covalently binding to proteins, they also teach the limitation “thereby enhancing an NMR signal” as recited in claim 6.
Regarding claim 7, Zhang teaches functionalizing the ND-SPDP nanodiamond particles (which read on claim 2, as described above) with a thiolated antibody (pg. 4771, Figure 1a; and pg. 4771, right column, second paragraph).
Regarding claim 8, Zhang teaches functionalizing the ND-SPDP nanodiamond particles with drug-oligonucleotide conjugate (which is a charged molecule) and a thiolated antibody (pg. 4771, Figure 1a; and pg. 4771, right column, second paragraph). Thus, the product contains a charged group and a functional group bonded to a protein.
Regarding claim 9, Zhang teaches a method for producing a product that reads on that of claim 2 comprising modifying the nanodiamond particle modified to be amine functionalized (Supplemental Information pg. 1, Synthesis of ND-SPDP) with sulfo-LC-SPDP to generate ND-SPDP (pg. 4771, Figure 1a and left column last paragraph). The SPDP group is capable of covalently binding to proteins and contains an -S-S-Py group.
Regarding claim 10, Zhang teaches a method for producing a product that reads on that of claim 3 comprising modifying the nanodiamond particle modified to be amine functionalized (Supplemental Information pg. 1, Synthesis of ND-SPDP) with sulfo-LC-SPDP to generate ND-SPDP (pg. 4771, Figure 1a and left column last paragraph). The SPDP group is capable of covalently binding to proteins. The nanodiamond particle is also modified with a drug-oligonucleotide conjugate (pg. 4771, Figure 1a and right column, second paragraph), which is a charged group.
Regarding claim 11, as described above, Zhang, as evidenced by Dutta, anticipates the DNP-NMR polarizing agent of claim 2. Zhang teaches using the ND-SPDP particle possessing an -S-S-Py group to covalently modify thiol containing proteins (pg. 4771, right column, second paragraph and Figure 1a). The only required structural step of claim 11 is the binding of a target protein to a functional group capable of covalently binding to proteins. The aforementioned method of Zhang reads on this process. Additionally, insofar as the “thereby” statement is a necessary outcome of the binding process, it is met as nanodiamond particles are known to be DNP-NMR polarizing agents (Dutta, pg. 599, right column, third paragraph). In the interest of compact prosecution, the reference that meets the clearly stated process limitation is applied. Therefore, as Zhang teaches the limitation of binding a target protein to a functional group capable of covalently binding to proteins, they also teach the limitation “thereby enhancing an NMR signal” as recited in claim 11.
Regarding claim 12, as described above, Zhang, as evidenced by Dutta, anticipates the DNP-NMR polarizing agent of claim 3. Zhang teaches using the ND-SPDP particle to covalently modify thiol containing proteins (pg. 4771, right column, second paragraph and Figure 1a). Zhang teaches that the protein binding can occur simultaneously with the attachment of the oligonucleotide (pg. 4771, right column, second paragraph). Thus, during the reaction, there will be charged group-modified nanodiamonds reacting with the protein. The only required structural step of claim 12 is the binding of a target protein to a functional group capable of covalently binding to proteins. The aforementioned method of Zhang reads on this process. Additionally, insofar as the “thereby” statement is a necessary outcome of the binding process, it is met as nanodiamond particles are known to be DNP-NMR polarizing agents (Dutta, pg. 599, right column, third paragraph). In the interest of compact prosecution, the reference that meets the clearly stated process limitation is applied. Therefore, as Zhang teaches the limitation of binding a target protein to a functional group capable of covalently binding to proteins, they also teach the limitation “thereby enhancing an NMR signal” as recited in claim 12.
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.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 6, 11, and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Voinov (Voinov, M. A.; et al., J. Phys. Chem. B, 2015) in view of by Zhang (Zhang, X. Q.; et al., Adv. Mater., 2011) as evidenced by Dutta (Dutta, P.; et al., J. Phys. Chem. Lett., 2014 – provided by applicant in IDS filed January 7, 2025).
En arguendo, for the purpose of compact prosecution, the examiner considers that the applicant may mean by the “thereby” clause in claims 6, 11, and 12 that the method of using the DNP-NMR polarizing agents of claims 1, 2, and 3, respectively, further requires (in addition to the protein binding step) the acquisition of NMR data in order to perform the act of acquiring the enhanced NMR signal (as achieving an enhanced signal requires acquiring data, since the signal itself can be considered the result of a property, not the property itself). Such a method is rendered obvious by the above cited art for the following reasons.
Voinov teaches using dynamic nuclear polarization NMR (DNP-NMR) to study the structure of a protein (pg. 10180, Abstract). More specifically, Voinov teaches covalently labeling N148C and S26C mutants of the Anabaena sensory rhodopsin (ASR) protein with a derivative of the TOTAPOL DNP-NMR polarizing agent (pg. 10182-10183, Labeling of ASR with Paramagnetic ToSMTSL and Diamagnetic MMTS and Reconstitution of ASR for DNP Experiments). This covalent bonding occurred specifically on a cysteine residue of the protein via a reaction between the TOTAPOL derivative (ToSMTSL) and a thiol group on the cysteine in the mutant proteins (pg. 10187, Conclusions, first paragraph). Voinov teaches that the ToSMTSL polarizing agent is a biradical (pg. 10182, Scheme 1) and notes that traces of reducing agents in a protein preparation could reduce one or both nitroxide radicals in the polarizing agent (pg. 10184, right column, last paragraph). Voinov teaches that the NMR signal intensity is enhanced with the incorporation of the ToSMTSL label in the protein (pg. 10182, Table 1; pg. 10188, Figure 7; and pg. 10187, Conclusions, second paragraph).
Voinov does not teach a method of covalently binding a DNP-NMR polarizing agent to a protein and enhancing an NMR signal using a nanodiamond particle polarizing agent.
As described above, Zhang teaches bifunctionalized nanodiamond particles (pg. 4771, Figure 1a). To prepare these nanodiamond particles, the nanodiamond particles were first functionalized with amines (Supporting Information pg. 1, Synthesis of ND-SPDP). Then, the surfaces was modified with sulfosuccinimidyl 6-(3’-[2-pyridyldithio]propionamido)hexanoate (sulfo-LC-SPDP) (pg. 4771, left column, last paragraph). Then, these particles were further modified with a thiolated antibody and a fluorescently labeled drug-oligonucleotide conjugate (pg. 4771, right column, second paragraph). The oligonucleotide was poly-dT, or poly-deoxythymidine (pg. 4771, right column, second paragraph), which is a charged molecule at least in part due to the phosphates in the oligonucleotide backbone.
As described above, Dutta characterizes the polarization and related properties of nanodiamond material (pg. 598, Figures 1 and 2; and pg. 599, Figure 3), including DNP-NMR signal (pg. 598, figure 2A). Dutta notes that nanodiamond polarization is achieved without exogenous radicals (pg. 598, right column, last paragraph, continued to first paragraph of next page). Dutta concludes that nanodiamond particles can be used as DNP-NMR hyperpolarizing agents (pg. 599, right column, third paragraph).
A person of ordinary skill in the art would have recognized that both Voinov and Zhang teach methods of covalently labeling a thiol-containing protein with a modified DNP-NMR polarizing agent. Voinov teaches the use of a derivative of the known DNP agent TOTAPOL. While Zhang does not explicitly teach the nanodiamond particles as DNP-NMR polarizing agents, as evidenced by Dutta, a person of ordinary skill in the art would recognize nanodiamond particles as possessing this property and utility. It would additionally be recognized that, as Voinov points out, the biradical ToSMTSL is sensitive to reducing agents. It is common in the field of protein biochemistry for reducing agents to be present in protein-containing solutions. For some proteins, it is even necessary for the reducing agent to be present in order to maintain the protein’s stability. It would be recognized that the nanodiamond particle of Zhang does not contain radicals (or at least does not require the presence of radicals to be a polarizing agent) and therefore does not possess the same lack of stability that could hinder its use in the study of certain proteins. As both DNP-NMR polarizing agents covalently modify thiol groups on proteins, the ND-SPDP (along with its drug-oligonucleotide modification) could be substituted into the method of protein labeling (use of the polarizing agent) taught by Voinov and predictably result in a similarly site-specific labeled protein with a nanodiamond particle (MPEP § 2143(I)(B)). It would be recognized that since both ToSMTSL and ND-SPDP are DNP-NMR polarizing agents, the ND-SPDP modified protein, upon NMR data acquisition, would produce an enhanced NMR signal (as was the case for the ToSMTSL-protein conjugate).
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the protein-labeling DNP-NMR method of Voinov with the SPDP-modified nanodiamond particle taught by Zhang as the polarizing agent (as evidenced by Dutta). This would result in the predictable result of an NMR-signal enhanced conjugate of a protein and a nanodiamond particle that does not require stable radicals.
Regarding claim 6, as described above, Zhang, as evidenced by Dutta, anticipates the DNP-NMR polarizing agent of claim 1. Zhang teaches using the ND-SPDP particle to covalently modify thiol containing proteins (pg. 4771, right column, second paragraph and Figure 1a). Furthermore, Voinov teaches site-specific labeling of thiol-containing cysteine residues with a DNP-NMR polarizing agent, forming a covalent bond (pg. 10182-10183, Labeling of ASR with Paramagnetic ToSMTSL and Diamagnetic MMTS and Reconstitution of ASR for DNP Experiments; and pg. 10187, Conclusions, first paragraph). Voinov teaches that the conjugation of the polarizing agent to the protein enhances NMR signal (pg. 10182, Table 1; pg. 10188, Figure 7; and pg. 10187, Conclusions, second paragraph). Therefore, the combined teachings of Voinov, Zhang, and Dutta render claim 6 obvious.
Regarding claim 11, as described above, Zhang, as evidenced by Dutta, anticipates the DNP-NMR polarizing agent of claim 2. Zhang teaches using the ND-SPDP particle possessing an -S-S-Py group to covalently modify thiol containing proteins (pg. 4771, right column, second paragraph and Figure 1a). Furthermore, Voinov teaches site-specific labeling of thiol-containing cysteine residues with a DNP-NMR polarizing agent, forming a covalent bond (pg. 10182-10183, Labeling of ASR with Paramagnetic ToSMTSL and Diamagnetic MMTS and Reconstitution of ASR for DNP Experiments; and pg. 10187, Conclusions, first paragraph). Voinov teaches that the conjugation of the polarizing agent to the protein enhances NMR signal (pg. 10182, Table 1; pg. 10188, Figure 7; and pg. 10187, Conclusions, second paragraph). Therefore, the combined teachings of Voinov, Zhang, and Dutta render claim 11 obvious.
Regarding claim 12, as described above, Zhang, as evidenced by Dutta, anticipates the DNP-NMR polarizing agent of claim 3. Zhang teaches using the ND-SPDP particle to covalently modify thiol containing proteins (pg. 4771, right column, second paragraph and Figure 1a). Zhang teaches that the protein binding can occur simultaneously with the attachment of the oligonucleotide (pg. 4771, right column, second paragraph). Thus, during the reaction, there will be charged group-modified nanodiamonds reacting with the protein. Furthermore, Voinov teaches site-specific labeling of thiol-containing cysteine residues with a DNP-NMR polarizing agent, forming a covalent bond (pg. 10182-10183, Labeling of ASR with Paramagnetic ToSMTSL and Diamagnetic MMTS and Reconstitution of ASR for DNP Experiments; and pg. 10187, Conclusions, first paragraph). Voinov teaches that the conjugation of the polarizing agent to the protein enhances NMR signal (pg. 10182, Table 1; pg. 10188, Figure 7; and pg. 10187, Conclusions, second paragraph). Therefore, the combined teachings of Voinov, Zhang, and Dutta render claim 12 obvious.
Conclusion
All claims are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Eric P Mosher whose telephone number is (571)272-3258. The examiner can normally be reached Monday-Friday 9am-5pm.
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/E.P.M./Examiner, Art Unit 1612
/SAHANA S KAUP/Supervisory Primary Examiner, Art Unit 1612
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