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 .
Claim Objections
Claims 2-8, 10-18, and 20 are objected to because of the following informalities:
Regarding claim 20, lines 1-2 states “the mesoporous graphitized carbon in a packed into 10 mm or less”. Applicant may correct this to read “the mesoporous graphitized carbon is packed into 10 mm or less”.
Regarding claims 2-8, 10-18, and 20, line 1 does not include a comma after each statement of dependency. For example, claim 2 states “claim 1 further” which should read “claim 1, further”.
Appropriate correction is required.
Specification
The disclosure is objected to because of the following informalities:
The Abstract reads “A method, system, and apparatus for chromatography comprises a chromatographic system can include a column packed with mesoporous graphitized carbon (MGC).”. Applicant may correct this to read “A method, system, and apparatus for chromatography comprising a chromatographic system including a column packed with mesoporous graphitized carbon (MGC).”.
The Abstract reads “The MGC serves as an ideal stationary phase and facilitates the efficient isomeric separation of compounds such as permethylated glycans with unprecedented 10 mm long column.”. Applicant may correct this to read “The MGC serves as an ideal stationary phase and facilitates the efficient isomeric separation of compounds such as permethylated glycans when packed within an
Paragraph [0001] states “Provisional Patent Application Ser. No. 63/106,277 filed Sep. 27, 2020”. However, Provisional Patent Application Ser. No. 63/106,277 was filed Oct. 27, 2020. Applicant may correct this by changing “Sep. 27, 2020” to “Oct. 27, 2020”.
Paragraph [0002] reads “Gloycomic”. Applicant may correct this to read “Glycomic”.
Paragraph[ [0005] reads “monosaccharaide”. Applicant may correct this to read “monosaccharide.
Paragraph [0015] states “the mesoporous graphitized carbon in a packed into 10 mm or less of the pulled capillary nanospray emitter column.”. Applicant may correct this to read “the mesoporous graphitized carbon is packed into 10 mm or less of the pulled capillary nanospray emitter column.”.
Appropriate correction is required.
Drawings
The drawings are objected to because in Figs. 4, 6, 7A, 7B, 10, and 12, the annotations and reference characters appear blurry and are not clearly legible. Clear and legible drawings are required to ensure proper understanding and examination of the claimed invention. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
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 6, 17-18 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 6, the term “efficient isomeric separation” in claim 6 is a relative term which renders the claim indefinite. The term “efficient” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The specification repeatedly uses the term “efficient isomeric separation,” and provides examples (e.g., 10 mm packed length, <500 nm particle size, ~64 Å pore size, temperature of about 75°C, and figures showing separated peaks). However, the specification does not identify an objective, quantitative threshold for “efficient,” such as minimum resolution, analysis time, percent recovery, or reproducibility criteria. One of ordinary skill in the art is unable to determine what performance qualifies as “efficient” and what falls outside the claim’s scope.
Regarding claim 17, claim 17 depends from claim 16 and appears intended to be a narrower version of claim 16 by specifying the particular constituent elements that are subjected to isomeric separation. However, claim 17 recites that “the mobile phase comprises one of” the listed glycan compositions, which renders the scope of the claim unclear. In liquid chromatography, the term “mobile phase” is ordinarily understood to refer to the solvent system that is pumped through the column, such as aqueous and organic solvents with optional additives, and is not revealed in spectra as discrete peaks at specific retention times as shown in Figs. 6,7A,7B (See drawing objection above). The specification consistently describes the mobile phase in this conventional manner and separately describes permethylated glycans as samples or analytes. For example, paragraph [0072] and Fig. 8 of the instant specification states that “at step 830, permethylated glycan samples and the mobile phase can be driven through the column,” thereby expressly distinguishing permethylated glycan samples from the mobile phase and treating them as different entities.
Notwithstanding this distinction in the specification, claim 17 states that the mobile phase “comprises” the listed permethylated glycan compositions. This language reasonably suggests that the listed glycan compositions are components of the mobile phase itself. The specification does not describe preparing or using a mobile phase formulated with permethylated glycans as solvent components, nor does it explain that the claim language is intended to refer instead to analytes that are introduced into and carried by the mobile phase during separations. The question remains “Are the listed glycans analytes to be separated,” or “are they components of the mobile phase solvent”?
Because claim 17 may reasonably be interpreted either as requiring a mobile phase that includes the listed glycan compositions as part of its formulation, or merely specifying analytes separated using a conventional solvent-based mobile phase, one of ordinary skill in the art would not be informed with reasonable certainty as to the scope of the claim. Accordingly, claim 17 is indefinite. Applicant may correct claim 17 to read:
“The chromatography method of claim 16, wherein one of the constituent molecules
subjected to isomeric separation comprises one
of:HexNAc3Hex3DeoxyHexl;HexNAc4Hex5NeuAc2; HexNAc2Hex8; HexNAc4Hex3DeoxyHexl;HexNAc4Hex5NeuAc1; and HexNAc4Hex5DeoxyHexl NeuAc2.”
Claim 18 is rejected based upon dependency of rejected claim 17.
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 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 1-3, 5-6 are rejected under AIA 35 U.S.C. 102(a)(1) as being anticipated by Thermo Scientific (“Thermo Scientific Hypercarb Columns”; 2009).
Regarding claim 1, Thermo Scientific teaches a chromatography system (Hypercarb Nanobore Columns…Picofrit; p. 47) comprising:
a column (Picofrit; p. 47);
a stationary phase (Hypercarb; p. 47) comprising mesoporous graphitized carbon (“Porous graphitic carbon (PGC, Hypercarb) has unique properties as a stationary phase in high performance liquid chromatography (HPLC),” wherein the PGC is mesoporous due to median pore diameter of 250 Å which corresponds to 25 nm and falls within the defined range of 2-50nm for mesoporous classification; See “Table 1: Physical properties of PGC” on p. 4 and ll. 1-3; See p. 2236, 4.5 of supplementary reference, Slomkowski, for “mesoporous particle” definition); and
frit inserted in the column (The Picofrit® column by definition has a frit inserted in the column as explained on p. 8 of supplementary manufacturer reference New Objective)(See the frit within the Picofrit column in the figure below).
PNG
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820
1166
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Greyscale
Pico Frit, p. 6, New Objective
Regarding claim 2, Thermo Scientific teaches the chromatography system of claim 1 further comprising: a fused silica capillary (“PicoFrit 75 μm ID x 15 μm Tip,” wherein the Picofrit column by definition has a fused silica capillary; Thermo Scientific, p. 47, Hypercarb Nanobore Columns; See fused-silica tubing in the figure from p. 6 of New Objective above and capillary design as stated on p. 3, ll. 4-7).
Regarding claim 3, Thermo Scientific teaches the chromatography system of claim 1 wherein the column (PicoFrit 75 μm ID x 15 μm Tip; Thermo Scientific, p. 47, Hypercarb Nanobore Columns) comprises: a pulled capillary nanospray emitter column (Picofrit column…fritted nanospray emitter; New Objective, see p. 6 above)(The Picofrit® column by definition is a pulled capillary nanospray emitter column; See pulled configuration in the figure above and capillary design as stated on p. 3, ll. 4-7).
Regarding claim 5, Thermo Scientific teaches the chromatography system of claim 1 wherein the column further comprises: a packed length of 10 mm (Length (mm)… 10; See Hypercarb Nanobore Columns on p. 47 of Thermo Scientific)(One of ordinary skill in the art would understand the disclosed 10mm column length to refer to the stationary-phase bed length, consistent with standard liquid chromatography column nomenclature).
Regarding claim 6, Thermo Scientific teaches the chromatography system of claim 5 wherein the system is configured for efficient isomeric separation (Goal To demonstrate the separation of a complex pool of branched, isomeric and underivatised oligosaccharides utilizing porous graphitized carbon liquid chromatography coupled with mass spectrometric detection; p. 17, col. 1; Goal)(Paragraph [0061] of the instant specification defines “efficient” in that “Using MGC as the stationary phase…is therefore efficient for isomeric separation,” which Thermo Scientific satisfies through the use of Porous graphitic carbon (PGC, Hypercarb) in the mesopore size range as a stationary phase in high performance liquid chromatography (HPLC); See claim 1).
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.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Thermo Scientific (“Thermo Scientific Hypercarb Columns”; 2009) in view of Ichikawa et al. (US 5270280 A; 1993) and further in view of Shollenberger et al. (“Characterization of Polymer Carbon Sieves, Graphitized Polymer Carbons and Graphitized Carbon Blacks for Sample Preparation Applications”; 2010).
Regarding claim 4, Thermo Scientific teaches the chromatography system of claim 1.
Thermo Scientific fails to teach that the PGC has a size of less than 500 nm and a pore size of 64 Angstroms, but instead teaches PGC with a size of 5µm and a pore size of 250 Å (See Thermo Scientific “Table 1: Physical properties of PGC” on p. 4 for pore size and p. 47 Hypercarb Nanobore Picofrit column for particle size).
Thermo Scientific does, however, teach that graphitized carbon black (GCB) is a widely used carbon-based sorbent exhibiting high trapping efficiency for polar compounds (p. 27, col. 2, ll. 11-15) and is therefore suitable as a stationary-phase material for separations involving polar analytes. As taught below, GCB is manufactured in a size of less than 500 nm and a pore size around 64 Angstroms. However, Thermo Scientific only reveals that GCB is used as a solid phase extraction (SPE) sorbent and is silent to its functionality in liquid chromatography.
Ichikawa teaches that mesoporous (an average micropore diameter was 120 .ANG.; col. 8, ll. 64-65)(Despite the term “micropore” often used in older literature, 120 .ANG. corresponds to 12 nm which falls within the mesoporous particle range of 2-50nm) graphitized carbon black may be packed and used as a stationary phase in liquid chromatography columns (a packing material for liquid chromatography produced by mixing carbon black and graphitizing (carbonizing) components; col. 1, ll. 9-12). This confirms the operability of GCB as a chromatographic packing material to be used for the same purpose as Thermo Scientific and not only as a SPE sorbent.
Ichikawa is considered to be analogous to the claimed invention because it is in the same field of endeavor for column packing in liquid chromatography using MGC as a stationary phase. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the PGC stationary-phase packing taught by Thermo Scientific with the GCB stationary-phase packing taught by Ichikawa since PGC and GCB share the same fundamental graphitic carbon surface and swapping one for the other would predictably maintain the carbon-based retention behavior. This expectation of success is supported by Thermo Scientific’s teaching that:
“The most widely used carbon-based SPE sorbent is graphitized carbon black (GCB)…its potential for trapping polar compounds with a higher efficiency than C18 silica sorbent has been largely demonstrated. Porous Graphitic Carbon…has also been largely used for the extraction of polar pollutants.”(p. 27, col. 2, ll. 11-19).
Both references reinforce that substitution of GCB for PGC represents the use of a known alternative carbon-based material for achieving predictable analyte separation (See MPEP 2143(I)(B)).
Modified Thermo Scientific does not explicitly teach that the GCB has a size of less than 500 nm and a mesoporous pore size of 64 Angstroms.
Modified Thermo Scientific instead teaches GCB sized between 2 and 120 µm and a mesoporous pore size of 120 Å (Ichikawa, col. 8, ll. 60, 64-65).
Shollenberger teaches mesoporous graphitized carbon (Graphitized Carbon Blacks; Title) having a size of less than 500 nm (See Table 1, p.8 with GCB particle size of 0.3 µm which equates to 300nm and average pore diameter of 90.4 angstroms which falls within the mesoporous range of 20-500Å).
Shollenberger is considered to be analogous to the claimed invention because it is in the same field of endeavor for mesoporous graphitized carbon for use in compound separation. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the GCB stationary-phase column packing taught by Thermo Scientific in view of Ichikawa with Shollenberger’s GCB having a size of less than 500 nm since particle size is a result-effective variable in chromatographic stationary phases that is used to optimize separation performance. Increasing accessible surface area through particle size would have been expected to enhance retention efficiency for polar analytes while maintaining the known carbon-based retention mechanisms. This expectation of success is reinforced by Thermo Scientific’s teaching regarding GCB: “In spite of its low surface area (120 m2/g), its potential for trapping polar compounds with a higher efficiency than C18 silica sorbent has been largely demonstrated” (p. 27, col. 2, ll. 12-15). This would have motivated a person of ordinary skill in the art to increase surface area by employing mesoporous GCB with a smaller particle size to further improve performance. Doing so represents a simple substitution of one known carbon-based stationary phase for another, yielding the predictable result of improved analyte separation through routine optimization (See MPEP 2143(I)(B))(See MPEP 2144.05).
Modified Thermo Scientific does not teach a GCB pore size of 64 Angstroms. However, Shollenberger does teach a GCB pore size of 90.4 Å which can be routinely optimized based on the intended use of the column (See Table 1, p.8 with GCB average pore diameter). Pore diameter is reported and measured as a structural property of the GCB, and mesoporosity (2-50nm or 20-500Å) is recognized in the art as affecting adsorption and separation performance. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have selected a pore size within the mesoporous range, including 64 Å (64 nm), as a matter of routine optimization in order to adjust separation characteristics. Shollenberger explains that “[o]ptimization of the carbons for the specified applications was based on the changes observed with the physical characterization methods employed” and that “[t]he data obtained indicate that the carbons performed effectively for the respective applications.” Thus, Shollenberger recognizes that structural parameters of the GCB including pore diameter and particle size, are variables that may be adjusted to achieve desired separation performance. Selecting a specific pore size within a known mesoporous range constitutes optimization of a result-effective variable (See MPEP 2144.05).
Claims 7-8 are rejected under 35 U.S.C. 103 as being unpatentable over Thermo Scientific (“Thermo Scientific Hypercarb Columns”; 2009) in view of Koivisto et al. (“Development of Techniques and Methods for Drug Analysis by Packed Capillary Liquid Chromatography with Octadecylbonded Silica and Porous Graphitic Carbon Columns”; 2001).
Regarding claim 7, Thermo Scientific teaches the chromatography system of claim 1.
Thermo Scientific fails to teach the stationary phase is inserted into the column as a solvent-MGC suspension.
Thermo Scientific does not specify the process by which the MGC is packed within the column, but only describes the end product of a Hypercarb Nanopore Picofrit Column which is pre-packed with MGC.
Koivisto teaches a stationary phase is inserted into the column as a solvent-PGC suspension (See 2.3.1 Slurry packing procedure on p. 8, and Table II. with a Stationary Phase of PGC with corresponding Slurry Solvent on p. 9).
Koivisto is considered to be analogous to the claimed invention because it is in the same field of endeavor for liquid chromatography using porous graphitized carbon (PGC) stationary phases packed into capillary columns for high-performance separations. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the Hypercarb Nanobore Picofrit Column taught by Thermo Scientific by incorporating the teachings of Koivisto by mixing Thermo Scientific’s PGC with a solvent to create a slurry prior to packing the column. Koivisto expresses that “Most of the packing procedures for columns in LC are performed by using the slurry packing technique,” (p. 8, 2.3.1, ll. 1-2) and proceeds to list commonly used slurry solvents to achieve these stationary phase-solvent suspensions. One of ordinary skill in the art would have been motivated to use the conventional and well-known slurry packing technique to insert the PGC into the Picofrit column when creating the Hypercarb Nanobore Picofrit Column in order to achieve a uniform bed and predictable separation performance (See MPEP 2143(I)(A and C)).
Regarding claim 8, Modified Thermo Scientific teaches the chromatography system of claim 7 wherein the solvent suspension comprises:
Tetrahydrofuran (Commonly used slurry solvents are…THF; p. 8, 2.3.1, ll. 4-5); and
Modified Thermo Scientific is silent to teaching that the tetrahydrofuran is coupled with MGC to create the solvent-MGC suspension. Modified Thermo Scientific instead teaches the combination of PGC with acetonitrile (Table II. with a Stationary Phase of PGC with corresponding Slurry Solvent on p. 9) and acknowledges that multiple organic solvents are commonly used for slurry packing including THF. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted THF for acetonitrile to pair with Thermo Scientific’s PGC since the two solvents are known, interchangeable organic slurry solvents for packing hydrophobic carbonaceous stationary phases. Both solvents are compatible with liquid chromatography, capable of wetting and dispersing graphitized carbon particles, and routinely removed after packing (See MPEP 2143(I)(B)). Koivisto states that “choice of slurry solvent…must be optimised for each specific type of stationary phase,” and is therefore routine experimentation (See MPEP 2144.05(II)(A)).
Claims 9-10, 12-14, 16-17 are rejected under 35 U.S.C. 103 as being unpatentable over Zhou et al. (“Isomeric Separation of Permethylated Glycans by Porous Graphitic Carbon (PGC)-LC-MS/MS at High Temperatures”; 2017) in view of Koivisto et al. (“Development of Techniques and Methods for Drug Analysis by Packed Capillary Liquid Chromatography with Octadecylbonded Silica and Porous Graphitic Carbon Columns”; 2001).
Regarding claim 9, Zhou teaches a chromatography method comprising:
a stationary phase comprising mesoporous graphitized carbon (“All the separations were conducted on a HyperCarb PGC column (75 μm * 100 mm, 5 μm particle size, Thermo Scientific, Pittsburgh, PA,” wherein the PGC within the HypercCarb column is naturally mesoporous as evidenced by supplementary reference Thermo Scientific; p. 6591, col. 2, Instrument Method, ll. 3-5)(“Porous graphitic carbon (PGC, Hypercarb) has unique properties as a stationary phase in high performance liquid chromatography (HPLC),” wherein the PGC is mesoporous due to median pore diameter of 250 Å which corresponds to 25 nm and falls within the defined range of 2-50nm for mesoporous classification; See “Table 1: Physical properties of PGC” on p. 4 of Thermo Scientific; See p. 2236 of supplementary reference, Slomkowski, for “mesopore particle” definition),
introducing a mobile phase in the column (Zhou explains that Mobile phase A and B are set to flow rates and separate glycans within the column; p. 6591, col. 2, Instrument Method)
separating constituent elements in the mobile phase (elute highly sialylated glycans; p. 6591, col. 2, Instrument Method, ll. 15-16); and
identifying the constituent elements in the mobile phase (Fig. 1, p. 6592 shows “permethylated glycan structures…which were separated using a PGC column”)(The Examiner interprets
“constituent elements” to refer to constituent molecules, analytes or glycans. See 112(b) rejection above).
Zhou fails to teach packing the column with the stationary phase.
Zhou only describes the use of the end product, a Hypercarb Column which is pre-packed with PGC (p. 6591, col. 2, Instrument Method, ll. 3-5).
Koivisto teaches packing a column with a stationary phase (See “Figure 3. Schematic of a slurry packing system” showing the column to be packed with stationary phases including PGC as listed in Table II. on pages 8-9).
Koivisto is considered to be analogous to the claimed invention because it is in the same field of endeavor of liquid chromatography using a porous (PGC) stationary phase packed into a capillary columns for high-performance separations. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the chromatography method taught by Zhou by applying the slurry packing method taught by Koivisto in order to arrive at a usable separation product for constituent separation in a sample. Although Zhou utilizes a commercially available prepacked porous PGC column, Zhou does not attribute any technical significance to the procurement of a prepacked column. One of ordinary skill in the art would recognize that the reported separations naturally rely on a packed stationary phase bed and that such columns are formed by packing particulate PGC material. Koivisto teaches established slurry-packing techniques for packing porous graphitic carbon into columns (p. 8, l. 1). Accordingly, a person of ordinary skill in the art would have been motivated to apply Koivisto’s packing method when forming the PGC column used in Zhou, as this represents a routine application of a known packing technique to a known stationary phase to achieve predictable chromatographic performance (See MPEP 2143(I)(A)).
Regarding claim 10, Modified Zhou teaches the chromatography method of claim 9, wherein the column comprises one of:
a fused silica capillary (NanoLC capillary columns having 75µm ID as taught by Zhou are conventionally formed of fused silica tubing, as stainless steel tubing is not manufactured at such internal diameters for LC use. Therefore, the disclosed capillary column is necessarily a fused silica capillary; see Zhou, p. 6591, col. 2, Instrument Method, ll. 3-5); and
a pulled capillary nanospray emitter column.
Regarding claim 12, Modified Zhou teaches the chromatography method of claim 9 wherein packing the column with a stationary phase further comprises: inserting a frit in the column (The frit is secured by butt connecting an empty fused silica capillary of an i.d. smaller than the column; Koivisto, p. 6, para. 3, ll. 6-7; Fig. 1).
Regarding claim 13, Modified Zhou teaches the chromatography method of claim 9 wherein the packing the column with a stationary phase further comprises:
selecting a solvent (The packing material is suspended in a solvent; Koivisto, See Table II, p. 9 for solvent chosen for the PGC stationary phase; p.8, l. 3); and
creating a suspension of the solvent and mesoporous graphitized carbon (The packing material is suspended in a solvent to get a slurry; Koivisto, p. 8, ll. 3-4).
Regarding claim 14, Modified Zhou teaches the chromatography system of claim 13 wherein the solvent suspension comprises:
Tetrahydrofuran (Commonly used slurry solvents are…THF; Koivisto, p. 8, 2.3.1, ll. 4-5).
Modified Zhou is silent to teaching that the tetrahydrofuran is coupled with MGC to create the solvent-MGC suspension. Modified Zhou instead teaches the combination of PGC with acetonitrile (Table II. with a Stationary Phase of PGC with corresponding Slurry Solvent on p. 9 of Koivisto) and acknowledges that multiple organic solvents are commonly used for slurry packing including THF (p. 8, ll. 4-5). It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted THF for acetonitrile to pair with Zhou’s PGC since the two solvents are known, interchangeable organic slurry solvents for packing hydrophobic carbonaceous stationary phases. Both solvents are compatible with liquid chromatography, capable of wetting and dispersing graphitized carbon particles, and routinely removed after packing (See MPEP 2143(I)(B)). Koivisto states that “choice of slurry solvent…must be optimised for each specific type of stationary phase,” and is therefore routine experimentation (See MPEP 2144.05(II)(A)).
Regarding claim 16, Modified Zhou teaches the chromatography method of claim 9 wherein separating constituent elements in the mobile phase comprises: isomeric separation of the constituent elements (See Table 1 , last row of Zhou for isomeric separation of glycans using PGC column)(The Examiner interprets “constituent elements” to refer to constituent molecules, analytes or glycans. See 112(b) rejection above).
Regarding claim 17, Modified Zhou teaches the chromatography method of claim 16 wherein the mobile phase comprises one of:
HexNAc3Hex3DeoxyHex1;
HexNAc4Hex5NeuAc2 (Figure 1. Extracted ion chromatograms (EICs) of reduced and permethylated glycan structures of…Hex5HexNAc4NeuAc2; Zhou, p. 6592, Fig. 1);
HexNAc2Hex8;
HexNAc4Hex3DeoxyHex1;
HexNAc4Hex5NeuAc1; and
HexNAc4Hex5DeoxyHex1 NeuAc2.
Regarding claim 18, Modified Zhou teaches the method of claim 17 wherein separating constituent elements in the mobile phase comprises:
isomeric separation of permethylated glycans (isomeric separation of permethylated glycans; Zhou, Title)(The Examiner interprets “constituent elements” to refer to constituent molecules, analytes or glycans. See 112(b) rejection above).
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Zhou et al. (“Isomeric Separation of Permethylated Glycans by Porous Graphitic Carbon (PGC)-LC-MS/MS at High Temperatures”; 2017) in view of Koivisto (“Development of Techniques and Methods for Drug Analysis by Packed Capillary Liquid Chromatography with Octadecylbonded Silica and Porous Graphitic Carbon Columns”; 2001), as applied to claim 9 above, and further in view of Ichikawa et al. (US 5270280 A; 1993) and Shollenberger et al. (“Characterization of Polymer Carbon Sieves, Graphitized Polymer Carbons and Graphitized Carbon Blacks for Sample Preparation Applications”; 2010).
Regarding claim 11, Modified Zhou teaches the chromatography method of claim 9.
Modified Zhou fails to teach selecting the mesoporous graphitized carbon to have a size of less than 500 nm and a pore size of 64 Angstroms.
Modified Zhou instead teaches Hypercarb PGC packing, which corresponds to a size of 5 μm and a pore size of 250 Å according to supplementary reference Thermo Scientific (See “Table 1: Physical properties of PGC”).
Modified Zhou (via Thermo Scientific) does, however, teach that graphitized carbon black (GCB) is a widely used carbon-based sorbent exhibiting high trapping efficiency for polar compounds (Thermo Scientific, p. 27, col. 2, ll. 11-15) and is therefore suitable as a stationary-phase material for separations involving polar analytes. As taught below, GCB is manufactured in a size of less than 500 nm and a pore size around 64 Angstroms. However, Thermo Scientific only reveals that GCB is used as a solid phase extraction (SPE) sorbent and is silent to its functionality in liquid chromatography.
Ichikawa teaches that mesoporous (an average micropore diameter was 120 .ANG.; col. 8, ll. 64-65)(Despite the term “micropore” often used in older literature, 120 .ANG. corresponds to 12 nm which falls within the mesoporous particle range of 2-50nm) graphitized carbon black may be packed and used as a stationary phase in liquid chromatography columns (a packing material for liquid chromatography produced by mixing carbon black and graphitizing (carbonizing) components; col. 1, ll. 9-12
This confirms the operability of GCB as a chromatographic packing material to be used for the same purpose as Modified Zhou and not only as a SPE sorbent.
Ichikawa is considered to be analogous to the claimed invention because it is in the same field of endeavor for column packing in liquid chromatography using MGC as a stationary phase. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the PGC stationary-phase packing taught by Zhou in view of Koivisto with the GCB stationary-phase packing taught by Ichikawa since PGC and GCB share the same fundamental graphitic carbon surface and swapping one for the other would predictably maintain the carbon-based retention behavior. This expectation of success is supported by Thermo Scientific’s teaching that:
“The most widely used carbon-based SPE sorbent is graphitized carbon black (GCB)…its potential for trapping polar compounds with a higher efficiency than C18 silica sorbent has been largely demonstrated. Porous Graphitic Carbon…has also been largely used for the extraction of polar pollutants.”( p. 27, col. 2, ll. 11-19).
Both references reinforce that substitution of GCB for PGC represents the use of a known alternative carbon-based material for achieving predictable analyte separation (See MPEP 2143(I)(B)).
Modified Zhou does not explicitly teach that the GCB has a size of less than 500 nm and a mesoporous pore size of 64 Angstroms.
Modified Zhou instead teaches GCB sized between 2 and 120 µm and a mesoporous pore size of 120 Å (Ichikawa, col. 8, ll. 60, 64-65).
Shollenberger teaches mesoporous graphitized carbon (Graphitized Carbon Blacks; Title) having a size of less than 500 nm (See Table 1, p.8 with GCB particle size of 0.3 µm which equates to 300nm and average pore diameter of 90.4 angstroms which falls within the mesoporous range of 20-500Å).
Shollenberger is considered to be analogous to the claimed invention because it is in the same field of endeavor for mesoporous graphitized carbon for use in compound separation. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the GCB stationary-phase column packing taught by Zhou in view of Koivisto and Ichikawa with Shollenberger’s GCB having a size of less than 500 nm since particle size is a result-effective variable in chromatographic stationary phases that is used to optimize separation performance. Increasing accessible surface area through particle size would have been expected to enhance retention efficiency for polar analytes while maintaining the known carbon-based retention mechanisms. This expectation of success is reinforced by Thermo Scientific’s teaching regarding GCB: “In spite of its low surface area (120 m2/g), its potential for trapping polar compounds with a higher efficiency than C18 silica sorbent has been largely demonstrated” (p. 27, col. 2, ll. 12-15). This would have motivated a person of ordinary skill in the art to increase surface area by employing mesoporous GCB with a smaller particle size to further improve performance. Doing so represents a simple substitution of one known carbon-based stationary phase for another, yielding the predictable result of improved analyte separation through routine optimization (See MPEP 2143(I)(B))(See MPEP 2144.05).
Modified Zhou does not teach a GCB pore size of 64 Angstroms. However, Shollenberger does teach a GCB pore size of 90.4 Å which can be routinely optimized based on the intended use of the column (See Table 1, p.8 with GCB average pore diameter). Pore diameter is reported and measured as a structural property of the GCB, and mesoporosity (2-50nm or 20-500Å) is recognized in the art as affecting adsorption and separation performance. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have selected a pore size within the mesoporous range, including 64 Å (64 nm), as a matter of routine optimization in order to adjust separation characteristics. Shollenberger explains that “[o]ptimization of the carbons for the specified applications was based on the changes observed with the physical characterization methods employed” and that “[t]he data obtained indicate that the carbons performed effectively for the respective applications”(See p. 19, ll. 3-6). Thus, Shollenberger recognizes that structural parameters of the GCB including pore diameter and particle size, are variables that may be adjusted to achieve desired separation performance. Selecting a specific pore size within a known mesoporous range constitutes optimization of a result-effective variable absent evidence of criticality (See MPEP 2144.05).
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Zhou et al. (“Isomeric Separation of Permethylated Glycans by Porous Graphitic Carbon (PGC)-LC-MS/MS at High Temperatures”; 2017) in view of Koivisto et al. (“Development of Techniques and Methods for Drug Analysis by Packed Capillary Liquid Chromatography with Octadecylbonded Silica and Porous Graphitic Carbon Columns”; 2001), as applied to claim 9 above, and further in view of Thermo Scientific (“Thermo Scientific Hypercarb Columns”; 2009).
Regarding claim 15, Modified Zhou teaches the chromatography method of claim 9.
Modified Zhou fails to teach the packing the column with a stationary phase further comprises: packing 10 mm of the column with the stationary phase.
Modified Zhou relies on a commercially available 100mm HyperCarb PGC column supplied by Thermo Scientific (p. 6591, col. 2, Instrument Method, ll. 3-5).
Thermo Scientific teaches a column packed with 10 mm of the stationary phase (See p. 47, Hypercarb Nanobore Columns with 10mm lengths)(The disclosed 10mm column length refers to a column packed with PGC over a 10mm stationary-phase bed length, consistent with standard LC column nomenclature).
Thermo Scientific is considered to be analogous to the claimed invention because it is in the same field of endeavor for MGC-packed stationary phase columns. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the 100mm HyperCarb PGC column taught by Zhou in view of Koivisto with the 10mm Hypercarb Nanobore Columns taught by Thermo Scientific for more efficient coupling of Zhou’s nanoLC-MS analysis system. Modified Zhou relies on a 100mm HyperCarb PGC column which is operated in direct nanoESI coupling to the mass spectrometer for analysis (“The outlet of the LC column was coupled to an LTQ Orbitrap Velos mass spectrometer…through a nanoESI source; Zhou, p. 6591, col. 2, Instrument Method, ll. 16-18). In nano-LC-nanoESI systems, column length and inner diameter are known result-effective variables routinely selected based on desired spray stability, backpressure, analysis time, and sensitivity. Shorter nanobore Hypercarb columns, such as the 10 mm columns available from Thermo Scientific, are commonly employed in nanESI-coupled systems to reduce dead volume between the column and the emitter, improve nanoESI spray stability, lower backpressure at nano-flow rates, and enable rapid separations or trapping prior to MS analysis. Accordingly, a person of ordinary skill in the art, having Zhou’s teaching that Hypercarb columns are effectively coupled to a nanoESI source, would have been motivate to select a shorter (e.g., 10mm) nanobore Hypercarb column as an alternative to the 100mm column disclosed by Zhou when optimizing the system for nanoESI interfacing, throughput, or pressure constraints, while maintaining the same PGC stationary phase and separation mechanism. Such a substitution represents routine optimization of column dimensions with a predictable effect on chromatographic performance (See MPEP 2143(I)(B) and MPEP 2144.05).
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Thermo Scientific (“Thermo Scientific Hypercarb Columns”; 2009) in view of Coon (US 20210239708 A1, claiming priority to parent US continuation 15988566, EFD 20180524).
Regarding claim 19, Thermo Scientific teaches a chromatography system (Hypercarb Nanobore Columns…Picofrit; p. 47) comprising:
a column comprising a pulled capillary nanospray emitter column (Picofrit…75 µm ID x 15 µm Tip; p. 47; Hypercarb Nanobore Columns)(Picofrit column…fritted nanospray emitter; New Objective, see p. 6 above)(The Picofrit® column by definition is a pulled capillary nanospray emitter column; See pulled configuration in the figure below and capillary design as stated on p. 3, ll. 4-7).
a stationary phase comprising mesoporous graphitized carbon (“Porous graphitic carbon (PGC, Hypercarb) has unique properties as a stationary phase in high performance liquid chromatography (HPLC),” wherein the PGC is mesoporous due to median pore diameter of 250 Å which corresponds to 25 nm and falls within the defined range of 2-5nm for mesoporous classification; See “Table 1: Physical properties of PGC” on p. 4 of Thermo Scientific; See p. 2236 of supplementary reference, Slomkowski, for “mesopore particle” definition); and
frit inserted in the column (The Picofrit® column by definition has a frit inserted in the column as explained on p. 8 of supplementary manufacturer reference New Objective)(See the frit within the Picofrit column in the figure below).
PNG
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820
1166
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Greyscale
Pico Frit, p. 6, New Objective
Thermo Scientific fails to teach a heater configured for controlling a temperature of the pulled capillary nanospray emitter column.
Coon teaches a heater (column heater; [0048]) configured for controlling a temperature of a pulled capillary nanospray emitter column (75 μm-360 μm inner-outer diameter bare-fused silica capillary, each with a laser pulled electrospray tip…Columns were…heated to 60 ° C. using a home-built column heater; [0048]).
Coon is considered to be analogous to the claimed invention because it is in the same field of endeavor for LC-MS analysis of biomolecules using temperature controlled chromatographic columns. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the chromatography system taught by Thermo Scientific by including the column heater taught by Coon in order to obtain the known advantages of improved separation efficiency and reproducibility. Elevated temperature operation in LC-MS systems was well understood to reduce solvent viscosity, improve mass transfer, enhance peak shape, and increase resolution, particularly for polar analytes and isomeric species (Thermo Scientific, p.23, Introduction). In view of this recognized benefit, a person of ordinary skill in the art would have recognized that such the addition of a column heater would have yielded the predictable benefits listed above without altering the functionality of the Hypercarb column (See MPEP(I)(A)).
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Thermo Scientific (“Thermo Scientific Hypercarb Columns”; 2009) in view of Coon et al. (US 20210239708 A1, claiming priority to parent US continuation 15988566, EFD 20180524), as applied to rejected claim 19, and further in view of Ichikawa (US 5270280 A; 1993) and Shollenberger et al. (“Characterization of Polymer Carbon Sieves, Graphitized Polymer Carbons and Graphitized Carbon Blacks for Sample Preparation Applications”; 2010).
Regarding claim 20, Modified Thermo Scientific teaches the chromatography system of claim 19 further wherein the mesoporous graphitized carbon in a [sic] packed into 10 mm or less of the pulled capillary nanospray emitter column (See Hypercarb Nanobore Picofrit Columns with 10mm length on p. 47 of Thermo Scientific)(The disclosed 10mm column length refers to a column packed with PGC over a 10mm stationary-phase bed length, consistent with standard LC column nomenclature).
Thermo Scientific fails to teach that the PGC has a size of less than 500 nm and a pore size of 64 Angstroms, but instead teaches PGC with a size of 5µm and a pore size of 250 Å (See Thermo Scientific “Table 1: Physical properties of PGC” on p. 4 for pore size and p. 47 Hypercarb Nanobore Picofrit column for particle size).
Thermo Scientific does, however, teach that graphitized carbon black (GCB) is a widely used carbon-based sorbent exhibiting high trapping efficiency for polar compounds (p. 27, col. 2, ll. 11-15) and is therefore suitable as a stationary-phase material for separations involving polar analytes. As taught below, GCB is manufactured in a size of less than 500 nm and a pore size around 64 Angstroms. However, Thermo Scientific only reveals that GCB is used as a solid phase extraction (SPE) sorbent and is silent to its functionality in liquid chromatography.
Ichikawa teaches that mesoporous (an average micropore diameter was 120 .ANG.; col. 8, ll. 64-65)(Despite the term “micropore” often used in older literature, 120 .ANG. corresponds to 12 nm which falls within the mesoporous particle range of 2-50nm) graphitized carbon black may be packed and used as a stationary phase in liquid chromatography columns (a packing material for liquid chromatography produced by mixing carbon black and graphitizing (carbonizing) components; col. 1, ll. 9-12). This confirms the operability of GCB as a chromatographic packing material to be used for the same purpose as Thermo Scientific and not only as a SPE sorbent.
Ichikawa is considered to be analogous to the claimed invention because it is in the same field of endeavor for column packing in liquid chromatography using MGC as a stationary phase. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the PGC stationary-phase packing taught by Thermo Scientific in view of Coon with the GCB stationary-phase packing taught by Ichikawa since PGC and GCB share the same fundamental graphitic carbon surface and swapping one for the other would predictably maintain the carbon-based retention behavior. This expectation of success is supported by Thermo Scientific’s teaching that:
“The most widely used carbon-based SPE sorbent is graphitized carbon black (GCB)…its potential for trapping polar compounds with a higher efficiency than C18 silica sorbent has been largely demonstrated. Porous Graphitic Carbon…has also been largely used for the extraction of polar pollutants.” (p. 27, col. 2, ll. 11-19).
Both references reinforce that substitution of GCB for PGC represents the use of a known alternative carbon-based material for achieving predictable analyte separation (See MPEP 2143(I)(B)).
Modified Thermo Scientific does not explicitly teach that the (GCB) has a size of less than 500 nm and a mesoporous pore size of 64 Angstroms.
Modified Thermo Scientific instead teaches GCB sized between 2 and 120 µm and a mesoporous pore size of 120 Å (Ichikawa, col. 8, ll. 60, 64-65).
Shollenberger teaches mesoporous graphitized carbon (Graphitized Carbon Blacks; Title) having a size of less than 500 nm (See Table 1, p.8 with GCB particle size of 0.3 µm which equates to 300nm and average pore diameter of 90.4 angstroms which falls within the mesoporous range of 20-500Å).
Shollenberger is considered to be analogous to the claimed invention because it is in the same field of endeavor for mesoporous graphitized carbon for use in compound separation. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the GCB stationary-phase column packing taught by Thermo Scientific in view of Coon and Ichikawa with Shollenberger’s GCB having a size of less than 500 nm since particle size is a result-effective variable in chromatographic stationary phases that is used to optimize separation performance. Increasing accessible surface area through particle size would have been expected to enhance retention efficiency for polar analytes while maintaining the known carbon-based retention mechanisms. This expectation of success is reinforced by Thermo Scientific’s teaching regarding GCB: “In spite of its low surface area (120 m2/g), its potential for trapping polar compounds with a higher efficiency than C18 silica sorbent has been largely demonstrated” (p. 27, col. 2, ll. 12-15). This would have motivated a person of ordinary skill in the art to increase surface area by employing mesoporous GCB with a smaller particle size to further improve performance. Doing so represents a simple substitution of one known carbon-based stationary phase for another, yielding the predictable result of improved analyte separation through routine optimization (See MPEP 2143(I)(B))(See MPEP 2144.05).
Modified Thermo Scientific does not teach a GCB pore size of 64 Angstroms. However, Shollenberger does teach a GCB pore size of 90.4 Å which can be routinely optimized based on the intended use of the column (See Table 1, p.8 with GCB average pore diameter). Pore diameter is reported and measured as a structural property of the GCB, and mesoporosity (2-50nm or 20-500Å) is recognized in the art as affecting adsorption and separation performance. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have selected a pore size within the mesoporous range, including 64 Å (64 nm), as a matter of routine optimization in order to adjust separation characteristics. Shollenberger explains that “[o]ptimization of the carbons for the specified applications was based on the changes observed with the physical characterization methods employed” and that “[t]he data obtained indicate that the carbons performed effectively for the respective applications.” Thus, Shollenberger recognizes that structural parameters of the GCB including pore diameter and particle size, are variables that may be adjusted to achieve desired separation performance. Selecting a specific pore size within a known mesoporous range constitutes optimization of a result-effective variable absent evidence of criticality (See MPEP 2144.05).
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Slomkowski et al., 2011 (instant PTO-892) teaches definition of mesoporous particle to be 2-50nm.
New Objective., 2013 (instant PTO-892) teaches the structure of Picofrit column.
No claims are allowed.
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/V.S./Examiner, Art Unit 1758
/MARIS R KESSEL/Supervisory Patent Examiner, Art Unit 1758