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 .
Priority
This application claims benefit of priority to Japan Application No. JP2021-138767 filed 08/27/2021. This application is also a 371 of PCT/JP2022/025780 filed 06/28/2022. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. However, an English translation of the foreign patent documents was not provided. Therefore, for the purposes of applying prior art, the effective filing date of the claimed invention is the filing date of the PCT, 06/28/2022.
Information Disclosure Statement
The Information Disclosure Statement filed 10/18/2023 is acknowledged and has been considered.
Drawings
The Drawings filed 10/18/2023 are accepted by the Examiner.
Claims Status
Claims 1-7 are currently pending and under examination.
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.
Claim 2 is 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.
Claim 2 recites the limitation "the analysis step according to claim 1" in the preamble. There is insufficient antecedent basis for this limitation in the claim. Claim 1 does not recite an analysis step, only an analysis method. Thus, there is insufficient antecedent basis for this limitation in the claim. Additionally, because this limitation lacks antecedent basis, it is unclear which step within claim 1 is the analysis step. Claim 1 in its entirety is directed to an analysis method, however, the steps within claim 1 are directed to a first step of releasing, a second step of recovering, a third step of hydrophobizing and a fourth step of measuring. Thus, there is no analysis step, making it unclear what step is being referred to. When the claim is taken as a whole, it appears ‘the analysis step according to claim 1’ is an inadvertent error and should instead read ‘the analysis method according to claim 1.” Thus, for the purposes of compact prosecution, the claim is being interpreted as reading “the analysis method according to claim 1…”.
Claim 2 recites “analyzing a structure of a sugar chain bound to the antibody” in line 2. It is unclear exactly what is being analyzed in this step because this is the last step in the method, after the sugar chain has been enzymatically released from the antibody, yet, the claim recites “analyzing a structure of a sugar chain bound to the antibody,” making it appear as though the sugar chain is still bound to the antibody during this analysis step. It is unclear whether the sugar chain being analyzed is a free sugar chain or a sugar chain still bound to the antibody. However, in the measurement step the sugar chain is not bound to the antibody which conflicts with claim 2. Thus, the metes and bounds of the claim are unclear, rendering the claim indefinite. For the purposes of compact prosecution, the claim is being interpreted as the free sugar chains, which were previously bound to the antibody before being enzymatically released, are what is being analyzed.
Claim 3 recites “wherein a stationary phase for use in the supercritical fluid chromatography has a phenyl group” in lines 1-2. It is unclear if the ‘use of’ the stationary phase is an actual limitation of the claim or if it is simply an intended use. The phrase ‘for use’ makes it unclear if the step is an active step in the method or if it is just an intended use of the method. Thus, claim 3 is indefinite.
Claim 6 recites the limitation "the stationary phase" in line 3. There is insufficient antecedent basis for this limitation in the claim. Claim 1, the claim from which claim 6 depends, does not recite a ‘stationary phase.’ Thus, this limitation lacks antecedent basis.
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 1-6 are rejected under 35 U.S.C. 103 as being unpatentable over Lauber et al. (US 20180188259 A1, 07/05/2018) in view of Morelle et al. (Protocol, 06/21/2007) (IDS Reference of 10/18/2023, 18 Pages) and as evidenced by Waters (Waters, 2026).
Regarding claim 1, Lauber et al. disclose methods to label N-glycans released from several monoclonal anti-bodies (See entire document, Paragraph [0059]). More specifically, Lauber et al. disclose Example 2 wherein human IgG was incubated with peptide N-glycosidase F (PNGase F), yielding complete deglycosylation of the Fc region of the IgG (Paragraph [0077]). Complete deglycosylation of the Fc region of the IgG results in released N-glycans, reading on free sugar chains. Additionally, IgG reads on an antibody and PNGase F reads on a sugar cleavage enzyme. Next, Lauber et al. dissolved Labeling Reagent-1 in anhydrous dimethylformamide (DMF) and subsequently mixed the Labeling Reagent mixture with the released N-glycans (Paragraph [0077]). Labeling Reagent-1 is 2, 5-dioxopyrrolidin-1- yl (2-((2- (diethylamino)ethyl)carbamoyl)quinolin-6-yl)carbamate, or RapiFluor-MS (Table 1). The reaction between the Labeling Reagent mixture and the released N-glycans was allowed to proceed for 5 minutes before quenching (Paragraph [0078]). The quenched sample was then subjected to solid-phase extraction (SPE) and subsequent washing and elution, resulting in a sample comprising enriched, labeled glycosylamines (Paragraph [0078]). The labeled glycosylamines were then analyzed via HILIC separations and a combination of fluorescence and mass spectrometric detection (Paragraph [0079]). Lauber et al. further disclose the methods for the rapid labeling of glycosylamines described herein can include alternative type of separation and detection methods, including supercritical fluid chromatography, matrix assisted laser desorption ionization mass spectrometry and electrospray ionization mass spectrometry (Paragraph [0011]).
Lauber et al. do not disclose a recovery step before hydrophobizing the free sugar chain, the use of supercritical fluid chromatography in the specific example, Example 2, discussed above or the use of tandem mass spectrometry (MS).
However, Morelle et al. disclose a protocol for the structural analysis of protein-linked glycans (See entire document, Abstract). Morelle et al. further disclose the determination of the structure of the glycans is determined based on tandem MS (Page 1585, Left Column, Bottom Paragraph – Right Column, Top Paragraph).
Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have utilized tandem mass spectrometry in the method of Lauber et al. motivated by the desire to accurately determine the structure of the free sugar chains and tandem mass spectrometry was a known and effective means of doing such as taught by Morelle et al.
Additionally, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have performed the recovery of the free sugar chain step before the hydrophobizing of the free sugar chain step because it is simply a rearrangement of the process steps. Selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results. See MPEP 2144.04(IV)(C). Thus, it would have been obvious to swap the hydrophobizing step with the recovery step in the method of Lauber et al. because it is obvious to to hydrophobized the free sugar based on the intended target of analysis.
It would have been further obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have utilized supercritical fluid chromatography as part of the method of analyzing the free sugar chain because Lauber et al. specifically state supercritical fluid chromatography is an alternative type of separation and detection method useful in the invention. Thus, it would have been obvious to utilize supercritical fluid chromatography because it was a known and effective means of separation and detection in Example 2 of Lauber et al. motivated by the desire to effectively analyze the free sugar chain.
Regarding claim 2, see multiple 112b rejections above. As discussed above, Lauber et al. disclose analysis of the sample via HILIC separations and a combination of fluorescence and mass spectrometric detection, reading on analyzing a structure of a sugar chain. The use of supercritical liquid chromatography and tandem mass spectrometry was addressed immediately above.
Regarding claim 3, Lauber et al. disclose Waters ACQUITY UPLC CSH18 (Phenyl-Hexyl and Fluoro-Phenyl) columns provide alternate selectivity compared to other columns (Paragraph [0076]). Waters UPLC CSH Phenyl-Hexyl Column comprises a trifunctionally bonded C6 phenyl ligand as evidenced by Waters (Page 6, Product Description). The trifunctionally bonded C6 phenyl ligand reads on a stationary phase having a phenyl group.
Lauber et al. do not specifically disclose the use of Waters UPLC CSH Phenyl-Hexyl in Example 2.
However, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize the Waters UPLC CSH Phenyl-Hexyl column in Example 2 motivated by the desire to have the proper selectively for the free sugar chain and Lauber et al. specifically disclose this column when discussing columns usable with the utilized mass spectrometry.
Regarding claim 4, Figure 4C of Lauber et al. shows the % of glycosylamines modified at the hydroxyl group (Paragraph [0016] and Figure 4C), reading on hydroxyl group being modified.
Regarding claim 5, Lauber et al. disclose a fluorescence chromatogram obtained from cetuximab glycosylamines labeled with Labeling Reagent-1 described in Example 2 (Paragraph [0022]). One of the peaks on the chromatogram is Hex9HexNAc5DHex1 (Figure 11A). Hex9HexNAc5DHex1 is an acetylated sugar chain. Thus, the hydrophobization was acetylation.
Regarding claim 6, Lauber et al. do not disclose adding an organic solvent containing a carboxylic acid to the free sugar chain after the supercritical liquid chromatography step.
However, Lauber et al. disclose a solid-phase extraction washing step involving 1:14:85 (v/v/v) formic acid/water/acetonitrile is effective in reducing reaction by-products which are manifested in LC chromatograms as detector saturating void peaks and sloping baselines (Paragraph [0065]). Lauber et al. further disclose the 1:14:85 (v/v/v) formic acid/water/acetonitrile is effective in reducing the fluorescence background and in shifting the pH of the loaded sample from high pH to low pH which is important because a high pH can induce epimerization of N-acetyl glucosamine residues (Paragraph [0066]). Formic acid is a carboxylic acid.
Thus, it would have been obvious to one of ordinary skill in the art to utilize the 1:14:85 (v/v/v) formic acid/water/acetonitrile wash after the supercritical liquid chromatography step and before the tandem mass spectrometry step motivated by the desire to reduce reaction by-products and saturated void peaks as well as to shift the pH to avoid epimerization of residues as taught by Lauber et al.
Claims 1-7 are rejected under 35 U.S.C. 103 as being unpatentable over Lauber et al. (US 20180188259 A1, 07/05/2018) in view of Morelle et al. (Protocol, 06/21/2007) (IDS Reference of 10/18/2023, 18 Pages) and as evidenced by Waters (Waters, 2026) and further in view of Toyama et al. (Analytical Chemistry, 09/24/2012) (IDS Reference of 10/18/2023, 8 Pages).
The teaching of Lauber et al. and Morelle et al. are discussed above.
Regarding claim 7, Lauber et al. do not disclose a triple quadrupole mass spectrometer is used in the tandem mass spectrometry.
However, Toyama et al. disclose a method for quantifying glycopeptides and their glycan structures, including the N-glycans on antibodies (See entire document, Abstract). Toyama et al. further disclose the common drawbacks experienced in mass spectrometric (MS) analysis of glycopeptides are the lack of sensitivity of glycopeptides in a mixture with non-glycosylated peptides and the difficulty in verifying the glycan structure by MS/MS analysis of glycopeptides because in most cases only the oligosaccharide composition can be determined (Page B, Left Column, Paragraph 1). To overcome those issues, Toyama et al. utilized a triple-quadrupole mass spectrometer (Page B, Left Column, Paragraph 1) which provided for the characterization of Fc glycans and Fab glycans in a single analysis (Page F, Right Column, Paragraph 1).
Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have utilized a triple-quadrupole mass spectrometer in the method of Lauber et al. motivated by the desire to effectively analyze multiple different types of N-glycans in a single analysis and triple-quadrupole mass spectrometry was a known and effective mass spectrometry method for accomplishing that analysis as taught by Toyama et al.
Conclusion
Claims 1-7 are rejected.
No claims are allowed.
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/A.T.W./Examiner, Art Unit 1653
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653