DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Response to Amendment
The Amendment filed 01/12/2026 has been entered. Claims 1, 3-16, 18-22 remain pending in the application. Claims 2 and 17 are previously canceled. Claims 1, 3-6, 8-10, 11-13, 16, and 21 have been amended. Claims
Status of Objections and Rejections
The objection to the specification is withdrawn in view of Applicant’s amendment.
The rejection of claims 1 and 12 under 35 U.S.C. 101 is withdrawn in view of Applicant’s arguments. The rejection of claims 3-11, 13-16 and 18-22 are withdrawn based on dependency of all of the limitations of claims 1 and 12.
The rejection of claim 10 under 35 U.S.C. 112(b) is maintained.
New grounds of rejection under 35 U.S.C. 103 are necessitated by the amendments.
Response to Arguments
Applicant’s arguments, see pp. 1-2, filed 01/12/2026, with respect to the rejection of claim 10 under 35 U.S.C 112(b) have been fully considered but they are not persuasive.
Applicant argues (pp. 1-2) that “the rejection is respected traversed. Claim 10 refers to polysaccharide content of the glycoprotein, either by reference to “polysaccharide content and acetylated polysaccharide content of the glycoprotein” or “polysaccharide content of the glycoprotein”.
The Examiner stated in the previous office action that it is unclear whether “polysaccharide content” refers to the total polysaccharide content or free polysaccharide in claim 7 from which claim 10 depends. Steps (a2) and (a3) refer to the total and free polysaccharide content of said glycoprotein in said reference material. Claim 10 goes on to state “determination of polysaccharide content and acetylated polysaccharide content of the glycoprotein” in steps (i)-(x). It is still unclear whether this is the PS content of the glycoprotein in the reference material in claim 7 or perhaps the PS content of the glycoprotein in the measured sample of claim 9 from which claim 10 also depends. Applicant may amend steps (i)-(x) of claim 10 to state “determination of polysaccharide content and acetylated polysaccharide content of the glycoprotein in the sample”.
Applicant’s arguments, see p. 2, filed 01/12/2026, with respect to the rejection of claims 1, 3-16, 18-22 under 35 U.S.C. 101 have been fully considered and are persuasive. The rejection of claims 1, 3-16, 18-22 has been withdrawn.
Claims 1 and 12 are using the judicial exception (abstract idea by mental processes) of comparing, identifying, and quantifying in conjunction with, a particular machine or manufacture (LC-MS) that is integral to the claim and therefore integrates into a practical application (See MPEP 2106.4(d)(I)). Thus, the rejection of claims 1 and 12 under 35 U.S.C. 101 have been withdrawn. The rejection of claims 3-11, 13-16 and 18-22 are withdrawn based on dependency of all of the limitations of claims 1 and 12.
Applicant’s arguments, see pp. 3-7, filed 01/12/2026, with respect to the rejection of claims 1, 3-16, 18-22 under 35 U.S.C. 103 have been fully considered but they are not persuasive.
Applicant argues that the rejection improperly significantly modifies primary reference Rosskopf to employ MS for a quantitative determination based on secondary reference Cao; however Cao only uses MS for identification (characterization) and not quantification.
The Examiner respectfully disagrees.
The rejection does not rely on Cao alone for the quantification step in the claims. Rosskopf supplies the primary quantitative framework including comparison against calibration data for determining analyte amounts (page 50, 5. Discussion, paragraph 5, lines 1-2; Figs. 3-4). Cao is relied upon for the known use of LC-MS/MS techniques for characterization and analysis of intact glycopeptides (Abstract). Rosskopf’s HPAED-PAD instrumentation is analogous to Cao’s LC-MS system in that HPAED is LC, and PAD and MS are both known ways of detecting and analyzing compounds after chromatography separation. One of ordinary skill in the art would expect to calibrate the LC-MS system and quantify the results, as per Rosskopf’s workflow, with a reasonable expectation of success since Cao already demonstrates the system’s ability to separate and both glycan structure and peptide sequence within a standard glycoprotein sample (Abstract) and quantitation is well-known on LC-MS/MS instrumentation. Additionally, Rosskopf recognizes the problem of retention time shift for ribitol after long runs which affects accurate identification and subsequent quantification (page 50, 5. Discussion, paragraph 4, lines 1-2). Therefore, 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 analysis method taught by Rosskopf by applying Rosskopf’s glycoprotein sample to both HPAEC-PAD and Cao’s LC-MS analysis because MS provides the known benefits of structural identification, sensitivity, glycan characterization, and fragmentation data, and this involves combining prior art elements according to known methods to yield predictable results (See MPEP(I)(A)).
Applicant mentions (p. 3) that both claims 1 and 12 state that the glycoprotein in the sample cannot be derivatized or modified to release the PC component from the protein before measuring the sample on the LC-MS system. Applicant has not explained how the references fail to meet these limitations.
For compact prosecution, the Examiner will address how the references meet these limitations. There is no mention of derivatization or modification for glycan release in the reference of Rosskopf, and Cao analyzes intact glycopeptides (Title). Although Cao performs proteolytic digestion to generate glycopeptides (p. 97, col. 1-2; Fig. 1), the glycans remain attached entering the LC-MS/MS system, and glycan fragmentation occurs during HCD analysis itself (Abstract). Cao performs a tryptic digestion as opposed to the more aggressive enzyme PNGase F as described in the instant publication ([0055]; US 20220236283 A1). Cao explains the same downfall as the instant publication in that traditional LC-MS workflows often remove glycans via PNGase F before analysis, but this loses important glycan structural information and does not work well for all glycans (p. 96-97). Thus, Cao does not require derivatization or enzymatic removal of the polysaccharide component from the carrier protein prior to LC-MS analysis and the combination of references therefore meet the claim limitations.
Claim Objections
Claims 1, 3-16, 18-22 are objected to because of the following informalities:
Regarding claim 1, l. 5 recites “comprises“. Applicant may amend the claim to recite “comprising”.
Claims 3-16, 18-22 are objected to based on dependency of all of the limitations of claim 1.
Appropriate correction is required.
Specification
The amended specification was received on 01/12/2026. The amended specification is acceptable.
Claim Rejections - 35 USC § 103
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 non-obviousness.
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, 3-5, 7, and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Rosskopf et al. (“Collaborative study on saccharide quantification of the Haemophilus influenzae type b component in liquid vaccine presentations”) in view of Cao et. al (“Characterization of intact N- and O-linked glycopeptides using higher energy collisional dissociation,”).
Regarding claim 1, Rosskopf teaches a method for identifying and quantifying a polysaccharide component of a glycoprotein in a sample (“saccharide quantification of the Haemophilus influenzae type b component,” wherein “(poly ribosyl-ribitol-phosphate, PRP)” is the polysaccharide and “Hib-TT or HibCRM197” is the glycoprotein within the glycoconjugate sample of “DTwP-HepB-Hib”; Title; Abstract; Table 1, column 2; p. 46, 3.1; p. 44, para. 3, ll. 1-2),
wherein said glycoprotein comprises one carrier protein and one or more of said polysaccharide component covalently joined to said carrier protein (“Haemophilus influenzae type b (Hib) vaccines are made from the capsular polysaccharide (PRP), which is conjugated to a carrier protein,” wherein “Hib polysaccharide is usually covalently linked to tetanus toxoid” or “CRM197”; p. 45, ll. 1-4; Table 1, col. 2), the method comprises the steps of:
(a) establishing a calibration curve of said polysaccharide component by means of an LC-PAD system (“quantify the PRP content using two calibration curves,” wherein “HPAEC-PAD chromatography has been found to be suitable for sugar analysis and is applied to the analysis of Hib vaccines”; page 50, Discussion, paragraph 5, line 1; page 45, paragraph 2, lines 1-2);
(b) measuring the sample on the same LC system-PAD (Each participant was requested to investigate each vaccine sample twice… and calculating both polysaccharide contents vs two calibration curves; p. 46; 3.4 Method and study design, para. 1, ll. 5-6)(all samples (1 ml of each point of the calibration curve… Each sample was then appropriately diluted, filtered and analysed by HPAEC-PAD; page 46; 3.4 Method and study design, paragraph 2, lines 5,8)(Table 2 of Rosskopf only shows one instrument per lab in row 3 (Chromatography Brand/ Model);
(c) comparing the results of (a) and (b) to identify and quantify said polysaccharide component in the sample (The participating Labs were asked to quantify the PRP content using two calibration curves; p. 50, 5. Discussion, para. 5, lines 1-2)(A summary of the reported results is presented in Table 3 (vs WHO PRP IS) and in Table 4 (vs ribitol reference standard); p. 48, para. 3, ll. 1-2; see retention time and peak for ribitol for identification in Figs. 1A-1B; See p. 47, Results, ll. 2-4);
wherein said glycoprotein present in the sample and measured in (b) is not derivatized and is not modified to release said polysaccharide component from said carrier protein, prior to measuring the sample on the LC-PAD system (Rosskopf is free of any teaching of derivatization and modification of the sample to release said polysaccharide component from said carrier protein, prior to measuring the sample on the LC-PAD system and therefore meets this negative limitation).
Rosskopf is silent to teaching LC-MS as the analysis system.
Cao teaches LC-MS as the analysis system for identifying a polysaccharide component of a glycoprotein in a sample (“In this study, we employed a recent type of fragmentation termed higher energy collisional dissociation (HCD) to examine fragmentation patterns of intact glycopeptides generated from a mixture of standard glycosylated protein… Our results indicated that HCD with lower NCE values preferentially fragmented the sugar chains attached to the peptides to generate a ladder of neutral loss of monosaccharides, thereby enabling the putative glycan structure characterization… in a single LC–MS/MS analysis”; Abstract)(page 12, lines of the instant specification state “The term "native state" is known in the field and relates to a biomolecule, such as a glycoconjugate, in its intact and functional state. When referring to native state within the invention, native state means that the glycoconjugate to be analysed is not derivatised or otherwise modified during sample preparation, for example with an enzyme such as PNGase F, or subjected to a chemical reaction).
Cao is considered to be analogous to the claimed invention because it is in the same field of endeavor for identification of polysaccharides in complex intact glycoconjugate compositions. Cao’s HPAED-PAD instrumentation is analogous to Cao’s LC-MS system in that HPAED is LC; and PAD and MS are both known ways of detecting, analyzing, and separating polysaccharides attached to proteins after chromatographic separation. One of ordinary skill in the art would expect to calibrate the LC-MS system and quantify the results, as per Rosskopf’s workflow, with a reasonable expectation of success since Cao already demonstrates the system’s ability to separate both glycan structure and peptide sequence within a standard glycoprotein sample (Abstract). Quantitation is also well-known on LC-MS instrumentation.
Additionally, Rosskopf recognizes the problem of retention time shift for ribitol after long runs, which affects accurate identification and subsequent quantification (p. 50, 5. Discussion, para. 4, ll. 1-2). LC-MS/MS uses m/z information, which allows for identification of structurally similar saccharides and contaminants. On the contrary, the retention times and electrochemical responses of structurally similar polysaccharides or contaminants using HPAEC-PAD may overlap and distort results. Therefore, 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 analysis method taught by Rosskopf by subjecting Rosskopf’s glycoprotein sample to both HPAEC-PAD and Cao’s LC-MS analysis because MS provides the known benefits of structural identification, sensitivity, glycan characterization, and fragmentation data, and this involves combining prior art elements according to known methods to yield predictable results (See MPEP(I)(A)).
Regarding claim 3, Modified Rosskopf teaches the method according to claim 1, wherein said carrier protein is selected from the group consisting of detoxified Exotoxin A of P. aeruginosa (EPA), E.coli flagellin (FliC), CRM197 (CRM197; Rosskopf, Table 1, row 2; p. 45, para. 1, l. 5), maltose binding protein (MBP), Diphtheria toxoid, Tetanus toxoid, detoxified hemolysin A of S. aureus, clumping factor A, clumping factor B, E. coli heat labile enterotoxin, detoxified variants of E. coli heat labile enterotoxin, Cholera toxin B subunit (CTB), cholera toxin, detoxified variants of cholera toxin, E. coli Sat protein, the passenger domain of E. coli Sat protein, Streptococcus pneumoniae Pneumolysin, Keyhole limpet hemocyanin (KLH), P. aeruginosa PcrV, outer membraneprotein of Neisseria meningitidis (OMPC), and protein D from non-typeable Haemophilus influenza.
Regarding claim 4, Modified Rosskopf teaches the method according to claim 1, wherein said polysaccharide component (poly ribosyl-ribitol-phosphate, PRP) comprises 1-10 repeating units (“Hib polysaccharide… as an oligosaccharide it is linked to…the cross-reacting material CRM197,” wherein an oligosaccharide is naturally 3-10; Rosskopf, p. 45, ll. 3-5),
said repeating units comprising non-modified monosaccharides and/or modified monosaccharides (After “Hydrolysis was performed adding 50 μL of 6 M HCl to all samples,” modified monosaccharides of ribose are naturally within the repeating units of PRP; Rosskopf, p. 46, 3.4 Method and study design, para. 2, ll. 4-5).
Regarding claim 5, Modified Rosskopf teaches the method according to claim 1, wherein said sample further comprises an aqueous matrix, said matrix including one or more of buffers (“the vaccine sample was treated with 5 mM phosphate buffer,” wherein phosphate buffer is naturally an aqueous matrix; Rosskopf, p. 46, last para., l. 2; See p. 19, ll. 5-6 of the instant specification), inorganic salts, sugar alcohols, and non-ionic surfactants.
Regarding claim 7, Modified Rosskopf teaches the method according to claim 1, wherein said step (a) includes the preparation of a reference material (1 ampoule of the WHO 1st International Standard (IS) Haemophilus influenzae b polysaccharide poly ribosylribitol phosphate (PRP), NIBSC code: 02/208, and 5 g of the ribitol reference standard (Fluka, cat. no. 02240, batch BCBJ6567V; Rosskopf, p. 47, Results, ll. 2-4; p. 46, 3.2 Reference standards, positive control, reagents, para. 1) and calibrating the LC-MS system with said reference material (see 3.4. Method and study design on p. 46 of Rosskopf) comprising:
(a1) determination of identity of said glycoprotein (“The ribitol elutes as a single peak at a retention time of about 15.9 min and can easily be assigned and integrated,” using “1 ampoule of the WHO 1st International Standard (IS) Haemophilus influenzae b polysaccharide poly ribosylribitol phosphate (PRP), NIBSC code: 02/208, and 5 g of the ribitol reference standard (Fluka, cat. no. 02240, batch BCBJ6567V),” wherein the glycoproteins are identified in Table 1, column 2; Rosskopf, p. 47, Results, l. 2-4; p. 46, 3.2 Reference standards, positive control, reagents, para. 1)(Under broadest reasonable interpretation, the Examiner understands “determination of identity of said glycoprotein” to be in either the reference material or the sample);
(a2) determination of total polysaccharide content of said glycoprotein in said reference material (“calculating both polysaccharide contents vs two calibration curves , i.e. vs the WHO PRP IS [9, 10] and vs the ribitol reference standard,” wherein both polysaccharide contents are “total and free PRP content”; Rosskopf, p. 46, 3.4 Method and study design, para. 1, ll. 3, 5-7);
(a3) determination of free polysaccharide content in said reference material (“calculating both polysaccharide contents vs two calibration curves , i.e. vs the WHO PRP IS [9, 10] and vs the ribitol reference standard,” wherein both polysaccharide contents are “total and free PRP content”; Rosskopf, page 46, 3.4 Method and study design, paragraph 1, lines 3, 5-7);
(a4) optional determination of the degree of modification of said glycoprotein in said reference material;
(a5) optional determination of purity of said glycoprotein in said reference material; to thereby obtain a reference material comprising the polysaccharide component of a glycoprotein; followed by
(a6) measuring aliquots of said reference material by means of the LC-MS system, to thereby establish said calibration curve (1 ml of each point of the calibration curve… analysed by HPAEC-PAD; Rosskopf, page 46, last 4 lines).
Regarding claim 11, The method according to claim 1, wherein said step (c) includes:
(c1) identifying characteristic peaks for each polysaccharide in the sample (“The ribitol elutes as a single peak at a retention time of about 15.9 min and can easily be assigned and integrated; Rosskopf, page 46, 3.4 Method and study design, paragraph 1, lines 3, 5-7; page 47, 4); and
(c2) comparing the area under the curve for the characteristic peaks for each polysaccharide in the sample identified in (c1) with the area under the curve for such peaks in the calibration curve (“The ribitol elutes as a single peak at a retention time of about 15.9 min and can easily be assigned and integrated,” then “calculating both polysaccharide contents vs two calibration curves,” wherein integration is finding the area under the curve; Rosskopf, page 46, 3.4 Method and study design, paragraph 1, lines 3, 5-7; page 47, 4. Results, paragraph 1, lines 2-4).
Claims 8, 12, 15-16, 18, and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Rosskopf et al. (“Collaborative study on saccharide quantification of the Haemophilus influenzae type b component in liquid vaccine presentations”) in view of Cao et. al (“Characterization of intact N- and O-linked glycopeptides using higher energy collisional dissociation”), as applied to claim 7 above, and in further view of Defaus (“Mammalian protein glycosylation– structure versus function”).
Regarding claim 8, Modified Rosskopf teaches the method according to claim 7, wherein
the calibration curve is established by separation of the aliquots via LC (“1.2 ug of glycopeptide mixture was reconstituted in 4 ul of nanopure water and further separated using…LC system,” wherein the aliquots would be the 1mL of each calibration point from Rosskopf; Cao, p. 97, Hypercarb LC-HCD MS/MS).
Modified Rosskopf fails to teach subjecting the eluate of the LC to in-source fragmentation inside the MS detector by adjusting the ionisation voltage.
Defaus teaches subjecting the eluate of the LC to in-source fragmentation inside the MS detector by adjusting the ionisation voltage (switching between high and low cone voltage during the LC-MS analysis; p. 2952, col. 2, 2.1.3, ll. 19-20).
Defaus is considered to be analogous to the claimed invention because it is in the same field of endeavor for the separation of polysaccharides from glycoprotein compositions. Modified Rosskopf relies on varying the normalized collisional energy (NCE) value for HCD and found that lower NCE values preferentially fragmented the sugar chains attached to the peptides while higher NCE values preferentially fragmented the peptide backbone (Abstract). Defaus uses the cone voltage technique for the same purpose (Whereas high voltage promotes glycan fragmentation, low voltage produces intact glycopeptides; p. 2952, col. 2, last 3 ll.). Therefore, 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 analysis method taught by Rosskopf in view of Cao by also adjusting the MS cone voltage as taught by Defaus because it would improve the control over glycan fragmentation, and this involves use of a known technique to improve a similar method in the same way (See MPEP 2143(I)(C)).
Regarding claim 12, Rosskopf teaches a method of identifying and quantifying a polysaccharide component of a glycoprotein in a sample (“saccharide quantification of the Haemophilus influenzae type b component,” wherein “(poly ribosyl-ribitol-phosphate, PRP)” is the polysaccharide and “Hib-TT or HibCRM197” is the glycoprotein within the glycoconjugate sample of “DTwP-HepB-Hib”; Title; Abstract; Table 1, column 2; p. 46, 3.1; p. 44, para. 3, ll. 1-2), comprising:
(a) establishing a calibration curve of said polysaccharide component comprising introducing reference material comprising said glycoprotein into an LC-PAD system (Two reference standards were provided for the calibration curve…Haemophilus influenzae b polysaccharide poly ribosylribitol phosphate (PRP)…and…the ribitol reference standard (Fluka, cat. no. 02240, batch BCBJ6567V),” wherein “HPAEC-PAD chromatography…is applied to the analysis of Hib vaccines”; p. 46, 3.2; p. 45, para. 2, ll. 1-2);
(b) analysing the sample on the same LC-PAD system (Each participant was requested to investigate each vaccine sample twice… and calculating both polysaccharide contents vs two calibration curves; page 46; 3.4 Method and study design, paragraph 1, lines 5-6)(all samples (1 ml of each point of the calibration curve… Each sample was then appropriately diluted, filtered and analysed by HPAEC-PAD; page 46; 3.4 Method and study design, paragraph 2, lines 5,8)(Table 2 of Rosskopf only shows one instrument per lab in row 3 (Chromatography Brand/ Model); and
(c) comparing the results of (a) and (b) to identify and quantify said polysaccharide component in said sample (Each sample was then appropriately diluted, filtered and analysed by HPAEC-PAD; page 46, 3.4, Method and study design, paragraph 2, last line)(The ribitol elutes as a single peak at a retention time of about 15.9 min and can easily be assigned and integrated; page 47, 4. Results, paragraph 1, lines 2-3)(quantify the total and free PRP content of each vaccine sample; page 46, 3.4. Method and study design, paragraph 1, line 2);
wherein said glycoprotein present in the sample and measured in (b) is not derivatized and is not modified to release said polysaccharide component from the protein component of said glycoprotein, prior to measuring the sample on the LC-PAD system (Rosskopf is free of any teaching of derivatization and modification of the sample to release polysaccharide component from the protein component of said glycoprotein, prior to measuring the sample on the LC-MS system and therefore meets this negative limitation).
Rosskopf fails to teach LC-MS system as the analysis system and using a cone voltage to separate glycan repeating units.
Cao teaches LC-MS as the analysis system to separate glycan repeating units of a native glycoprotein in a sample (“In this study, we employed a recent type of fragmentation termed higher energy collisional dissociation (HCD) to examine fragmentation patterns of intact glycopeptides generated from a mixture of standard glycosylated protein… Our results indicated that HCD with lower NCE values preferentially fragmented the sugar chains attached to the peptides to generate a ladder of neutral loss of monosaccharides, thereby enabling the putative glycan structure characterization… in a single LC–MS/MS analysis”; Abstract)
Cao is considered to be analogous to the claimed invention because it is in the same field of endeavor for identification of polysaccharides in complex intact glycoconjugate compositions. Cao’s HPAED-PAD instrumentation is analogous to Cao’s LC-MS system in that HPAED is LC; and PAD and MS are both known ways of detecting, analyzing, and separating polysaccharides attached to proteins after chromatographic separation. One of ordinary skill in the art would expect to calibrate the LC-MS system and quantify the results, as per Rosskopf’s workflow, with a reasonable expectation of success since Cao already demonstrates the system’s ability to separate both glycan structure and peptide sequence within a standard glycoprotein sample (Abstract), and the fact that quantitation is well-known on LC-MS instrumentation.
Additionally, Rosskopf recognizes the problem of retention time shift for ribitol after long runs, which affects accurate identification and subsequent quantification (p. 50, 5. Discussion, para. 4, ll. 1-2). LC-MS/MS uses m/z information, which allows for identification of structurally similar saccharides and contaminants. On the contrary, the retention times and electrochemical responses of structurally similar polysaccharides or contaminants using HPAEC-PAD may overlap and distort results. Therefore, 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 analysis method taught by Rosskopf by subjecting Rosskopf’s glycoprotein sample to both HPAEC-PAD and Cao’s LC-MS analysis because MS provides the known benefits of structural identification, sensitivity, glycan characterization, and fragmentation data, and this involves combining prior art elements according to known methods to yield predictable results (See MPEP(I)(A)).
Modified Rosskopf fails to teach that the LC-MS system comprises the use of a cone voltage.
Defaus teaches an LC-MS system comprising the use of a cone voltage (switching between high and low cone voltage during the LC-MS analysis; p. 2952, col. 2, 2.1.3, ll. 19-20).
Defaus is considered to be analogous to the claimed invention because it is in the same field of endeavor for the separation of polysaccharides from glycoprotein compositions. Modified Rosskopf aims to separate polysaccharide PRP from intact glycoconjugate DTwP-HepB-Hib using LC-MS analysis. Defaus teaches that “high voltage promotes glycan fragmentation, low voltage produces intact glycopeptides that are identied through accurate mass measurements and signal intensity,” so that “fragmentation is selectively directed to either carbohydrate or peptide” (pp. 2952-2953). Therefore, 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 analysis method taught by Rosskopf in view of Cao by adjusting the MS cone voltage as taught by Defaus because it would improve glycan structural characterization and fragmentation control for a cleaner separation of Rosskopf’s PRP from the glycoconjugate, and this involves use of a known technique to improve a similar method in the same way (See MPEP 2143(I)(C)).
Regarding claim 15, Modified Rosskopf teaches the method according to claim 12, wherein the glycoprotein comprises one carrier protein and one or more polysaccharides covalently bound to said carrier protein (“Haemophilus influenzae type b (Hib) vaccines are made from the capsular polysaccharide (PRP), which is conjugated to a carrier protein,” wherein “Hib polysaccharide is usually covalently linked to tetanus toxoid”; Rosskopf, page 45, lines 1-4; Table 1, column 2).
Regarding claim 16, Modified Rosskopf teaches the method according to claim 12, wherein: said glycoprotein comprises a carrier protein, wherein said carrier protein is selected from the group consisting of detoxified Exotoxin A of P. aeruginosa (EPA), E. coli flagellin (FliC), CRM197 (CRM197; Rosskopf, Table 1, row 2; Rosskopf, page 45, paragraph 1, line 5), maltose binding protein (MBP), Diphtheria toxoid, Tetanus toxoid, detoxified hemolysin A of S. aureus, clumping factor A, clumping factor B, E. coli heat labile enterotoxin, detoxified variants of E. coli heat labile enterotoxin, Cholera toxin B subunit (CTB), cholera toxin, detoxified variants of cholera toxin, E. coli Sat protein, the passenger domain of E. coli Sat protein, Streptococcus pneumoniae Pneumolysin, Keyhole limpet hemocyanin (KLH), P. aeruginosa PcrV, outer membrane protein of Neisseria meningitidis (OMPC), and protein D from non-typeable Haemophilus influenza; and/or
said polysaccharides comprise 1 -10 repeating units, said repeating units comprising non-modified monosaccharides and/or modified monosaccharides (“Hib polysaccharide… as an oligosaccharide it is linked to…the cross-reacting material CRM197,” wherein an oligosaccharide is naturally 3-10), said repeating units comprising non-modified monosaccharides and/or modified monosaccharides (After “Hydrolysis was performed adding 50 μL of 6 M HCl to all samples,” modified monosaccharides of ribose are naturally within the repeating units of PRP; Rosskopf, page 46, 3.4 Method and study design, paragraph 2, lines 4-5).
Regarding claim 18, Modified Rosskopf teaches the method according to claim 12, for in-process control in the production of glycoconjugates, for release control of produced glycoconjugates, for stability control of stored glycoconjugates, and/or for process optimization in the production of glycoconjugates (This claim does not impart patentable weight because it simply expresses the intended result of a process step positively recited; See MPEP 2111.04)(For compact prosecution, the examiner interprets the prior art as being capable of performing these limitations since Rosskopf teaches the application of polysaccharide quantification techniques for vaccine characterization (Hib-TT, Hib-CRM197) in order to “validate the methodology used by the manufacturer to determine the PRP content of any product they are requested to test” (Rosskopf , page 45, paragraph 3. lines 4-6). Monitoring the polysaccharide results by carrying out the method throughout the manufacturing process can allow modifications to the formula to optimize the production of the desired vaccine composition)
Regarding claim 21, Modified Rosskopf teaches the method of claim 8, comprising O- Acetylation and the release of O-Acetyl groups by hydrolysis (Hydrolysis was performed adding 50 μL of 6 M HCl to all samples (1 ml of each point of the calibration curve…Each sample was then appropriately diluted, filtered and analysed by HPAEC-PAD then “calculating both polysaccharide contents vs two calibration curves,” wherein using hydrolysis on the reference material naturally releases O-acetyl groups by modification; Rosskopf, page 46, last 5 lines; Rosskopf, page 46, 3.4 Method and design, paragraph 1, lines 5-6).
Claims 6 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Rosskopf et al. (“Collaborative study on saccharide quantification of the Haemophilus influenzae type b component in liquid vaccine presentations”) in view of Cao et. al (“Characterization of intact N- and O-linked glycopeptides using higher energy collisional dissociation”), as applied to claim 1 above, and in further view of Cook et al. (“Quantitation of serogroups in multivalent polysaccharide-based meningococcal vaccines: Optimisation of hydrolysis conditions and chromatographic methods”; 2013).
Regarding claim 6, Modified Rosskopf teaches the method according to claim 1.
Modified Rosskopf fails to teach said sample comprises a multitude of different glycoproteins, said glycoproteins differing in the polysaccharide components and/or in the carrier proteins.
Cook teaches a sample comprises a multitude of different glycoproteins (the three optimal conditions identified for each monovalent MenA, MenC, MenY and MenW135 PS-conj separately remained best for the respective serogroups in a quadrivalent MenACYW135 mixture (Fig. 2A and B); page 3704, column 2, paragraph 2, lines7-10), said glycoproteins differing in the polysaccharide components (See MenA, MenC, MenY and MenW135 polysaccharides in Table 1) and/or in the carrier proteins.
Cook is considered to be analogous to the claimed invention because it is in the same field of endeavor for determining polysaccharide content of a glycoconjugate in complex samples. Rosskopf conducts a study, organized by (WHO), (BSP) (EDQM) and the European Union Commission to verify the suitability of a single method for determining PRP content in liquid pentavalent vaccines (DTwP-HepB-Hib) (Abstract, paragraph 2, lines 1-5), wherein a pentavalent vaccine protects against five distinct infectious disease. The samples were donated by different manufacturers in order to establish a full validation of the test method that would be used to verify Hib vaccine quality and efficacy. Cook teaches a “quantitative determination of the individual polysaccharide components in multivalent meningococcal vaccines is an important step in manufacturing and regulatory control.” Vaccine manufactures and regulatory bodies (e.g., WHO, EDQM) seek harmonized, multiplexed quantification workflows to reduce cost, time, and variability favoring integration of known validated methods. Therefore, 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 combined the analytical workflow of Rosskopf in view of Cao with the multivalent serotype quantification described by Cook et al. because adapting a validated HPAEC-PAD method creates a broader application to multivalent glycoconjugate vaccine samples, and this involves combining prior art elements according to known methods to yield predictable results (See MPEP 2143(I)(A)).
Regarding claim 20, Modified Rosskopf teaches the method of claim 6, wherein the sample comprises 2-20 different glycoproteins (quadrivalent MenACYW135 mixture (Fig. 2A and B); Cook, page 3704, column 2, paragraph 2, lines7-10).
Claims 9-10 are rejected under 35 U.S.C. 103 as being unpatentable over Rosskopf et al. (“Collaborative study on saccharide quantification of the Haemophilus influenzae type b component in liquid vaccine presentations”) in view of Cao et. al (“Characterization of intact N- and O-linked glycopeptides using higher energy collisional dissociation”), as applied to claim 7 above, and in further view of Bruggink et al. (“Analysis of carbohydrates by anion exchange chromatography and mass spectrometry”; 2005).
Regarding claim 9, Modified Rosskopf teaches the method according to claim 7, where said step (b) includes:
measuring the sample in the same LC-MS system (Each participant was requested to investigate each vaccine sample twice… and calculating both polysaccharide contents vs two calibration curves; Rosskopf, page 46; 3.4 Method and study design, paragraph 1, lines 5-6)(See measured intensities of fragmented ions in Fig. 3 of Cao) in the same LC system (all samples (1 ml of each point of the calibration curve… Each sample was then appropriately diluted, filtered and analysed by HPAEC-PAD; Rosskopf, page 46; 3.4 Method and study design, paragraph 2, lines 5,8)(Table 2 of Rosskopf only shows one instrument per lab in row 3 (Chromatography Brand/ Model).
Modified Rosskopf fails to teach
subjecting a LC eluate to in-source fragmentation inside the MS detector by adjusting the ionisation voltage.
Bruggink teaches subjecting a LC eluate (splits the effluent to the integrated pulsed amperometric detector (IPAD) and to an on-line single quadrupole mass spectrometer (MS); Abstract) to in-source fragmentation inside the MS detector by adjusting the ionisation voltage (In source collision induced fragmentation (CID) of carbohydrates after ESI can be achieved in single quadrupole MS accelerating the ions into the focusing RF lens region with a high enough voltage applied to the exit cone.; page 105, column 1, paragraph 3, lines 1-4).
Bruggink is considered to be analogous to the claimed invention because it is in the same field of endeavor for identification of underivatized native polysaccharides in mixtures. Therefore, 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 Rosskopf in view of Cao to incorporate the teachings of Bruggink by including in-source fragmentation of the eluate obtained from the liquid chromatography because “In source formed fragment ions can confirm that unknown components are carbohydrates,” and can thereby reduce the possibility of false positives when identifying a polysaccharide (Bruggink, page 109, column 2, 4. Conclusions, lines 10-12), and this involves use of a known technique to improve a similar method in the same way (See MPEP 2143(I)(C)).
Regarding claim 10, Modified Rosskopf teaches the method according to claim 9, wherein said method comprises
(i) determination of polysaccharide content and acetylated polysaccharide content of the glycoprotein; OR
(ii) determination of polysaccharide content of the glycoprotein and determination of sample purity; OR
(iii) determination of polysaccharide content and acetylated polysaccharide content of the glycoprotein and determination of sample purity; OR
(iv) determination of polysaccharide content of the glycoprotein and determination of free polysaccharide content; OR
(v) determination of polysaccharide content and acetylated polysaccharide content of the glycoprotein and determination of free polysaccharide content; OR
(vi) determination of polysaccharide content and acetylated polysaccharide content of the glycoprotein and determination of free polysaccharide content and free acetylated polysaccharide content;
(vii) determination of polysaccharide content of the glycoprotein and determination of free polysaccharide content and purity of the sample; OR
(viii) determination of polysaccharide content and acetylated polysaccharide content of the glycoprotein and determination of free polysaccharide content and purity of the sample; OR
(ix) determination of polysaccharide content and acetylated polysaccharide content of the glycoprotein and determination of free polysaccharide content and free acetylated polysaccharide content and purity of the sample.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Rosskopf et al. (“Collaborative study on saccharide quantification of the Haemophilus influenzae type b component in liquid vaccine presentations”) in view of Cao et. al (“Characterization of intact N- and O-linked glycopeptides using higher energy collisional dissociation”) and Defaus (“Mammalian protein glycosylation– structure versus function”), as applied to claim 12 above, and in further view of Bruggink et al. (“Analysis of carbohydrates by anion exchange chromatography and mass spectrometry”; 2005).
Regarding claim 13, Modified Rosskopf teaches the method according to claim 12.
Modified Rosskopf fails to teach the LC-MS system is an LC-MS system with in-source fragmentation of the eluate obtained from the liquid chromatography.
Bruggink teaches an LC-MS system is an LC-MS system with in-source fragmentation (In source collision induced fragmentation (CID); page 105, column 1, paragraph 3, line 1) of the eluate obtained from the liquid chromatography (splits the effluent to the integrated pulsed amperometric detector (IPAD) and to an on-line single quadrupole mass spectrometer (MS); Abstract).
Bruggink is considered to be analogous to the claimed invention because it is in the same field of endeavor for identification of underivatized native polysaccharides in mixtures. Therefore 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 Rosskopf in view of Cao and Defaus to incorporate the teachings of Bruggink by including in-source fragmentation of the eluate obtained from the liquid chromatography because “In source formed fragment ions can confirm that unknown components are carbohydrates,” and can thereby reduce the possibility of false positives when identifying a polysaccharide (Bruggink, page 109, column 2, 4. Conclusions, lines 10-12), and this involves use of a known technique to improve a similar method in the same way (See MPEP 2143(I)(C)).
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Rosskopf et al. (“Collaborative study on saccharide quantification of the Haemophilus influenzae type b component in liquid vaccine presentations”) in view of Cao et. al (“Characterization of intact N- and O-linked glycopeptides using higher energy collisional dissociation”) and Defaus (“Mammalian protein glycosylation– structure versus function”), as applied to claim 12 above, and in further view of Aerts et al. (US 20190195897 A1).
Regarding claim 14, Modified Rosskopf teaches the method according to claim 12.
Modified Rosskopf fails to teach the LC-MS system further comprises a divert valve in front of the MS detector.
Aerts teaches a divert valve in front of the MS detector. (“The divert valve of the mass spectrometer was programmed to discard the UPLC effluent before (0 to 0.25 min) and after (4 to 5 min) the elution of the analytes to prevent system contamination,” wherein the effluent flows from the UPLC into the mass spectrometer and the divert valve is therefore positioned in between the two or in from of the MS detector; [0096])
Aerts is considered to be analogous to the claimed invention because it is in the same field of endeavor of glycan analysis. Therefore 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 Rosskopf in view of Cao and Defaus to incorporate the teachings of Aerts using a divert valve because a divert valve is programmable and can “prevent system contamination” (Aerts, [0096]), and this involves combining prior art elements according to known methods to yield predictable results (See MPEP 2143(I)(A)).
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Rosskopf et al. (“Collaborative study on saccharide quantification of the Haemophilus influenzae type b component in liquid vaccine presentations”) in view of Cao et. al (“Characterization of intact N- and O-linked glycopeptides using higher energy collisional dissociation”), as applied to claim 5 above, and in further view of Dhere et al. (US 20230149524 A1, EFD 2020-09-02)
Regarding claim 19, Modified Rosskopf teaches the method according to claim 5, wherein said sample further comprises one or more of:
polysaccharides not bound to carrier protein (One vaccine lot was especially prepared for the study with a…high free, unconjugated PRP content; page 46, 3.1 Vaccine samples, lines 2-3); and
wherein said sample is obtained from a host cell (whole-cell pertussis component; Abstract, paragraph 2, line 5)
is silent to teaching:
a carrier protein free of polysaccharides;
wherein said sample comprises up to 50% host cell proteins.
However, Rosskopf does teach testing lots from the manufacturers. It is known that the composition of the manufactured vaccine does not typically exhibit 100% binding of the carrier protein and polysaccharide with no impurities from the host cell.
Dhere teaches
a carrier protein free of polysaccharides (free protein in the conjugate; [0208]);
a sample comprises up to 50% host cell proteins (Nucleic acid impurity Not more than 2% by weight of PS; Table 41).
Dhere is considered to be analogous to the claimed invention because it is in the same field of endeavor of glycan analysis. “An international study was organised by the World Health Organization (WHO),” in the method taught by Rosskopf and seeks “to verify the suitability of a single method for determining PRP content in liquid pentavalent vaccines (DTwP-HepB-Hib) containing a whole-cell pertussis component” (Abstract). Similarly, Dhere also tests multivalent vaccines from whole-cell pertussis ([0536]) in order “to achieve higher yields of Purified Vi Polysaccharide which is meeting WHO specifications” ([0700]). Testing a sample including a free carrier protein and percentage of host cells provides a more realistic characterization of the manufacturer’s product and evaluates a true spectrum for analysis of the polysaccharide component which would optimize a “standardised test protocol for HPAEC-PAD methodology should be used to determine the PRP content in liquid vaccine combinations” (Rosskopf, page 45, paragraph 5, last 2 lines). Therefore, 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 Rosskopf in view of Cao to incorporate the teachings of Dhere by testing a sample with a carrier protein free of polysaccharides and 50% host cell proteins because this would enable “successful isolation of bacterial polysaccharide with WHO specifications” (Dhere, [0032]), and this involves the use of a known technique to improve similar methods in the same way (See MPEP 2143(I)(C)).
Claim 22 is rejected under 35 U.S.C. 103 as being unpatentable over Rosskopf et al. (“Collaborative study on saccharide quantification of the Haemophilus influenzae type b component in liquid vaccine presentations”) in view of Cao et. al (“Characterization of intact N- and O-linked glycopeptides using higher energy collisional dissociation”), as applied to claim 1 above, and in further view of Donald et al. (US 20200061177 A1).
Regarding claim 22, Modified Rosskopf teaches the method of claim 1.
Modified Rosskopf fails to teach said one or more of said polysaccharide component covalently joined to said carrier protein is selected from the group consisting of:
one or more O4 antigen polysaccharide covalently joined to a detoxified Exotoxin A of P. aeruginosa (EPA) carrier protein having four glycosylation sites, wherein said O4 antigen polysaccharide has the structure:
PNG
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129
659
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Greyscale
one or more O1A antigen polysaccharide covalently joined to a detoxified Exotoxin A of P. aeruginosa (EPA) carrier protein having four glycosylation sites, wherein said O1A antigen polysaccharide has the structure:
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115
697
media_image2.png
Greyscale
one or more O2 antigen polysaccharide covalently joined to a detoxified Exotoxin A of P. aeruginosa (EPA) carrier protein having four glycosylation sites, wherein said O2 antigen polysaccharide has the structure:
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126
674
media_image3.png
Greyscale
one or more O6A antigen polysaccharide covalently joined to a detoxified Exotoxin A of P. aeruginosa (EPA) carrier protein having four glycosylation sites, wherein said O6A antigen polysaccharide has the structure:
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124
681
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Greyscale
one or more O8 antigen polysaccharide covalently joined to a detoxified Exotoxin A of P. aeruginosa (EPA) carrier protein having four glycosylation sites, wherein said O8 antigen polysaccharide has the structure:
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46
651
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one or more O15 antigen polysaccharide covalently joined to a detoxified Exotoxin A of P. aeruginosa (EPA) carrier protein having four glycosylation sites, wherein said O15 antigen polysaccharide has the structure:
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44
533
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Greyscale
one or more O16 antigen polysaccharide covalently joined to a detoxified Exotoxin A of P. aeruginosa (EPA) carrier protein having four glycosylation sites, wherein said O16 antigen polysaccharide has the structure:
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media_image7.png
88
656
media_image7.png
Greyscale
one or more O18A antigen polysaccharide covalently joined to a detoxified Exotoxin A of P. aeruginosa (EPA) carrier protein having four glycosylation sites, wherein said O18A antigen polysaccharide has the structure:
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media_image8.png
120
675
media_image8.png
Greyscale
one or more O25B antigen polysaccharide covalently joined to a detoxified Exotoxin A of P. aeruginosa (EPA) carrier protein having four glycosylation sites, wherein said O25B antigen polysaccharide has the structure:
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228
613
media_image9.png
Greyscale
one or more O75 antigen polysaccharide covalently joined to a detoxified Exotoxin A of P. aeruginosa (EPA) carrier protein having four glycosylation sites, wherein said O75 antigen polysaccharide has the structure:
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122
621
media_image10.png
Greyscale
wherein each N is independently an integer of 3-50.
Donald teaches:
one or more O2 antigen polysaccharide covalently joined to a detoxified Exotoxin A of P. aeruginosa (EPA) carrier protein having four glycosylation sites, wherein said O2 antigen polysaccharide has the structure:
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126
674
media_image3.png
Greyscale
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27
809
media_image11.png
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Donald, Fig. 9A
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370
623
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Donald, Table 15
wherein each N is independently an integer of 3-50 (paragraph [0100] states that the number of repeating units “n” of the O-antigens can be between 1-100 and more total repeat units).
Donald is considered to be analogous to the claimed invention because it is in the same field of endeavor for identifying polysaccharides in complex glycoprotein compositions. Donald also assesses the free sacc % as a marker for drug efficacy as shown in Fig. 15 above and states that “previous attempts to develop E. coli glycoconjugate vaccines using conventional chemical conjugation or bioconjugation approaches have failed to generate robust functional immune responses for all serotypes” ([0006]). Accordingly, there exists an unmet need for immunogenic compositions against E. coli that generate robust functional immune responses” ([0006]). Using the quality tests taught by Rosskopf to verify the sample purity of bioconjugates made from specific O-antigen of exotoxin A from Pseudomonas aeruginosa allow the assessment of vaccine purity that is consistence with WHO specifications. Rosskopf broadly states that “HPAEC-PAD chromatography has been found to be suitable for sugar analysis,” in combination with either alkaline or acid hydrolysis for the appropriate calibration saccharide (page 45, paragraph 2, lines 1-2). Applying the same technique to other glycoconjugates will, in turn, would help progress more robust functional immune responses within the population. Therefore, 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 Rosskopf in view of Cao to incorporate the teachings of Donald by testing a vaccine sample from a manufacturer for a different glycoconjugate (O2 antigen polysaccharide covalently joined to a detoxified Exotoxin A of P. aeruginosa (EPA) carrier protein having four glycosylation sites) because this would have encouraged skilled practitioners of the World Health Organization (WHO) to extend the method to other bacterial polysaccharides and carrier proteins in order to improve quality control and batch consistency for other vaccines, and this involves the use of a known technique to improve similar methods in the same way (See MPEP 2143(I)(C)).
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Berti et al.., 2009 (instant PTO-892) teaches analysis of polysaccharides using a calibration curve run on the same instrument as the samples.
Huifeng et al., 2002 (instant PTO-892) teaches glycoconjugate vaccine identification and characterization through use of NanoLC-MS analysis.
Rohrer et al., (instant PTO-892) teaches HPAEC-PAD coupled with MS for detection of glycoconjugates without derivatization
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/V.S./Examiner, Art Unit 1758
/MARIS R KESSEL/Supervisory Patent Examiner, Art Unit 1758
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