DETAILED CORRESPONDENCE
Application Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Applicant’s amendment to the claims filed on 11/07/2025 in response to the Non-Final Rejection mailed on 08/12/2025 is acknowledged. This listing of claims replaces all prior listings of claims in the application.
3. Claims 1-12 are pending.
4. Applicant’s remarks filed on 11/07/2025 in response to the Non-Final Rejection mailed on 08/12/2025 have been fully considered and are deemed not persuasive to overcome the rejections and/or objections as previously applied.
The text of those sections of Title 35 U.S. Code not included in the instant action can be found in the prior Office Action.
Claim Rejections - 35 USC § 102
5. The rejection of claims 1, 4-7, and 12 under 35 U.S.C. 102(a)(1) as being anticipated by Michaud et al. (US Patent Application Publication 2011/0137022 A1; cited on IDS filed 08/25/2022) is maintained for the reasons of record and the reasons set forth below. The rejection has been modified in order to address applicants’ amendment to the claims.
6. As amended, claims 1 and 4-7 are drawn to an analysis method comprising: subjecting a sample containing an ionic analyte to liquid chromatography using a mobile phase containing a basic ion-pair reagent; and further subjecting the analyte to mass spectrometry, and preventing deterioration of the mobile phase during the analysis method.
As amended, claim 12 is drawn to a method for preventing deterioration of a mobile phase comprising: preparing a mobile phase in which a basic ion-pair reagent is dissolved in a nonaqueous solvent; and performing liquid chromatography while gradient mixing the first mobile phase with a second mobile phase containing water.
7. With respect to claims 1, 4, and 12, Michaud et al. teach an analysis method comprising subjecting a sample containing an oligonucleotide (ionic analyte) to liquid chromatography using a mobile phase containing a basic ion-pair reagent comprising an amine [see paragraphs 0013-0014] and further subjecting the analyte to mass spectrometry [see Abstract; paragraphs 0013-0014]. Michaud et al. teach the method wherein the operation comprises use of gradient mixing a mobile phase containing water, the basic ion-pair reagent in an non-aqueous solvent such as acetonitrile [see paragraphs 0013-0014 and Examples]. Although Michaud et al. does not explicitly teach preventing deterioration of the mobile phase, Michaud et al. teach identical non-aqueous solvents such as acetonitrile and C1-3 alcohols [see paragraph 0014] which are disclosed in the specification as preventing deterioration of the mobile phase. As such, absent evidence otherwise, it is the examiner’s position that this feature is inherent to the methods of Michaud et al. Since the Office does not have the facilities for examining and comparing applicants’ method with the method of the prior art, the burden is on the applicant to show a novel or unobvious difference between the claimed method and the method of the prior art (i.e., that the method of the prior art using nonaqueous solvent does not possess the same material structural and functional characteristics of preventing deterioration of the mobile phase that the claimed method achieves). See In re Best, 562 F.2d 1252, 195 USPQ 430 (CCPA 1977) and In re Fitzgerald et al., 205 USPQ 594.
With respect to claim 5, Michaud et al. teach the method wherein the basic ion pair reagent is an amine compound [see paragraph 0014].
With respect to claim 6, Michaud et al. teach the method wherein the basic ion-pair reagent is N,N-diemthylbutylamine (DMBA), tributylamine, and tripropylamine [see paragraph 0014].
With respect to claim 7, Michaud et al. teach the method wherein the ionic analyte is an oligonucleotide [see Abstract; paragraphs 0013-0014].
RESPONSE TO REMARKS: Beginning on p. 4 of applicants’ remarks, applicants in summary contend that Michaud does not provide disclosure sufficient to meet the characteristic of inherency and Michaud provides no disclosure that would necessarily lead to use of a non-aqueous solvent.
These arguments are found to be not persuasive in view of the modified rejection set forth above. As stated in the rejection above, Michaud et al. teach identical non-aqueous solvents such as acetonitrile and C1-3 alcohols [see paragraph 0014] which are disclosed in the specification as preventing deterioration of the mobile phase. As such, absent evidence otherwise, it is the examiner’s position that this feature is inherent to the methods of Michaud et al. Furthermore, the examples of Michaud demonstrate the performance of liquid chromatography while gradient mixing [see Examples 1-5].
Claim Rejections - 35 USC § 103
8. The rejection of claims 2-3 and 10-11 under 35 U.S.C. 103 as being unpatentable over Michaud et al. (US Patent Application Publication 2011/0137022 A1; cited on IDS filed 08/25/2022) in view of Fogelman et al. (US Patent Application Publication 2005/0272162 A1; cited on IDS filed on 08/25/2022) is maintained for the reasons of record and the reasons set forth below.
9. Claim 11 is drawn to a method for preventing deterioration of a mobile phase of liquid chromatography, comprising bubbling the mobile phase of liquid chromatography containing a basic ion-pair reagent.
10. The relevant teachings of Michaud et al. as applied to claims 1, 4-7 and 12 are set forth in the 102(a)(1) rejection above.
With respect to claims 2-3 and 10-11, Michaud et al. teach an analysis method comprising subjecting a sample containing an oligonucleotide (ionic analyte) to liquid chromatography using a mobile phase containing a basic ion-pair reagent comprising an amine [see paragraphs 0013-0014] and further subjecting the analyte to mass spectrometry [see Abstract; paragraphs 0013-0014]. Michaud et al. teach the method wherein the operation comprises use of mobile phase containing water, the basic ion-pair reagent in an non-aqueous solvent such as acetonitrile [see paragraphs 0013-0014 and Examples].
However, Michaud et al. does not teach the analysis method of claims 2-3, 10, and 11, wherein the operation to prevent deterioration of the mobile phase comprises bubbling of the mobile phase with an inert gas, wherein the inert gas is at least one or more types selected from nitrogen gas, argon gas, neon gas, krypton gas, xenon gas, and a helium gas.
Fogelman et al. teach liquid chromatography/mass spectrometry methods for the analysis of lipids and teach the prevention of dissolved oxygen from interfering with the analysis of the lipids by purging a mobile phase with an inert gas such as nitrogen or argon gas to obtain stable measurements [see paragraphs 0014-0015; 0094].
Before the effective filing date of the claimed invention, it would have been obvious for one of ordinary skill in the art to combine the teachings of Michaud et al. and Fogelman et al. to include an inert gas purged into the mobile phase of the liquid chromatography methods of Michaud et al. because Michaud et al. teach liquid chromatography/mass spectrometry methods for preparation and analysis of oligonucleotides. Fogelman et al. teach similar methods comprising purging the mobile phase with an inert gas in order to obtain stable measurements and removing oxygen to avoid interference with the analysis. One of ordinary skill in the art would have had a reasonable expectation of success and a reasonable level of predictability to combine the teachings of Michaud et al. and Fogelman et al. because Fogelman et al. acknowledges purging of the mobile phase with an inert gas avoids interference in the analysis of samples. Therefore, the above invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Furthermore, it is within the level of one of ordinary skill in the art to determine the appropriate parameters to control the purging/bubbling of inert gas in the mobile phase. MPEP 2144.05.II.A states “[g]enerally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)”. In the instant case, one of ordinary skill in the art would desire to control and manage the bubbling of the mobile phase with the inert gas depending on the type of analyte being studied or analyzed.
RESPONSE TO REMARKS: Beginning on p. 5 of applicants’ remarks, applicants in summary contend that there is no recognition in Michaud of the technical problem of degradation of the mobile phase and Fogelman describes purging inert gas to remove oxygen to interfere with the analysis of oxidized lipids and one would have no reason to incorporate its teachings into the teachings of Michaud.
These arguments are found to be not persuasive because the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). Furthermore, MPEP 2145.II sates “[m]ere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention. In re Wiseman, 596 F.2d 1019, 201 USPQ 658 (CCPA 1979) (Claims were directed to grooved carbon disc brakes wherein the grooves were provided to vent steam or vapor during a braking action. A prior art reference taught noncarbon disc brakes which were grooved for the purpose of cooling the faces of the braking members and eliminating dust. The court held the prior art references when combined would overcome the problems of dust and overheating solved by the prior art and would inherently overcome the steam or vapor cause of the problem relied upon for patentability by applicants. Granting a patent on the discovery of an unknown but inherent function (here venting steam or vapor) "would remove from the public that which is in the public domain by virtue of its inclusion in, or obviousness from, the prior art." 596 F.2d at 1022, 201 USPQ at 661.); In re Baxter Travenol Labs., 952 F.2d 388, 21 USPQ2d 1281 (Fed. Cir. 1991) (Appellant argued that the presence of DEHP as the plasticizer in a blood collection bag unexpectedly suppressed hemolysis and therefore rebutted any prima facie showing of obviousness. However, the closest prior art utilizing a DEHP plasticized blood collection bag inherently achieved same result, although this fact was unknown in the prior art.).”
11. The rejection of claim 8 under 35 U.S.C. 103 as being unpatentable over Michaud et al. (US Patent Application Publication 2011/0137022 A1; cited on IDS filed 08/25/2022) in view of Cen et al. (Journal of Pharmaceutical and Biomedical Analysis, 2012; cited on PTO-892 mailed on 08/12/2025) is maintained for the reasons of record and the reasons set forth below.
12. The relevant teachings of Michaud et al. as applied to claims 1, 4-7 and 12 are set forth in the 102(a)(1) rejection above.
With respect to claim 8, Michaud et al. teach an analysis method comprising subjecting a sample containing an oligonucleotide (ionic analyte) to liquid chromatography using a mobile phase containing a basic ion-pair reagent comprising an amine [see paragraphs 0013-0014] and further subjecting the analyte to mass spectrometry [see Abstract; paragraphs 0013-0014]. Michaud et al. teach the method wherein the operation comprises use of mobile phase containing water, the basic ion-pair reagent in an non-aqueous solvent such as acetonitrile [see paragraphs 0013-0014 and Examples].
However, Michaud et al. does not teach the analysis method according to claim 8, wherein the oligonucleotide is at least one or more types of oligonucleotide therapeutics selected from the group consisting of antisense, a decoy, siRNA, miRNA, a ribozyme, CpG oligo, and an aptamer.
Cen et al. teach that CpG oligodeoxynucleotide could be used as a novel radiosensitizer for glioma [see Abstract]. Cen et al. further teach a reversed-phase HPLC coupled to electrospray triple quadropole mass spectrometry following a solid phase extraction from a biological matrix for determination of CpG oligonucleotides and metabolites [see Abstract].
Before the effective filing date of the claimed invention, it would have been obvious for one of ordinary skill in the art desiring to separate and isolate CpG oligonucleotides and metabolites for therapeutic purposes to combine the teachings of Michaud et al. and Cen et al. according to the teachings of Cen et al. because Michaud et al. teach liquid chromatography/mass spectrometry methods for preparation and analysis of oligonucleotides. Cen et al. teach the therapeutic use of CpG oligonucleotides and that they can be analyzed and separated by liquid chromatography and mass spectrometry. One of ordinary skill in the art would have had a reasonable expectation of success and a reasonable level of predictability to combine the teachings of Michaud et al. and Cen et al. because Cen et al. acknowledges that CpG oligonucleotides can be analyzed and separated using liquid chromatography. Therefore, the above invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
RESPONSE TO REMARKS: Beginning on p. 7 of applicants’ remarks, applicants contend that Cen provide no suggestion that would address the deficiencies in combining Fogelman with Michaud.
This argument is found to be not persuasive for the reasons set forth above regarding Michaud et al.
13. The rejection of claim 9 under 35 U.S.C. 103 as being unpatentable over Michaud et al. (US Patent Application Publication 2011/0137022 A1; cited on IDS filed 08/25/2022) in view of Koizumi et al. (Carbohydrate Research, 1991; cited on PTO-892 mailed on 08/12/2025) is maintained for the reasons of record and the reasons set forth below.
14. The relevant teachings of Michaud et al. as applied to claims 1, 4-7 and 12 are set forth in the 102(a)(1) rejection above.
With respect to claim 9, Michaud et al. teach an analysis method comprising subjecting a sample containing an oligonucleotide (ionic analyte) to liquid chromatography using a mobile phase containing a basic ion-pair reagent comprising an amine [see paragraphs 0013-0014] and further subjecting the analyte to mass spectrometry [see Abstract; paragraphs 0013-0014]. Michaud et al. teach the method wherein the operation comprises use of mobile phase containing water, the basic ion-pair reagent in an non-aqueous solvent such as acetonitrile [see paragraphs 0013-0014 and Examples].
However, Michaud et al. does not teach the analysis method according to claim 9, wherein the saccharide and the glycan are each at least one or more types selected from the group consisting of a monosaccharide, a disaccharide, and an oligosaccharide.
Koizumi et al. teach HPLC methods for the analysis of mono and oligosaccharides [see Abstract; p. 67, Table 1].
Before the effective filing date of the claimed invention, it would have been obvious for one of ordinary skill to combine the teachings of Michaud et al. and Koizumi et al. according to the teachings of Koizumi et al. because Michaud et al. teach liquid chromatography/mass spectrometry methods for preparation and analysis of oligonucleotides. Koizumi et al. teach the analysis of mono- and oligosaccharides by HPLC. One of ordinary skill in the art would have had a reasonable expectation of success and a reasonable level of predictability to combine the teachings of Michaud et al. and Koizumi et al. because Koizumi et al. acknowledges that mono- and oligosaccharides can be analyzed by liquid chromatography. Therefore, the above invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
RESPONSE TO REMARKS: Beginning on p. 7 of applicants’ remarks, applicants contend that Cen provide no suggestion that would address the deficiencies in combining Fogelman with Michaud.
This argument is found to be not persuasive for the reasons set forth above regarding Michaud et al.
Conclusion
15. Status of the claims:
Claims 1-12 are pending.
Claims 1-12 are rejected.
No claims are in condition for an allowance.
THIS ACTION IS MADE FINAL. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PAUL J HOLLAND whose telephone number is (571)270-3537. The examiner can normally be reached Monday to Friday from 8AM to 5PM.
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/PAUL J HOLLAND/Primary Examiner, Art Unit 1656