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. A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 05/22/2026 has been entered.
3. Applicant’s amendment to the claims filed on 05/22/2026 in response to the Final Rejection mailed on 02/27/2026 is acknowledged. This listing of claims replaces all prior listings of claims in the application.
4. Claim 2 is cancelled.
5. New claims 17-25 are added.
6. Claims 1, 3-12 and 17-25 are pending.
7. Applicant’s remarks filed on 05/22/2026 in response to the Final Rejection mailed on 02/27/2026 have been fully considered and are deemed persuasive to overcome at least one of 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
8. 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 (US Patent Application Publication 2011/0137022 A1; cited on IDS filed 08/25/2022) is withdrawn in view of applicant’s amendment to the claims to incorporate the limitations of cancelled claim 2 into claim 1 and to recite “wherein the analysis method comprises, in order to prevent deterioration of the mobile phase, bubbling the mobile phase with an inert gas continuously or intermittently while performing the analysis of the ionic analyte”.
Claim Rejections - 35 USC § 103
9. 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 (US Patent Application Publication 2005/0272162 A1; cited on IDS filed on 08/25/2022) is withdrawn in view of the cancellation of claim 2 and in favor of the new rejection set forth below, which is necessitated by applicants’ amendment to the claims.
10. 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 withdrawn for the reasons set forth above regarding Michaud et al.
11. 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 Cen et al. (Journal of Pharmaceutical and Biomedical Analysis, 2012; cited on PTO-892 mailed on 08/12/2025) is withdrawn for the reasons set forth above regarding Michaud et al.
12. Claims 1, 3-7, 10-12, and 17-23 are newly rejected 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) and Dolan et al. (LCGC North America, 2014; examiner cited). This new grounds of rejection is necessitated by applicants’ amendment to the claims and upon further consideration of the prior art.
13. As amended, claims 1, 3-7, 10, and 17-23 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, wherein the analysis method comprises, in order to prevent deterioration of the mobile phase, bubbling the mobile phase with an inert gas continuously or intermittently while performing analysis of the ionic analyte.
As amended, 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 continuously or intermittently while performing the analysis of the ionic analyte.
As amended, claim 12 is drawn to a method for preventing deterioration of a mobile phase, the method comprising preparing in separate containers, at least a first mobile phase containing a basic ion-pair reagent in a nonaqueous solvent and a second mobile phase containing water and not containing the basic ion-pairing reagent; and supplying the first mobile phase and the second mobile phase by respective pumps and separating the ionic analyte using a mobile phase mixed by a mixer.
14. 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 (interpreted as two mobile phases) [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 claims 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].
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].
With respect to claim 17, Michaud et al. teach the method further comprising a third mobile phase comprising a non-aqueous solvent for desalting the oligonucleotide and mixing the third mobile phase with the first and second mobile phase [see paragraphs 0014-0019].
With respect to claim 18, 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].
With respect to claim 20, Michaud et al. teach the method wherein the first mobile phase comprise at least 55% organic solvent and the second mobile phase comprises at least 90% water [see paragraph 0014].
With respect to claim 21, Michaud et al. teach the method wherein the basic ion pair reagent is an amine compound [see paragraph 0014].
With respect to claim 22, 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 23, Michaud et al. teach the method wherein the ionic analyte is an oligonucleotide [see Abstract; paragraphs 0013-0014].
However, Michaud et al. does not teach the analysis method of claims 1, 3, 10, 11, and 12 wherein the operation to prevent deterioration of the mobile phase comprises bubbling of the mobile phase with an inert gas continuously or intermittently, 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].
Dolan et al. teach that mobile phase out-gassing were some of the most common problems encountered in routine use of liquid chromatography, and teach bubbling inert gasses such as helium and nitrogen removes ~80% of the dissolved air [see p. 1-4]. Dolan et al. teach that one possible solution to the problem of air redissolving in the mobile phase and affecting signal is to continuously bubble nitrogen through the mobile phase and use an in-line degasser to remove any excess nitrogen [see p. 6 bottom to top of p. 7].
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., Fogelman et al., and Dolan 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. Dolan et al. teach that one possible solution to the problem of air redissolving in the mobile phase and affecting signal is to continuously bubble nitrogen through the mobile phase and use an in-line degasser to remove any excess nitrogen. 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., Fogelman et al., and Dolan et al. because Fogelman et al. acknowledges purging of the mobile phase with an inert gas avoids interference in the analysis of samples and Dolan et al. acknowledges that continuously bubble nitrogen through the mobile phase and use an in-line degasser could overcome the loss of signal in analysis due to air redissolving in the mobile phase. 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 flow rate and 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 flow rate and the bubbling of the mobile phase with the inert gas depending on the type of analyte being studied or analyzed.
14. Claims 8 and 24 are newly rejected under are newly rejected 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) and Dolan et al. (LCGC North America, 2014; examiner cited) as applied to claims 1, 3-7, 10-12, and 17-23 above, and further in view of Cen et al. (Journal of Pharmaceutical and Biomedical Analysis, 2012; cited on PTO-892 mailed on 08/12/2025). This new grounds of rejection is necessitated by applicants’ amendment to the claims and upon further consideration of the prior art.
15. The relevant teachings of Michaud et al., Fogelman et al. and Dolan et al. as applied to claims 1, 3-7, 10-12 and 17-23 are set forth above.
With respect to claims 8 and 24, 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, the combination of Michaud et al., Fogelman et al. and Dolan et al. does not teach the analysis method according to claims 8 and 24, 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., Fogelman et al., Dolan et al. and Cen et al. according to the teachings of Cen et al. because Michaud et al., Fogelman et al. and Dolan 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., Fogelman et al., Dolan 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.
16. Claims 9 and 25 are newly rejected under are newly rejected 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) and Dolan et al. (LCGC North America, 2014; examiner cited) as applied to claims 1, 3-7, 10-12, and 17-23 above, and further in view of Koizumi et al. (Carbohydrate Research, 1991; cited on PTO-892 mailed on 08/12/2025). This new grounds of rejection is necessitated by applicants’ amendment to the claims and upon further consideration of the prior art.
17. The relevant teachings of Michaud et al., Fogelman et al. and Dolan et al. as applied to claims 1, 3-7, 10-12 and 17-23 are set forth above.
With respect to claims 9 and 25, 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, the combination of Michaud et al., Fogelman et al. and Dolan et al. does not teach the analysis method according to claims 9 and 25, 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., Fogelman et al., Dolan et al. and Koizumi et al. according to the teachings of Koizumi et al. because Michaud et al., Fogelman et al. and Dolan 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., Fogelman et al., Dolan 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 Regarding Prior Art Rejections
18. Applicants’ remarks filed on 05/22/2026 have been fully considered by the examiner; however, they are rendered moot in view of the new rejections set forth above.
Conclusion
19. Status of the claims:
Claims 1, 3-12 and 17-25 are pending.
Claims 1, 3-12 and 17-25 are rejected.
No claims are in condition for an allowance.
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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Manjunath Rao can be reached at 571-272-0939. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/PAUL J HOLLAND/Primary Examiner, Art Unit 1656
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