DETAILED ACTION
Request for reconsideration of the application filed on 09/02/2026 is acknowledged. No amendment was made to the claims. Claims 1-2, 4-10 and 12-25 are pending in the application and are considered on merits.
In response to reconsideration, the examiner maintains rejections over prior art established in the previous Office action.
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim(s) 1-2, 4-10 and 12-23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kaur et al. (US 8,679,767, IDS) (Kaur) in view of Xiang et al. (Analytical Chemistry, 2012) (Xiang).
Regarding claim 1, Kaur teaches a method for quantifying target antibodies in a sample (abstract) comprising:
(a) spiking the sample with a labeled internal standard antibody (col. 29, line 18-20);
(b) digesting the antibodies in the sample to produce peptides (col. 29, line 20-21);
(c) fractionating the peptides, wherein the peptides are fractionated by solid phase extraction (SPE) (col. 29, line 21); and
(d) quantifying the target antibodies using a MS2 system containing one or more ion traps and two or more quadrupole mass filters and an electrospray ionizer (col. 29, lines 65; col. 34, line 5-23).
Kaur does not specifically teach direct infusion MS2 system. However, Xiang teaches direct infusion MS2 system (abstract). Xiang teaches that “The increased throughput of DI-MRM analysis is useful for rapid analysis of large batches of similar samples, such as time course measurements of cellular responses to therapy.” (abstract). It would have been obvious to one of ordinary skill in the art to use direct infusion MS2 system in Kaur’s method, in order to increase throughput for rapid analysis.
Regarding claim 2, Kaur teaches that the method further comprising the step of spiking the peptides with labeled, tagged Fc peptide VVSVLTVLHQDWLNGK (SEQ ID NO:1) prior to fractionation (col. 29, line 58-60, Table 3, SEQ ID 5).
Regarding claim 4, Kaur teaches that wherein the solid phase extraction is reverse phase solid phase extraction (col. 41, line 11-13).
Regarding claim 5, Kaur teaches that wherein labeled internal standard antibody and the mass-tagged Fc peptide are labeled with a heavy isotope (col. 29, lines 58-60).
Regarding claim 6, Kaur teaches that wherein the heavy isotope is selected from the group consisting of 13C, 15N, and 2H (col. 29, line 60).
Regarding claim 7, Kaur teaches that wherein the target antibody is a human monoclonal antibody (col. 29, lines 29-31).
Regarding claim 8, Kaur teaches that wherein the mass spectrometry system is a tandem mass spectroscopy system (col. 34, line 5-23).
Regarding claim 9, Kaur teaches a method of quantitating a protein drug product in a biological sample (abstract) comprising:
(a) spiking the sample with a known amount of a heavy mass tagged peptide surrogate having an amino acid sequence according to SEQ ID NO:1 (col. 29, 58-60, Table 3, SEQ 5);
(b) digesting protein drug product in the sample into peptides (col. 29, line 20-21);
(c) fractionating the peptides under conditions that retain peptides having an ammo acid sequence according to SEQ ID NO: 1 (col. 29, line 21), wherein the peptides are fractionated using reverse phase solid phase extraction (col. 41, line 11-13);
(d) analyzing the sample containing the protein drug product peptides and the peptide surrogates for the presence of the peptide having an amino acid sequence according to SEQ ID NO: 1 using an MS2 system to calibrate the system, wherein the MS2 system comprises one or more ion traps and two or more quadrupole mass filters and an electrospray ionizer (col. 29, lines 65; col. 34, line 5-23); and
(e) quantitating the amount of protein drug product present in the sample based upon the presence of the peptide (col. 34, line 5-23).
Kaur does not specifically teach direct infusion MS2 system. However, Xiang teaches direct infusion MS2 system (abstract). Xiang teaches that “The increased throughput of DI-MRM analysis is useful for rapid analysis of large batches of similar samples, such as time course measurements of cellular responses to therapy.” (abstract). It would have been obvious to one of ordinary skill in the art to use direct infusion MS2 system in Kaur’s method, in order to increase throughput for rapid analysis.
Regarding claim 10, Kaur teaches that wherein the data for quantifying drug product ions and mass tagged peptide standard ions are acquired in different MS2 scans (col. 34, line 14-17, Table 4).
Regarding claim 12, Kaur teaches that wherein the reverse phase solid phase extraction uses 15 to 25% acetonitrile as a wash and 20 to 30% acetonitrile as an elution (col. 41, line 11-13).
Regarding claim 13, Kaur teaches that the method further comprising spiking the sample of protein drug product with a heavy isotope-labeled protein drug product prior to digesting the sample (col. 29, line 28-20, 58-60).
Regarding claim 14, Kaur teaches that wherein the protein drug product comprises an antibody or an antigen binding fragment thereof, a recombinant protein, a fusion protein, or a combination thereof (col. 29, line 29-31).
Regarding claim 15, Kaur teaches that wherein the sample comprises serum (col. 2, line 47).
Regarding claim 16, Kaur teaches that wherein the method has a dynamic range of 1 to 1000 μg/mL (col. 29, line 24).
Regarding claim 17, Kaur teaches that wherein the method has Lower Limit of Quantification (LLOQ) of 1-2 μg/mL (col. 38, line 21-22).
Regarding claim 18, Xiang teaches that wherein the method is an automated high throughput method (page 1981, par 1).
Regarding claim 19, the phrase” wherein the method has an analytic speed of less than 1 minute per sample” merely describes an intended result and does not further limit the steps of the method.
Regarding claim 20, the phrase “wherein the method has a dynamic range of 2 to 2000 μm/mL” merely describes an intended result and does not further limit the steps of the method. Thus, carries no weight in patentability determination.
Regarding claim 21, Kaur teaches that wherein the reverse phase solid phase extraction uses 20% acetonitrile as a wash and 24% acetonitrile as an elution (col. 41, line 11-13).
Regarding claim 22, the phrase “the method has an analytic speed of 1.2 minutes per sample” merely describes an intended result and does not further limit the steps of the method. Thus, carries no weight in patentability determination.
Regarding claim 23, Kaur teaches that wherein the protein drug product comprises an antibody (col. 3, line 1-3).
Claim(s) 24-25 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kaur in view of Xiang as applied to claim 1-2, 3-10 and 12-23 above, and further in view of Daly et al. (US 7,279,159) (Daly).
Regarding claim 24, Kaur does not specifically teach that wherein the protein drug product comprises a trap protein. However, Daly teaches that wherein the protein drug product comprises a trap protein (abstract). It would have been obvious to one of ordinary skill in the art to use Kaur-Xiang method to analyze a trap protein, the result is predictable.
Regarding claim 25, Daly teaches that wherein the protein drug product comprises a VEGF trap protein (abstract).
Response to Arguments
Applicant's arguments filed 09/02/2026 have been fully considered but they are not persuasive.
Applicant argues that one of ordinary skill in the art would not have had a reasonable expectation of success in modifying Kaur according to Xiang because Xiang identifies limitations associated with low-intensity peptides, Kaur describes FSP5 (SEQ ID NO: 1) as exhibiting relatively weaker ionization and a low signal-to-noise ratio at the LLOQ, Xiang develops its DI-MRM assay using LC-MRM data, and Xiang cautions regarding application to samples having different biological backgrounds.
The arguments are not persuasive because Xiang does not teach that direct infusion is inoperative for lower-intensity peptides or that such peptides cannot be quantified. Rather, Xiang identifies conditions affecting the accuracy of DI-MRM and provides guidance for evaluating signal intensity and interference. Xiang reports a strong correlation between DI-MRM intensity and LC-MRM peak area when DI-MRM intensity is greater than 10 au and explains that each transition should be evaluated because the limits of detection and quantification depend upon the background noise associated with the particular transition. Thus, Xiang's identification of preferred signal levels reflects optimization of the direct-infusion assay rather than a teaching that lower-intensity peptides necessarily cannot be analyzed by direct infusion.
Further, Kaur's disclosure that FSP5 exhibits relatively weaker ionization and a signal-to-noise ratio of less than 5 at the 1 µg/mL LLOQ does not establish that FSP5 would fall below Xiang's DI-MRM intensity threshold or that direct-infusion quantification would be expected to fail. Kaur's reported signal-to-noise ratio and Xiang's reported DI-MRM intensity in arbitrary units are different measurements, and Applicant has not established that an S/N of less than 5 in Kaur's LC-MS/MS assay corresponds to a DI-MRM intensity of less than 10 au in Xiang. Moreover, Kaur expressly reports FSP5 as quantifiable at the stated LLOQ notwithstanding its relatively weaker ionization.
Additionally, Applicant's argument concerning FSP5 does not apply to the full scope of claim 1. Claim 1 does not require quantification using SEQ ID NO: 1, but broadly recites quantifying target antibodies after digestion and solid phase extraction. Claim 9 expressly recites SEQ ID NO: 1, but, as discussed above, the cited evidence does not establish that use of Xiang's direct-infusion approach with that peptide would have been expected to fail.
Applicant's argument that Xiang depends upon liquid chromatography is also not persuasive. Although Xiang used existing LC-MRM data to develop and evaluate its DI-MRM assay, Xiang expressly teaches removal of the LC separation step and direct infusion for increased-throughput protein quantification. The use of LC-MRM data for transition selection, interference assessment, or assay development does not mean that liquid chromatography is utilized by the subsequently performed direct-infusion MS analysis. The presently claimed methods likewise do not prohibit the use of previously generated LC data during assay development; they require that the direct infusion MS2 system does not utilize liquid chromatography.
Applicant's reliance on Xiang's discussion of differing biological backgrounds is likewise not persuasive. Xiang states that its particular correction-factor strategy may not be applicable to samples having different biological backgrounds because the interference contributions may differ. Applicant's cited passage therefore concerns the transferability of a particular correction-factor approach, not the operability of direct-infusion MRM itself. The claims do not require Xiang's correction-factor strategy, nor do they require application of the same correction factor across different species, tissues, or biological backgrounds.
Accordingly, Xiang's discussion of signal intensity, interference, and sample background would have provided one of ordinary skill in the art with considerations for optimizing a direct-infusion assay rather than discouraging the skilled artisan from using direct infusion. Xiang expressly teaches direct infusion as an alternative to LC-MRM for increasing analytical throughput, while Kaur teaches quantitative analysis of antibody-derived peptides. Therefore, one of ordinary skill in the art would have been motivated to employ Xiang's direct-infusion approach in Kaur's method with a reasonable expectation of successfully quantifying suitable antibody-derived peptides.
Applicant's arguments regarding dependent claims 2, 4-8, 10, and 12-23 are not persuasive because they rely upon the asserted nonobviousness of independent claims 1 and 9. Likewise, Applicant's argument regarding claims 24-25 is not persuasive because the alleged deficiency in Kaur and Xiang has not been established, and Daly remains relied upon for the additional trap-protein limitations. The rejections are therefore maintained.
Conclusion
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 XIAOYUN R XU, Ph. D. whose telephone number is (571)270-5560. The examiner can normally be reached M-F 8am-5pm.
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/XIAOYUN R XU, Ph.D./Primary Examiner, Art Unit 1797
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