DETAILED ACTION
The amendment and RCE filed on 03/20/2026 has been entered and fully considered. Claims 1-2, 4-10 and 12-25 are pending, of which claims 1 and 9 are amended.
Response to Amendment
In response to amendment, the examiner maintains rejection over the 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 02/23/2026 have been fully considered but they are not persuasive.
Applicant argues that Xiang teaches only a DI-MRM system using a triple quadrupole and therefore does not teach the claimed "direct infusion MS2 system".
This argument is not persuasive. Multiple Reaction Monitoring (MRM) performed on a triple quadrupole instrument is a well-established form of tandem mass spectrometry (MS/MS) operated in MS2 mode.
In MRM:
a first quadruple selects a precursor ion (Q1),
fragmentation occurs in a collision cell (Q2),
a third quadrupole filters product ions (Q3).
This is a classical MS/MS work flow.
Thus, Xiang's disclosure of direct infusion MRM mass spectrometry inherently teaches direct infusion tandem mass spectrometry (MS/MS) performed in MS2 mode. The fact that Xiang abbreviates its system as "DI-MRM" does not distinguish it structurally or functionally from MS/MS analysis.
Applicant's assertion that the term "direct infusion MS/MS (DI-MRM)" does not appear verbatim in Xiang is not dispositive. Obviousness does not require identical terminology, it requires that the prior art teaches or suggests the claimed subject matter. Xiang expressly teaches direct infusion tandem mass spectrometric quantification of peptides without liquid chromatography and therefore satisfies the claimed "direct infusion MS2 system" limitation.
Applicant argues that Xiang does not teach a system "containing one or more ion traps and two or more quadrupole mass filters"
This argument is not persuasive.
First, Xiang expressly teaches a triple quadrupole mass spectrometer, which necessarily includes two or more quadrupole mass filters. A triple quadrupole mass filtering stages (Q1 and Q3). Therefore, the "two or more quadrupole mass filters" limitation is satisfied by Xiang.
Second, the claims broadly recite "one or more ion traps and two or more quadrupole mass filters" without requiring that the ion trap be distinct from or functionally separate from the quadrupole stages. Hybrid quadrupole/ion-trap systems were well known in the art at the time of the invention. The selection of a known hybrid mass analyzer (e.g. quadrupole-Orbitrap or quadrupole-ion trap) in place of a conventional triple quadrupole would have been a routine substitution of one known mass spectrometry platform for another to perform the same tandem MS function.
Kaur already teaches peptide-level quantification using MS/MS instrumentation. Xiang teaches performing such MS/MS analysis by direct infusion and eliminating LC to increase throughput. It would have been obvious for a person of ordinary skill in the art to employ any known MS/MS platform capable of precursor selection and product ion detection, including hybrid quadrupole/ion-trap system, to implement the obvious combination.
Accordingly, the claimed mass spectrometer architecture represents, at most, the predictable use of known instrument configurations to perform known tandem MS peptic quantification.
Applicant argues that the claimed "fractionating the peptide... by solid phase extraction" distinguished over Xiang.
This argument is not persuasive. Kuar teaches digestion of antibodies into peptides and performing sample preparation steps, including solid phase extraction, prior to MS/MS quantification. The use of solid phase extraction (SPE) for peptide cleanup and fractionation was conventional and widely used for reduce matrix interference prior to MS analysis.
When eliminating liquid chromatography as taught by Xiang, a person of ordinary skill in the art would have recognized the need to manage sample complexity and matrix effects. Employing solid phase extraction prior to direct MS/MS would have been an obvious and routine preparative step to improve signal quality and reproducibility in the absence of chromatographic separation.
Therefore, the SPE limitation does not confer patentable distinction over the combination of Kaur and Xiang.
Applicant argues that because Xiang uses DI-MRM and Kaur uses LC-MRM, there would be no motivation to modify LC-MRM to arrive at a DI-MS/MS system.
This argument is not persuasive. Xiang expressly teaches that elimination of liquid chromatography increases throughput and reduces analysis time. Kaur teaches quantitative antibody peptide analysis using MS/MS. A person of ordinary skill in the art seeking to increase throughput in Kaur's would have been motivated to adopt Xiang's direct infusion approach to eliminate LC while retaining MS/MS quantification.
This represents a straight forward application of one known improvement (direct infusion tandem MS for high throughput) to another known method (antibody peptide quantification), yielding predictable results.
Conclusion
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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