DETAILED ACTION
Response to Arguments
Applicant's arguments filed 30 December 2025 have been fully considered but they are not persuasive.
Rejections under 35 USC § 112(b)
Claim 50 has been cancelled. Therefore the rejection is withdrawn.
Rejections under 35 USC § 103: Pawliszyn in view of Zaitsu et al. or Hiraoka
Initially, the remarks take the position that that the combination of Pawliszyn in view of Zaitsu or Hiraoka is based on hindsight.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Here, the combination was taken only from knowledge available from Pawliszyn in view of Zaitsu or Hiraoka and not gleaned from the applicant’s disclosure. Therefore, the combination is proper.
Next the remarks take the position that the combination does not take into account the unexpected technical effects achieved by the claimed invention.
This has not been found persuasive. Specifically, there are no disclosed “unexpected results” in the instant specification. MPEP 2145 recites:
“ A showing of unexpected results must be based on evidence, not argument or speculation. In re Mayne, 104 F.3d 1339, 1343-44, 41 USPQ2d 1451, 1455-56 (Fed. Cir. 1997) ”
Here, no evidenced has been provided that immersing the probe in a solvent would lead to unexpected results. Therefore, this point has also been found unpersuasive.
Next, the remarks admit that Pawliszyn discloses a step of adhering solvent, wherein the solvent is applied by droplet or inject sprayer. However, suggest that Pawliszyn in unaware of the technical problems associated with such a step, in that it is difficult to efficiently and uniformly elute the analytes from the extraction phase.
Initially, it is noted that the Non-Final rejection, at page 4, acknowledges the deficiency of Pawliszyn failing to disclosure the adhering of solvent by immersing the probe into the solvent. However, it is important to note, as admitted in the results that adhereing a solvent to the extraction phase is disclosed by Pawlizyn. Pawlizyn therefore merely fails to disclose how the solvent is applied (i.e. by immersion).
The remarks next point out that Hiraoka and Zaistu are not coated with an extraction phase. This does not overcome the combination, because Hiraoka/Zaistu were not relied upon for teaching applying a solvent to an extraction phase. This feature was already disclosed in Pawlizyn as admitted in the remarks.
The applicant is reminded, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
That is, because Pawlizyn merely fails to disclose how the solvent is applied, the secondary references were only used to demonstrate that immersion of a probe into a solvent was known to the art.
In response to applicant's argument that Hiraoka nor Zaitsu teaches the technical problems involved in adsorbing target components to an extraction phase or how to solve them, 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).
In the instant case, as pointed out in the last office action. Pawliszyn and Zaitsu both teach blood as the sample. Zaitsu teaches that, when blood is the sample, in a relatively short time upon being exposed to air the blood will coagulate. Thus, if blood adheres to the surface of the probe, it will gradually coagulate, making it difficult to generate ions derived from the target component by apply a high voltage to the probe ([0012] of Zaitsu). Therefore, the immersion of the probe in the solvent will improve ionization of the target analytes in the blood.
Additionally, Zaitsu is evidence that “since the solvent itself does not readily mix with blood and since the amount of solvent is large, as described above, the coagulation of blood adhered to the tip of the probe can also be avoided.” ([0028]). That is, Zaitsu teaches a large amount of solvent avoids the negative effects of coagulation of blood.
In other words, while Pawlizyn teaches applying a small amount of solvent by droplets or injection spray. Zaitsu teaches coagulation occurs if the sample is exposed to air making it difficult to generate ions. Therefore, by immersing the sample and probe into a large amount of solvent avoids coagulation and improves ionization in the method of Pawlizyn.
The remarks then suggest the combination fails to provide an important and unexpected technical advantage that a person skilled in the art could not of expected of a new immersion method which allows the solvent to be distributed evenly over the entire surface of the extraction phase. Initially, it is noted there is no evidence to suggest this would be unexpected. Additionally, there is no claimed requirement that the immersion results in the solvent be evenly distributed or by what distinguishing immersion technique allows for such a result to occur. That is, with respect to any particular technique of immersion, claim 1 is silent, therefore any teaching of immersion is sufficient to meet the claimed invention.
The remarks then suggest a hidden problem faced by Pawlizyn and a person skilled in the art would not have been motivated to apply the disclosures of Hiraoka or Zaitsu as a solution to that hidden problem.
It is not clear what hidden problem the remarks refer. As pointed out above, Pawlizyn already discloses applying a solvent to the extraction phase (using minimal solvent provided by drops or spray), wherein the sample may be blood. Zaitsu teaches the problem of exposing blood to air and a solution being to immerse the probe and sample into a large amount of solvent. Zaitsu teaches the advantage being preventing improving ionization of the target analyte molecules in the blood. Therefore, modifying the application of the solvent of Pawlizyn to be an immersion as suggested in Zaitsu would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention because it would prevent the blood sample from being in contact with air, therefore avoiding coagulation and improving ionization of target ions.
The remarks then contend that Pawliszyn already discloses the use of solvent, therefore there would be no motivation to substitute the application of immersion as suggested by Zaitsu.
This again has not been found persuasive because the solvent application discussed in Pawliszyn is by droplet or spray, whereas Zaitsu suggests to use a large amount of solvent so as to prevent coagulation of the target ions in the blood sample. Immersion in a large amount of solvent would inherently result in adhesion of more solvent then the application by drop or by spray. Moreover, by such an application it would ensure entire coverage of the sample on the probe. Thus as suggested in Zaitsu such a method of application would have the advantage of avoiding coagulation by the solvent coating the sample entirely and avoiding contact of the sample with air.
Lastly, the remarks again reiterate similar points discussed above, which are not persuasive for the same reasons discussed above.
Therefore, the remarks are not persuasive and the rejection stands as reiterated herein below.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim 29 is rejected under 35 U.S.C. 103 as being unpatentable over Pawliszyn et al. (WO 2015/188282) (submitted with IDS of 09/30/2022) in view of Zaitsu et al. (US pgPub 2019/0079050).
Alternatively, claims 29, 31-33, 35-44, 47-50 and 55 are rejected under 35 U.S.C. 103 as being unpatentable over Pawliszyn et al. (WO 2015/188282) (submitted with IDS) in view of Hiraoka (WO2018/207903) (copy of publication submitted herewith) as evidenced by Zaitsu.
Regarding claim 29, Pawliszyn et al. teach a method for identifying a target component of interest in a specimen by probe electrospray ionization mass spectrometry ([0002] teaches MS is a tool to identify and quantitate molecules, figure 2 shows a coated SPME probe 22 where the sample undergoes MS, see paragraph [0060]. Paragraph [0044] teaches extraction coating adsorbs analytes of interest, thus the method of MS identifies molecules, wherein the molecules extracted by SPME for MS analysis are the target component of interest), the method comprising:
(1) adsorbing the target component of interest onto an extraction phase for adsorbing the target component of interest from the specimen ([0044] coating adsorbs analytes of interest) by immersing a probe into the specimen ([0060], preconditioned substrate is inserted into a vail containing the sample (i.e. coated substrate is immersed in the specimen)), wherein the probe is at least partially coated with the extraction phase ([0044] solid substrate is coated with an extraction polymer);
(2) removing the probe from the specimen ([0060], rapidly rinsed in a vial containing water at 16, thus removed from vial 12 to be rinsed);
(3) applying solvent to the extraction phase ([0060] solvent applied to wet solid coated substrate and extract or concentrate analytes adsorbed by coating);
(4) desorbing the target component of the interest into the solvent applied to the probe from the extraction phase ([0049] and [0060]);
(5) electrospraying the target component of interest desorbed in the solvent adhered to the probe on the ionization source at atmospheric pressure by applying a voltage to the probe to spray aerosolized ionized droplets out of the probe ([0060]); and,
(6) identifying the small molecule component of interest present in the aerosolized ionized droplets (identification by MS as discussed in paragraph [0002] and [0060], wherein since the analytes of interest are extracted by SPME, the identification is of the desorbed and ionized molecules of interest).
Pawliszyn fails to disclose the solvent is adhered and wherein the step of adhering solvent includes adhering the solvent to the extraction phase by immersing the probe into the solvent and removing the probe from the solvent.
However, Zaistu teaches the solvent is adhered (abstract) and wherein the step of adhering solvent includes adhering the solvent to the probe by immersing the probe into the solvent and removing the probe from the solvent ([0065] and figure 2).
Zaitsu modifies Pawliszyn by suggesting immersing the probe in a solvent such that a portion of the sample come to be encased in the solvent.
Since both inventions are directed towards using a probe for sampling and electrospray ionization, it would have been obvious to one of ordinary skill in the art to apply the immersion and adhesion of the solvent of Zaistsu to the extraction phase coated probe of Pawliszyn because Zaitsu teaches when blood is the sample (as suggested in Pawliszyn ([0015])), in a relatively short time upon being exposed to air the blood will coagulate, thus, if blood adheres to the surface of the probe, it will gradually coagulate, making it difficult to generate ions derived from the target component by apply a high voltage to the probe ([0012] of Zaitsu). Therefore, since the solvent itself does not readily mix with blood ([0028]), by immersing the probe in the solvent the coagulation of blood adhered to the probe can be avoided ([0028]) thus improving the ionization of target analytes from a blood sample as described in Pawlizyn.
Alternatively, Hiraoka teaches the solvent is adhered ([0034]-[0035] teaches bringing the probe 11 in contact with the solvent storage unit 31 (see figures 4 and 8) to allow the sample to repeatedly obtain the solvent and intermittently supplying the solvent to the sample. Since the probe is dipped into the solvent reservoir ([0034]) at least some solvent is adhered in order for it to be supplied to the sample on probe 11) and wherein the step of adhering solvent includes adhering the solvent to the probe by immersing the probe into the solvent and removing the probe from the solvent (see figures 4 and 8 and paragraphs [0034]-[0035] which teach dipping (i.e. immersing) the probe into the solvent storage or reservoir).
Hiraoka modifies Pawliszyn by suggesting dipping the coated probe into the solvent (note Hiraoka envisioned a coated probe see figure 7 coating insulator 15).
Since both inventions are directed towards probe electrospray ionization, it would have been obvious to one of ordinary skill in the art to modify the solvent application process of Pawliszyn to include an immersion of the probe in the solvent as suggested by Hiraoka because it would enable ionization of components in a sample that are relatively difficult to ionize ([0012]). Since Pawlizyn teaches ionization of blood and as evidenced by Zaitsu, blood is difficult to ionize, providing the immersion suggested by Hiraoka would enable ionization of such a difficult to ionize sample.
Regarding claim 31 Pawlizyn in view of Hiraoka teaches wherein the target component of interest is eluted into the solvent being adhered to at least one of the extraction phase and the probe by repeating the step of adhering (Hiraka, paragraph [0034] note dipping into solvent at least once and paragraph [0035] intermittently supplying the solvent (i.e. repeatedly). Note Pawlizyn teaches the extraction phase on probe, thus modified by Hiraoka as discussed above in claim 29).
Regarding claim 55, Pawliszyn in view of Hiraoka teach the step of rinsing the extraction phase and the probe before the step of adhering (Pawliszyn teaches rinsing before application of solvent in paragraph [0060], adhering suggested in Hiraoka discussed above in claim 29).
Regarding claim 32, Pawliszyn further teaches wherein the step of rinsing includes rinsing at least one of the extraction phase and the probe with at least one selected from the group consisting aqueous, organic solvent and mixture thereof (rinsing with water (i.e. aqueous))..
Regarding claim 33, Pawliszyn teaches wherein the step of rinsing includes rinsing the probe with water to remove large molecular weight interferences ([0046] rinsing to remove artefacts adhered to the coating surface, paragraph [0015] teaches artefacts such as fibers, proteins, cells. Thus large molecular weight interferences).
Regarding claim 35, Pawliszyn teaches wherein the solvent further comprises at least one selected from the group consisting of aqueous, organic solvent and mixture thereof ([0060] teaches solvent included in desorption solution, paragraph [0058] teaches water, acetonitrile , isopropanol, methanol with 0.1% formic acid as the solvents).
Regarding claim 36, Pawliszyn in view of Hiraoka teaches wherein an abundance rate of aqueous based on the solvent is from 30 to 70% in weight (Pawliszyn teaches combinations of water and methanol [0058], however does not disclose the abundance. However, paragraph [0084] of Hiraoka teaches a 1:1 water: methanol mixed solvent, thus 50% abundance water or aqueous. The combination is obvious because it provides an appropriate combination of water and methanol to achieve the intended purpose).
Regarding claim 37, Pawliszyn teaches wherein the solvent comprises an organic solvent ([0058], isopropanol).
Regarding claim 38, Pawliszyn teaches wherein the organic solvent is alcohol ([0058], isopropanol).
Regarding claim 39, Pawliszyn teaches wherein the alcohol is isopropanol ([0058]).
Regarding claim 40, Pawliszyn teaches wherein the solvent further comprises acidic compound ([0058], formic acid).
Regarding claim 41, Pawliszyn in view of Hiraoka teaches dipping the probe into the solvent after the step of electrospraying, wherein the step of electrospraying and the step of dipping are repeated (Hiraoka see paragraph [0076]).
Regarding claim 42, Pawliszyn teaches wherein the extraction phase comprises a polymer having solid pores and particles that are sized to adsorb the target components ([0020] teaches polyacrylonitrile, which is one of the instant application’s disclosed extraction phases, thus interpreted to have solid pores and particles sized to adsorb the target components. Note there are other overlapping extraction phases between the instant invention and Pawliszyn).
Regarding claim 43, Pawliszyn teaches wherein the extraction phase comprises coating binder to prevent adsorption of non-target components onto the extraction phase ([0054] teaches a coating dissolved in solvent, specifically DMF and applied to substrate. As evidenced by the instant specification DMF is a coating binder [0105], thus results in the claimed prevention. MPEP 2112 (II) an inherent feature need not be recognized at the relevant time. Here, as evidenced by the instant specification DMF is a binder to prevent adsorption of non-target components onto the extraction phase. Since Pawliszyn teaches DMF, the same result will inherently occur).
Regarding claim 44, Pawliszyn teaches wherein the extraction phase comprises substituted or unsubstituted poly (dimethylsiloxane), polyacrylate, poly (ethylene glycol), poly(divinylbenzene) or polypyrrole (polyethylene glycol polyroole ([0050]), wherein each is either substituted or unsubstituted).
Regarding claim 47, Pawliszyn teaches wherein the extraction phase comprises a bioaffinity agent selected from the group consisting of a selective cavity, a molecular recognition moiety, a molecularly imprinted polymer and an immobilized antibody ([0052] wherein the coating is formed with extractive particles including molecular imprinted polymer particles).
Regarding claim 48, Pawliszyn teaches wherein the specimen is a biological system ([0050] note tissue specifically organs. See also Hiroake [0084] salmon roe (i.e. biological system)).
Regarding claim 49, Pawliszyn teaches wherein the extraction phase comprising a component preventing adsorbing macromolecules ([0054] teaches a coating dissolved in solvent, specifically DMF and applied to substrate. As evidenced by the instant specification DMF is a coating binder [0105], thus results in the claimed prevention).
Regarding claim 50, Pawliszyn teaches wherein a volume of the extraction phase is in a low nL range and a volume of the solvent adhered to the probe in the low pL range (Pawliszyn teaches an extraction phase volume coated on the probe ([0044]) and a volume of solvent applied to the probe ([0060] and figure 2, 20). Since the fluid amount may be measured in nL and pL, the volume of extraction phase and solvent in the respective nL and pL units is interpreted to be in a low range to a greater volume).
Claim 34 is rejected under 35 U.S.C. 103 as being unpatentable over Pawliszyn in view of Hiraoka and further in view of Miao (CN208937594) (copy of translated abstract submitted herewith).
Regarding claim 34, the Pawliszyn teaches a vortex agitator to rinse the extraction phase and the probe ([0060]), however fails to disclose the rinsing is via spray.
However, Miao teaches rinsing a needle via a spray generated vortex (see translated abstract).
Miao modifies the combined device by suggesting a structure for the vortex agitator.
Since both inventions are directed towards vortex generators for the purpose of cleaning a probe, it would have been obvious to one of ordinary skill in the art to apply the spray generated vortex generator to the vortex agitator of Pawliszyn in view of Hiraoka because the washing effect is remarkably improved compared with a traditional needle cleaner (see translated abstract).
Claims 45-46 are rejected under 35 U.S.C. 103 as being unpatentable over Pawliszyn in view of Hiraoka and further in view of Pawliszyn (US pgPub 2005/0276727)(herein P2).
Regarding claims 45-46, while Pawliszyn in view of Hiroaka teach several non-limiting suitable extraction phase elements, the combined device fails to expressly suggest substituted or unsubstituted poly(divinylbenzene or an extraction phase comprising a bioaffinity agent that has a selective cavity.
However, P2 teaches substituted or unsubstituted poly(divinylbenzene) ([0166], [0260]) or an extraction phase comprising a bioaffinity agent that has a selective cavity ([0084]).
P2 modifies the combined device by teaching other types of extraction phase coatings and bioaffinity agents that could be substituted for polypyrrole or polyethelyene glycol (Pawlyszyn [0051]) or the molecular imprint polymer disclosed in Pawliszyn ([0052]).
Since both inventions are directed towards extraction phase coated probes and P2 teaches the substituted elements of the extraction phase were known to be used as alternatives to the elements of the extraction phase disclosed by Pawliszyn, it would have been obvious to one of ordinary skill in the art to substitute the components of Pawliszyn for those of P2 because it would lead to the predictable results of extracting target molecules for desorption, ionization and mass analysis (MPEP 2143 (I)(B)).
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 MICHAEL J LOGIE whose telephone number is (571)270-1616. The examiner can normally be reached M-F: 7:00AM-3:00PM.
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/MICHAEL J LOGIE/Primary Examiner, Art Unit 2881