DETAILED 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 § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-9 and 43 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites “wherein the steps b) to f) are performed on an automated system and on a cartridge” wherein it is unclear what method requirements Applicant intends for “performed on an automated system” given that no automation steps or means for automation are provided. Does Applicant intend to positively provide the automated system through a recitation on the order of “providing an automated system for performing...”? Similarly, Applicant’s recitation to the method performed “on a cartridge” appears to require the cartridge through a narrative-type discussion, but as currently recited the performed “on a cartridge” is drawn to a mere intended use. Does Applicant intend to positively provide the automated system through a recitation on the order of “providing a cartridge for performing...”?
Claim 2 recites “in step d) the obtained mix of the nucleic acid fragments and said preservative or a stabilizing agent”. However, the mix containing preservative is not obtained until step f). Applicant may intend to recite step f) in Claim 2 instead of step d).
Claim 3 is thereby rejected for its dependence on Claim 2.
Claim 43 recites, similarly as above regarding Claim 1, “at least steps (b) and (c) are performed on a cartridge”. Does Applicant intend to positively provide the automated system through a recitation on the order of “providing a cartridge for performing...”?
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 4, and 6-9, as best understood, are rejected under 35 U.S.C. 103 as being unpatentable over Hu et al. (Hu, Fei; et al., “Rapid isolation of cfDNA from large-volume whole blood on a centrifugal microfluidic chip based on immiscible phase filtration”, Analyst, 2019,144, 4162-4174.), hereinafter “Hu”, in view of Rubio et al. (US 2004/0229368 A1), hereinafter “Rubio”, and Williams et al. (US 2018/0344568 A1), hereinafter “Williams”.
Regarding Claim 1, Hu teaches a method for extraction of nucleic acid fragments from a blood sample comprising the steps of:
providing a blood sample taken from an individual (See the “Sample preparation and loading” section: “Venous blood was obtained from a healthy volunteer of our laboratory.”);
contacting the plasma sample with a binder material specific to nucleic acids (See the “Sample preparation and loading” section: “lysis/binding buffer (1.25 ml) was introduced into the sample chamber for cfDNA extraction” – See also the “cfDNA extraction by IFAST” section: “lysis/binding buffer to effectively bind the cfDNA” – Further note that Hu produces the plasma sample via gentle centrifugation to remove the whole red blood cells, see Rubio below regarding the fixation and filtering steps.), or alternatively subjecting the plasma sample to electrophoresis in a separating medium, in order to purify nucleic acid fragments present in said plasma sample, wherein said separating medium is prepared so that nucleic acid fragments are capable of migrating in the medium and can be separated in said medium by size (See the “Introduction” section: “A variety of microfluidic technologies have been developed for the extraction and purification of cfDNA from blood such as...dielectrophoresis (DEP)”);
collecting the nucleic acid fragments (See the “cfDNA extraction by IFAST” section: “After plasma separation, the disk began with the nucleic acid extraction.”); and
wherein the steps are performed on an automated system (See the “The limiting factors of DNA recovery” section: “...automatic and rapid cfDNA extraction from large volume samples.”) and on a cartridge comprising a first compartment for filtering plasma from a blood sample (See Fig. 1: “plasma separation chamber” – Note that “filtering” is defined as “to remove solids from liquids or gases” as in Cambridge Dictionary.) and a second compartment for contacting the plasma sample with a binder material specific to nucleic acids (See Figs. 4a-c showing the plasma flowing into the nucleic acid extraction structure (Fig. 1) containing binding buffer.),
as in Claim 1.
Further regarding Claim 1, Hu does not specifically teach the method discussed above comprising b) stabilizing blood cells in the sample with a fixative reagent; and c) filtering the blood sample in order to separate plasma from said blood sample by using a hollow fiber filter, as in Claim 1.
However, Rubio teaches a respective method for isolating red blood cells from plasma wherein the cells are stabilizes using a fixative and filtered out using a hollow fiber filter (See Fig. 2A and paras. [0039, 0044, 0051].) so as to isolate whole cell components from DNA for analysis ([0035]). Similarly, Hu seeks to isolate whole blood components from DNA but does so through gentle centrifugation instead of fixation and filtering, wherein fixation and filtering thereby represent a mere obvious alternative to gentle centrifugation for isolating plasma and DNA from whole cell components, and wherein the fixative provides a stabilization to further prevent blood cell degradation during the separation that may contaminate the plasma (having the cfDNA therein).
Thus, one of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to modify the method of Hu further comprising b) stabilizing blood cells in the sample with a fixative reagent; and c) filtering the blood sample in order to separate plasma from said blood sample by using a hollow fiber filter, such as suggested by Rubio, as a mere obvious alternative for achieving the identical result of removal of whole red blood cell components in Hu, and would have a reasonable expectation of success therein.
Further regarding Claim 1, Hu does not specifically teach the method discussed above comprising f) mixing the nucleic acid fragments with a preservative or a stabilizing agent, as in Claim 1.
However, Williams teaches a patient sample collection system 100 for nucleic acid samples having a sample collection chamber loaded 110 with a sample preservation reagent 108 (Fig. 1 and para. [0037]: “the reagent or buffering solution stabilizes at least one element or compound within the sample (e.g., nucleic acids, such as DNA and RNA, protein, and combinations thereof) during transfer, transportation, and/or storage at a laboratory, clinic, or other destination.”), wherein this arrangement reduces sample degradation while samples are stored for future analysis, thereby reducing errors related to degraded samples.
Thus, one of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to modify the method of Hu further comprising f) mixing the nucleic acid fragments with a preservative or a stabilizing agent, such as suggested by Williams, so as to reduce sample degradation while samples are stored for future analysis, thereby reducing errors related to degraded samples.
Regarding Claim 4, the prior art meets the limitations of Claim 1 as discussed above. Further, Hu teaches the method discussed above wherein the length of said nucleic acid fragments is less than 400 bp (See the “Sample preparation and loading” section: “100–200 bp cfDNA”), as in Claim 4.
Further note limitations based on the intended use of a structure do not confer patentability if the prior art is capable of performing the same function – see MPEP 2111.02(II).
Regarding Claim 6, the prior art meets the limitations of Claim 1 as discussed above with respect to Hu in view of Rubio (and Williams). Further, as discussed above regarding Claim 1, Hu is modified with a hollow fiber filter supplied by Rubio via obvious modification as an obvious alternative to the gentle centrifugation in Hu. Furthermore thereto, Rubio discloses the hollow fiber filter as a hollow fiber membrane ([0039] – See also [0005].), as in Claim 6.
Thus, one of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious that, when modifying the device of Hu with the hollow fiber filter of Rubio, as in Claim 1, to provide said hollow fiber filter as a hollow fiber membrane so as to achieve the intended filtering effects sought by Rubio.
Regarding Claim 7, the prior art meets the limitations of Claim 1 as discussed above. Further, Hu teaches the method discussed above wherein the plasma sample is contacted with a binder material specific to nucleic acids (See the “Sample preparation and loading” section: “The lysis/binding buffer, elution buffer, and magnetic bead suspension used in this study were obtained from the MagMAX Cell-Free Total Nucleic Acid Kit (A36716, ThermoFisher, USA).” – See also the “cfDNA extraction by IFAST” section.), as in Claim 7.
Regarding Claim 8, the prior art meets the limitations of Claim 7 as discussed above. Further, Hu teaches the method discussed above wherein said binder material comprises magnetic beads (See the “cfDNA extraction by IFAST” section: “mix magnetic beads with plasma and lysis/binding buffer to effectively bind the cfDNA onto the surface of magnetic beads”), as in Claim 8.
Regarding Claim 9, the prior art meets the limitations of Claim 1 as discussed above. Further, Hu teaches the method discussed above further comprising contacting the nucleic acid fragments bound to said binder material with a nucleic acid binding dye and measuring the amount of collected nucleic acid fragments (See the “Real-time fluorescence quantitative PCR” section: “probes”.), as in Claim 9.
Claims 2-3, as best understood, are rejected under 35 U.S.C. 103 as being unpatentable over Hu in view of Rubio and Williams, as applied to Claims 1, 4, and 6-9 above, and in further view of Kloke et al. (Kloke, A.; et al., “The LabTube – a novel microfluidic platform for assay automation in laboratory centrifuges”, Lab Chip, 2014,14, 1527-1537.), hereinafter “Kloke”.
Regarding Claim 2, the prior art meets the limitations of Claim 1 as discussed above. Further, Hu/Rubio/Williams does not specifically teach the method discussed above wherein in step d) the obtained mix of the nucleic acid fragments and said preservative or a stabilizing agent is stored into a removable container, as in Claim 2.
However, Kloke teaches a respective method for DNA extraction from whole blood (Abstract) comprising a three-stage revolving system wherein the first stage is for sample input, the third stage is for DNA extraction, and the third stage is for collection of the extracted DNA sample in a removable tube (See Fig. 2 and the “Cartridge design and integrated unit operations” section.), thereby allowing the isolated DNA sample to be automatically stored in a standard container for future analysis. Thus, one of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to modify the method of Hu/Rubio/Williams wherein the obtained mix of the nucleic acid fragments and said preservative or a stabilizing agent is stored into a removable container, such as suggested by Kloke, so as to allow the isolated DNA sample to be automatically stored in a standard container for future analysis.
Regarding Claim 3, the prior art meets the limitations of Claim 2 as discussed above. Further, given that Hu/Rubio/Williams teaches binding of the nucleic acid fragments without specifying a reversal step (of the DNA becoming unbound), the mix recited in Claim 2 as flowing into a removable container (provided by Kloke) thereby comprises the nucleic acid fragments bound to said binder material, as in Claim 2.
Claim 5, as best understood, is rejected under 35 U.S.C. 103 as being unpatentable over Hu in view of Rubio and Williams, as applied to Claims 1, 4, and 6-9 above, and in further view of Augello et al. (US PAT 6,821,789 B2), hereinafter “Augello”.
Regarding Claim 5, the prior art meets the limitations of Claim 1 as discussed above. Further, Hu/Rubio/Williams does not specifically teach the method discussed above wherein the blood sample is mixed with an anticoagulant before subjecting the sample to the filtering step, as in Claim 5.
However, Augello teaches a respective method for nucleic acids isolation from a whole blood sample wherein the blood sample is collected directly into a tube pre-loaded with citrate anticoagulant and stabilization buffer (See Example 4.). Thereafter, the sample is subject to a filtration step through a membrane (See Example 4.). Therein, this arrangement prevents the blood sample from coagulating and clogging the filter, which would be similarly appreciated for its anti-clogging effects in the narrow channels of the microfluidic device of Hu.
Thus, one of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to modify the method of Hu/Rubio/Williams wherein the blood sample is mixed with an anticoagulant before subjecting the sample to the filtering step, such as suggested by Augello, so as to prevent the blood sample from coagulating and clogging the filter, which would be similarly appreciated for its anti-clogging effects in the narrow channels of the microfluidic device of Hu.
Claim 43, as best understood, is rejected under 35 U.S.C. 103 as being unpatentable over Hu in view of Rubio. Hu and Rubio have been discussed above.
Regarding Claim 43, Hu teaches a method for extracting nucleic acid fragments from a blood sample, comprising:
providing a blood sample obtained from an individual (See the “Sample preparation and loading” section: “Venous blood was obtained from a healthy volunteer of our laboratory.”);
separating plasma from the blood sample (See Fig. 4 and the “Plasma separation” section.);
isolating nucleic acid fragments from the plasma by contacting the plasma with a binder material specific to nucleic acids (See the “Sample preparation and loading” section: “lysis/binding buffer (1.25 ml) was introduced into the sample chamber for cfDNA extraction” – See also the “cfDNA extraction by IFAST” section: “lysis/binding buffer to effectively bind the cfDNA” – Further note that Hu produces the plasma sample via gentle centrifugation to remove the whole red blood cells, see Rubio below regarding the fixation and filtering steps.) or by subjecting the plasma to electrophoresis in a separating medium (See the “Introduction” section: “A variety of microfluidic technologies have been developed for the extraction and purification of cfDNA from blood such as...dielectrophoresis (DEP)”),
wherein at least steps (b) and (c) are performed on a cartridge comprising a first compartment (Fig. 1: “plasma separation chamber) where step (b) of separating plasma is carried out (See Fig. 4 and the “plasma separation” section.) and a second compartment (Fig. 1: “nucleic acid extraction structure”) where step (c) of isolating nucleic acid fragments is carried out (See Fig. 4 and the “cfDNA extraction by IFAST” section.),
as in Claim 43.
Further regarding Claim 43, Hu does not specifically teach the method discussed above wherein the plasma separation step is performed using a hollow fiber filter, as in Claim 43.
However, Rubio teaches a respective method for isolating red blood cells from plasma wherein the cells are stabilizes using a fixative and filtered out using a hollow fiber filter (See Fig. 2A and paras. [0039, 0044, 0051].) so as to isolate whole cell components from DNA for analysis ([0035]). Similarly, Hu seeks to isolate whole blood components from DNA but does so through gentle centrifugation instead of fixation and filtering, wherein fixation and filtering thereby represent a mere obvious alternative to gentle centrifugation for isolating plasma and DNA from whole cell components.
Thus, one of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to modify the method of Hu wherein the plasma separation step is performed using a hollow fiber filter, such as suggested by Rubio, as a mere obvious alternative for achieving the identical result of removal of whole red blood cell components in Hu, and would have a reasonable expectation of success therein.
Conclusion
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/B.J.K./Examiner, Art Unit 1798
/NEIL N TURK/Primary Examiner, Art Unit 1798