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.
Claim 9 is 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. The language “wherein the digital signal is within a single-vesicular manufacture threshold” is not understood, rendering the scope of the claim indefinite. It is also unclear how this would relate to the language in claim 1 that the “digital signal” comprises “a percentage of fluorescing reactor microenvironments”. Appropriate clarification is required.
Claims 10-12 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. The language of claim 10 is unclear. In particular it is unclear what is meant by “a respective count”. Appropriate clarification is required.
Claim 11 is 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. The term “several thousand” is vague and indefinite, as there could be disagreement as to how many thousand is needed to constitute “several thousand”.
Allowable Subject Matter
Claims 1-8 and 13-18 are allowed.
The following is a statement of reasons for the indication of allowable subject matter: the claimed invention requires capturing manufactured vesicles comprising target nucleic acids (e.g., liposomes or lipid nanoparticles loaded with, e.g. mRNA or miRNA). The vesicles are captured onto an “intermediate capture medium” (e.g. a magnetic bead) which is then sealed within “a plurality of sealable reactor environments”. This latter aspect means that the intermediate capture medium must be a plurality of discrete entities, rather than a single monolithic structure, so as to allow for the production of a plurality of reactor environments each having intermediate capture medium. PCR is then conducted within these reactor environments, and two different types of measurements are taken. First, a percentage of fluorescing reactor environments is determined (a digital readout of each reactor environment being positive or negative for target). Second, for each reactor environment, a fluorescence intensity is measured after each cycle for a plurality of PCR cycles. These two different types of measurement allow for the determination of the number of vesicles containing target, and for each such vesicle, the number of target nucleic acid molecules contained within the vesicle, respectively. This procedure is not taught or fairly suggested in the prior art.
CN110106233A discloses a method for PCR detection of exosomes containing nucleic acid. Such exosomes are not manufactured as such, but naturally occurring in the circulation. The method includes capturing exosomes to microspheres. The reference also discloses (paragraph [0021] of the translation included herewith): “The digital PCR detection method for extracellular vesicles/exosomes is characterized in that the quantification method in step 2) includes a relative quantification method based on fluorescence signal intensity and an absolute quantification method based on the counting of fluorescence signal points.” However, this reference does not disclose carrying out the “relative quantification method based on fluorescence signal intensity” on the same reaction volumes as used for the digital PCR (i.e., the “absolute quantification method based on the counting of fluorescence signal points”. The two types of amplification were conducted separately.
Henley discloses a system and method for performing digital PCR to quantify target nucleic acids. Target nucleic acids from a sample are captured onto beads, and the beads are distributed to individual wells of an array such that each well contains a single bead. As disclosed in the abstract: “At low target concentrations, most beads capture, on average, less than one target molecule, and precise, digital PCR quantification can be derived from the percentage of positive reactions. At higher concentrations, qPCR signal is used to determine the average number of target molecules per reaction, significantly extending the dynamic range beyond the digital saturation point.” That is, Henley’s method performs the same two types of measurement as the claims (counting the number of positive wells, while also determining a fluorescence signal for each well of a plurality of positive wells after each of a plurality of cycles; see Fig. 41). However, Henley did not disclose or fairly suggest using the method to capture vesicles.
Conclusion
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/SAMUEL C WOOLWINE/Primary Examiner, Art Unit 1681
1 Henley averaged the signals from the positive wells, rather than track the signal from each well discretely.