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 .
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 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.
Claim Status
Claims 48-71 are pending.
Claims 1-47 and 72-92 are canceled.
Claims 58 and 64-65 are objected to.
Claims 48-71 are rejected.
Priority
This application is a CON of 17/317,547 filed May 11 2021 (now USP 11,306,353), which claims priority to US Provisional Applications 63/023,071 filed May 11 2020, 63/023,342 filed May 12 2020, 63/066,628 filed Aug 17 2020, and 63/165,559 filed Mar 24 2021. However, provisional applications 63/023,071 and 63/023,342 do not provide support for the instant claims.
Accordingly, each of claims 48-71 are afforded the effective filing date of Aug 17 2020.
Information Disclosure Statement
The information disclosure statement (IDS) filed on Oct 17 2022 is in compliance with the provisions of 37 CFR 1.97 and has therefore been considered. A signed copy of the IDS document is included with this Office Action.
Drawings
The drawings are objected to for the following informalities:
in FIG. 15, the Protocol “pcr(s1, s2)” appears to be incorrect and should instead say “pcr(s1, 2)”. Table 1 of the disclosure describes the PCR operation as being pcr(s1, y) for a sample (s1) for y cycles, and [0142] describes the PCR operation as acting on sample s1 for 2 cycles and does not mention sample s2;
at least FIG. 19B and FIG. 19B Cont. contains descriptions of the colors blue, green, yellow, and orange. While the figures have not been submitted to contain color, it is not apparent what those colors are intended to refer to. Reference to these colors should be removed;
the drawing sheets numbered as “FIG. 19B” and “FIG. 19B CONTINUED” should be changed to “FIG. 19B” and “FIG. 19C”, because partial views intended to form one complete view, on one or several sheets, must be identified by the same number followed by a capital letter, according to 37 CFR 1.84(u)(1).
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to for the following informalities. It is noted that for purposes of the instant Office Action, any reference to the specification pertains to the specification as originally filed on Mar 14 2022.
Disclosure
At [0138], the specification refers to Figure 16 as demonstrating examples of logical operations performed over analog encoded data stored by an identifier sequence across two samples, s1 and s2. However, such information seems to be demonstrated instead in Figure 15. The specification should be amended to refer to the correct figure.
Appropriate correction for all objections to the specification is required.
Claim Objections
The claims are objected to for the following informalities:
Claim 58 recites “PCR”, which should be amended to recite “polymerase chain reaction (PCR)” because it is the first time PCR has been recited in this series of claims.
Claims 64 and 65 recite “the operation”, which should be amended to recite “the double-stranded DNA selection operation” to maintain consistent claim language.
Claim Rejections - 35 USC § 112
35 U.S.C. 112(b)
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.
Claims 51-54 and 58-70 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claims 51 and 53-54 recite to changes to “the number” caused by inputting the sample to an operation. However, it is not clear that such an operation of performing PCR as in claim 51, an aliquot in claim 53, and a mixing operation as in claim 54 to the sample would result in a change in the number because the number is part of the numerical data which is stored in the nucleic acids. It is not considered that actions performed on the nucleic acids would result in actual changes in the number of the numerical data, because the numerical data is separate from the nucleic acid sample. It is not clear if the claim actually intends for the number in the numerical data to be changed (i.e., recorded) by performance of the operation on the nucleic acid sample, or if the recited changes to the number is intended to be an intended outcome of the performance of the operation on the nucleic acid sample, where, for example, performance of a PCR cycle in claim 51 doubles the actual number of identifier nucleic acid molecules, which approximates or represents a doubling of the number in the numerical data. For compact examination, it is assumed that the operation approximates or represents an operation on the number of the numerical data rather than requiring the actual change of the number by the operation. The rejection may be overcome by clarifying the metes and bounds of the limitation. Claim 52 is rejected based on its dependency from claim 51.
Claim 58 is similarly rejected and interpreted for the reasons stated above for its recitation of “performing a linear function on the vector”, as the number is a first element of a vector, as recited in claim 56. Claims 59-70 are rejected based on their dependency from claim 58.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 48-50, 55-57, and 71 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Mills et al. (Nature Genetics, 1999, 23(3):63-63; newly cited).
Regarding claims 48-49, claim 48 discloses a method for storing numerical data in nucleic acids, the method comprising: determining an expected copy count of an identifier nucleic acid sequence based on the numerical data and a proportionality constant; and generating a sample containing an actual number of identifier nucleic acid molecules each having the identifier nucleic acid sequence, wherein the actual number approximates the expected copy count. Claim 49 further adds that the numerical data is a number and the expected copy count is proportional to the number.
Mills discloses the interconversion of electrical and DNA data for molecular computation (title). Mills teaches that in the DNA computer, single-stranded DNA in 1:1 correspondence with the basis vectors (i.e., an expected copy count of an identifier nucleic acid sequence), where the concentration of strands with index (i.e., identifier) in a DNA sample representing a vector is proportional (i.e., proportionality constant) to the amplitude of the i-th component of the vector (i.e., numerical data) (par. 1). Mills teaches that the concentration of the DNA molecules is proportional to the image intensity at the i-th pixel (i.e., based on the numerical data and the proportionality constant) (par. 2).
Regarding claims 50 and 55, Mills teaches the method of claim 48-49 as described above. Claim 50 further adds inputting the sample to an operation to produce an output sample. Claim 55 further adds inputting the output sample to a second operation.
Mills teaches flashing an image on a DNA microplate (i.e., inputting the sample to an operation) whose pixels match image pixels and each of which is covered with unique DNA strands attached by hybridization to complementary anchored strands, where the image flash causes local heating that melts the double-stranded DNA to liberate some single stranded DNA (i.e., to produce an output sample) (par. 2). Mills teaches a second operation as instantly claimed in claim 55 by teaching: that the DNA image solution may be used for DNA computation; that the DNA image solution may be reconverted to electrical form at any time by being read out by allowing a portion of the solution to rehybridize with a single-stranded microarray; or by teaching determining the amount of duplex DNA at each pixel by fluorescence analysis (par. 2).
Regarding claim 56-57, Mills teaches the method of claim 48-49 as described above. Claim 56 further adds the number is a first element of a vector. Claim 57 further adds determining a second expected copy count of the identifier nucleic acid sequence based on a second element of the vector and the proportionality constant; and generating a second sample containing a second actual number of identifier nucleic acid molecules each having the identifier nucleic acid sequence, wherein the second actual number approximates the second expected copy count.
Mills teaches that in the DNA computer, single-stranded DNA in 1:1 correspondence with the basis vectors (i.e., a first and second expected copy count of an identifier nucleic acid sequence), where the concentration of strands with index (i.e., identifier) in a DNA sample representing a vector is proportional (i.e., proportionality constant) to the amplitude of the i-th component of the vector (i.e., numerical data that are numbers of a vector with multiple elements) (par. 1). Mills teaches that the concentration of the DNA molecules is proportional to the image intensity at the i-th pixel (i.e., based on the numerical data and the proportionality constant) (par. 2).
Regarding claim 71, Mills teaches the method of claim 48-49 as described above. Claim 71 further adds that at least a portion of each identifier nucleic acid molecule is configured to bind to one or more probes.
Mills teaches that the DNA strands are attached to DNA microplates by hybridization to complementary anchored strands (par. 2), which reads on a portion of each identifier nucleic acid molecule being configured to bind to one or more probes as instantly claimed.
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.
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.
A. Claims 51-54 and 58-62 are rejected under 35 U.S.C. 103 as being unpatentable over Mills, as applied to claim 48-50 and 56-57 in the above 35 USC 102 rejection, and in view of Maley (Evolutionary Computation, 1998, 6(3):201-229; newly cited).
Regarding claims 51-54 and 58-59, Mills teaches the method of claim 48-50 and 56-57 as described above. Claim 51 further limits the operation to multiplying the number by a power of 2 by performing a polymerase chain reaction (PCR) with primers that bind to common regions on an edge of the identifier nucleic acid sequence to form the output sample containing a PCR product. Claim 52 further adds that the power of 2 corresponds to a number of PCR cycles. Claim 53 further limits the operation to multiplying the number by a fraction by performing an aliquot that isolates a fractional volume of the sample to form the output sample. Claim 54 further limits the operation to adding the number as a first number to a second number in a second input sample by a mixing operation that combines the sample and the second input sample to form the output sample. Claim 58 further adds performing a linear function on the vector by at least one of PCR, aliquoting, and mixing. Claim 59 further adds converting a binary vector to a unary value in an output sample by performing the linear function.
Mills does not teach these operations or performing a linear function by at least one of PCR, aliquoting, and mixing.
However, Maley discloses an assessment of different manipulations of DNA and the implementation of algorithms for realistic problems in DNA computation (abstract). Maley the manipulation “Amplify”, where “Given a test tube of DNA, make multiple copies of a subset of the strands present. Copies are made with a polymerase chain reaction (PCR). PCR requires a beginning and an ending subsequence, called “primers,” which are usually about 20 base pairs long, to identify the sequence (called the “template”) to be replicated. Copies of these subsequences anneal to the single strands and polymerase enzymes build the complementary strands… Heat then melts apart the double strands, reducing them to single strands, and the process repeats, doubling the number of strands in the test tube each cycle (i.e., power of 2; claim 52).” (p. 202-203, 2.; p. 207, par. 6), which teaches claim 51 and PCR as instantly recited in claim 58. As “performing a linear function on the vector” in claim 58 and “converting a binary vector to a unary value in an output sample by performing the linear function” in claim 59 are interpreted as an intended result of performing at least one of PCR, aliquoting, and mixing in claim 58 (see the above 35 USC 112(b) rejection), it is considered that Maley fairly teaches the limitations of claims 58-59. Maley teaches the manipulation “Separate by Subsequence”, where DNA in a test tube is split into two test tubes, one with the sequences that contain the specified subsequence and the other with rest (p. 207, par. 7), which reads on performing an aliquot that isolates a fractional volume of the sample to form the output sample as in instant claim 53 and aliquoting in instant claim 58. Maley teaches the manipulations “Anneal”, “Ligate”, and “Merge”, where annealing occurs when complementary base pairs of single-stranded complementary DNA are brought into proximity, that ligation concatenates strands of DNA (p. 205, par. 3 and 5), and that two test tubes can be combined by pouring one into the other to merge samples (p. 207, par. 3), each of which read on a mixing operation that combines the sample and the second input sample to form the output sample as instantly recited in claim 54 and mixing in instant claim 58.
Regarding claim 60-61, Mills teaches the method of claim 48-50 and 56-57, and, in view of Maley, the method of claim 58. Claim 60 further adds that the linear function is a scoring function. Claim 61 further adds that the scoring function computes a higher output value for target vectors than for non-target vectors, such that copy counts for identifier sequences corresponding to target vectors are enriched in the output sample.
As “performing a linear function on the vector” in claim 58 and “the linear function is a scoring function” in claim 60 are interpreted as an intended result of performing at least one of PCR, aliquoting, and mixing in claim 58 (see the above 35 USC 112(b) rejection), it is considered that Maley fairly teaches the limitations of claim 60. Maley teaches that good paths (i.e., target vectors) can be replicated using PCR such that the proportion of good paths out-weigh the proportion of bad paths (p. 202-203, 2.), which read on copy counts for identifier sequences corresponding to target vectors being enriched in the output sample as instantly claimed in claim 61.
Regarding claim 62, Mills teaches the method of claim 48-50 and 56-57, and, in view of Maley, the method of claims 58 and 60-61. Claim 62 further adds that identifier sequences corresponding to target vectors are determined by sequencing the output sample, which Mills does not teach.
However, Maley teaches that sequencing DNA is performed by reading the order of nucleotides in a strand (p. 217, par. 3).
Regarding claims 51-54 and 58-62, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine, in the course of routine experimentation and with a reasonable expectation of success, the methods of Mills and Maley because both references teach methods for DNA computation. The motivation to use the manipulations taught by Maley would have been to use realizable processes for manipulating DNA in models built on a set of operations, as taught by Maley (p. 205, par. 2). Thus one of skill in the art would have realized that DNA which correspond to basis vectors as taught by Mills could be manipulated as taught by Maley for the expected result of altering the number of DNA strands. Specifically regarding claim 62, it would be obvious to read the output of the manipulations taught by Maley using sequencing, as taught by Maley at p. 217, par. 3, because such a combination represents the mere application of the known technique of sequencing to the method of Mills in view of Maley as described above.
B. Claims 63-68 are rejected under 35 U.S.C. 103 as being unpatentable over Mills, as applied to claim 48-50 and 56-57 in the above 35 USC 102 rejection, in view of Maley, as applied to claims 58-59 as above, and in further view of Cherry et al. (Nature, 2018; 559(7714):370-376; newly cited).
Regarding claim 63-64, Mills teaches the method of claim 48-50 and 56-57, and, in view of Maley, the method of claims 58 and 60-62. Claim 63 further adds that a ratio of copy counts between two identifier sequences in the output sample is increased by using a double-stranded DNA selection operation to form a new output sample where identifier sequences corresponding to target vectors are even more enriched in the output sample, which neither Mills nor Maley teach. Claim 64 further adds the operation, or a repeated application thereof, corresponds to an activation function in a neural network.
However, the prior art to Cherry discloses DNA winner-take-all neural networks (title). Cherry teaches implementation through DNA-strand-displacement reactions (abstract; Figure 1) where weight multiplications occur through double-stranded displacement (i.e., a double-stranded DNA selection operation) reaction to produce intermediate products which result in the annihilation of other weighted-sum species until only a single winner remains (p. 370, col. 1, par. 3 through col. 2, par. 1). It is considered that the method of Cherry would result in the increase of the copy count of identifier sequence over the others as instantly claimed. Cherry teaches activation of weight molecules and specific set of wires using their method (i.e., claim 64) (p. 375, col. 2, par. 2).
Regarding claim 65, Mills teaches the method of claim 48-50 and 56-57, and, in view of Maley, the method of claims 58 and 60-62, and, in view of Cherry, the method of claims 63-64. Claim 65 further adds that the operation corresponds to a quadratic function, which neither Mills nor Maley teach.
However, Cherry teaches the number of annihilators grows quadratically with the number of patterns (p. 374, col. 2, par. 2), which reads on a quadratic function as instantly claimed).
Regarding claim 66, Mills teaches the method of claim 48-50 and 56-57, and, in view of Maley, the method of claims 58 and 60-62, and, in view of Cherry, the method of claims 63-65. Claim 66 further adds letting the output sample go to equilibrium prior to the double stranded DNA selection operation, which Mills does not teach.
However, Maley teaches allowing manipulations to finish their work (p. 219, par. 1), which reads on a sample going to equilibrium as instantly claimed.
Regarding claim 67, Mills teaches the method of claim 48-50 and 56-57, and, in view of Maley, the method of claims 58 and 60-62, and, in view of Cherry, the method of claims 63-66. Claim 67 further adds changing the temperature or adding cofactors to the output sample prior to double stranded DNA selection operation, which neither Mills nor Maley teach.
However, Cherry teaches adding fuel strands (i.e., cofactors) to the reaction during the DNA-strand-displacement procedure (p. 370; col. 2, par. 3; Fig. 1).
Regarding claim 68, Mills teaches the method of claim 48-50 and 56-57, and, in view of Maley, the method of claims 58 and 60-62, and, in view of Cherry, the method of claims 63-67. Claim 68 further adds that the double stranded DNA selection operation is at least one of chromatography, gel electrophoresis, mass spectrometry, flow cytometry, fluorescent-activated sorting, membrane capture, silica column capture, silica bead capture, or affinity capture, which neither Mills nor Maley teach.
However, Cherry illustrates that the DNA-strand-displacement process occurs by sequence complementarity (i.e., affinity capture) (Fig. 1d).
Regarding claims 63-68, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine, in the course of routine experimentation and with a reasonable expectation of success, the method of Mills in view of Maley with Cherry because Mills and Cherry both teach methods for DNA-based neural networks. The motivation to perform the operation of Cherry would have been to use a DNA-based neural network which can be trained to recognize patterns, as taught Cherry (abstract).
C. Claims 69-70 are rejected under 35 U.S.C. 103 as being unpatentable over Mills, as applied to claim 48-50 and 56-57 in the above 35 USC 102 rejection, in view of Maley, as applied to claims 58 as above, and in further view of De Silva et al. (BioMed Research International, 2016(1), p.8072463; newly cited).
Regarding claims 69-70, Mills teaches the method of claim 48-50 and 56-57, and, in view of Maley, the method of claim 58. Claim 69 further adds that the vector is a compressed representation of a larger data object, the compressed representation being a hash, a bloom filter, a signature, a structural array, or a fingerprint of the larger data object. Claim 70 further adds that the larger data object is retrieved using the corresponding identifier nucleic acid sequence as a key. Neither Mills nor Maley teach these claims.
However, De Silva discloses methods for encoding and encrypting data onto DNA (abstract). De Silva teaches that many methods exist for compressing data to be stored in DNA sequences (p. 4, col. 1, par. 4; p. 5, col. 1, par. 4 through p. 6, col. 2, par. 4), which reads on at least a signature, structural array, or fingerprint of the larger data object as recited in instant claim 69. De Silva teaches retrieval of DNA encoded data by PCR based amplification (p. 4, col. 1, par. 2), including the use of keys to retrieve certain data (Figure 3; p. 3, col. 1, par. 4 through col. 2, par. 2), each of which reads on retrieving the larger data object using the corresponding identifier nucleic acid sequence as a key as recited in instant claim 70.
Regarding claims 69-70, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine, in the course of routine experimentation and with a reasonable expectation of success, the method of Mills in view of Maley with De Silva because each reference teaches methods for storing information in DNA. The motivation would have been to employ a DNA computer using the methods as taught by De Silva (p. 2, col. 1, par. 3 through col. 2, par. 1). It would have been obvious to compress a larger data object and retrieve it with a key because such a combination represents the mere application of the known techniques of data compression and retrieval in DNA as taught by De Silva to the known method of DNA neural networks as taught by Mills in view of Maley.
Conclusion
No claims are allowed.
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/JANNA NICOLE SCHULTZHAUS/Examiner, Art Unit 1685