DETAILED ACTION
1. Applicant’s response, filed 12 June 2026, has been fully considered. The following rejections and /or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Notice of Pre-AIA or AIA Status
2. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim status
3. Claims 1-20 are currently pending and under examination herein.
Claims 1-5, 7, 9-15, 17 and 19-20 are rejected.
Priority
4. The instant application claims benefit to provisional application No 63/216,464 filed on 6/29/2021. Domestic benefit is acknowledged. Thus the effective filing date of claims 1-20 in the instant application will be considered to be 6/29/2021. In future actions, the effective filing date of one or more claims may change, due to amendments to the claims, or further analysis of the disclosure(s) of the priority application(s).
Specification
5. The use of the terms Oxford Nanopore MinION, Pacific Biosciences SMRT, Java, Python, and Perl, which are trade names or a mark used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appear or, where appropriate, include proper symbols indicating use in commerce such as ™, SM , or ® following the terms.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Interpretation
6. Claims 3 and 13 contain the phrase “ a [nucleotide] sequence of a predicted protein that is not associated with a position in the reference genome”. For the purposes of examination, this will be interpreted to be equivalent to “a sequence encoding a predicted protein that is not associated with a position in the reference genome”.
Claims 5 and 15 recite that “the value representing the Hamming distance between the first string and the second string is a value that is four times the Hamming distance.” Hamming distance between two character strings of equal length is defined in the specification as the number of positions at which the corresponding characters are different (para. 0004). Therefore, this limitation is interpreted to mean that the value representing the Hamming distance resulting from the methods in claims 1 and 11, which is a bit-wise Hamming distance, is four times the Hamming distance, which includes but is not limited to a symbol-wise Hamming distance, which is derived from nucleic acid symbols.
Claims 10 and 20 recite “clustering of the first set of nucleotide sequences and the second set of nucleotide sequences”. Using the broadest reasonable interpretation, for the purpose of examination, this will be considered to be clustering of either the first set or the second set of nucleotide sequences alone or clustering of the first and second sets of nucleotide sequence together.
Claim Objections
7. Claims 6, 8, 16 and 18 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Claim Rejections - 35 USC § 112
8. The rejection of claims 3-4 and 13-14 under 35 U.S.C 112(b) is withdrawn in view of the claim amendments filed 12 June 2026.
Claim Rejections - 35 USC § 101
9. The rejection of claims 1-20 under 35 U.S.C 101 is withdrawn in view of the claim amendments filed 12 June 2026.
Response to Declaration:
The Declaration under 37 CFR 1.132 filed 12 June 2026 is sufficient to overcome the rejection of claims 1-20 based upon the declaration by Ling-Hong Jung that the method and system claimed in amended claims 1 and 11 has a practical application of improving nucleic acid sequencing data workflows by substantially reducing computational processing time through bitwise encoding combined with XOR analysis. Therefore, the amended claims 1 and 11 are patent eligible at step 2A prong 2 and amended claims 2-10 and 12-20 are also eligible by virtue of their dependence on claims 1 and 11, respectively.
Response to Arguments:
Applicant argued that the amended claims are patent eligible because the invention is a practical application
The applicant asserts that because they amended independent claims 1 and 11 so that the XOR processor functions are performed simultaneously, these operation are additional elements in the amended claims. They further argue that encoding strings into bit representations and comparing them using bitwise XOR processor instructions is a practical application because of an improvement to technology by substantially reducing processing time. They further cited support in the specification para. 0075 and Rule 132 declaration (see remarks p. 10, para. 3 – p. 11, para. 3).
Response to argument:
In light of the amendments to the claims, the arguments are persuasive and the rejection is withdrawn. The amended claims are patent eligible at step 2A prong 2 because the invention claimed in claims 1 and 11 has a practical application of improving nucleic acid sequencing data workflows by substantially reducing computational processing time through bitwise encoding combined with XOR analysis. Claims 2-10 and 12-20 are also eligible by virtue of their dependence on claims 1 and 11, respectively.
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.
10. The rejection of claims 6 and 16 under 35 USC 103(a) as being unpatentable over Chang et al. (US 2020/0013483 A1, previously cited), in view of Carbunar et al. (Secure Data Management (SDM), 2010, vol. 6358, pp. 70-86, previously cited) and Carper et al. (PeerJ, 2020 vol. 8, No. 8534, pp. 1-18, previously cited), as applied to claims 1-5 and 1-15 above, and further in view of Carver (EMBOSS DistMat manual, 2001, previously cited) and Bleasby et al. (EMBOSS ajbase source code, 2011, previously cited) is withdrawn in view of the claim amendments filed 12 June 2026.
11. The rejection of claims 8 and 18 under 35 USC 103(a) as being unpatentable over Chang et al. (US 2020/0013483 A1, previously cited), in view of Carbunar et al. (Secure Data Management (SDM), 2010, vol. 6358, pp. 70-86, previously cited), Carper et al. (PeerJ, 2020 vol. 8, No. 8534, pp. 1-18, previously cited), as applied to claims 1-5 and 11-15 above, and further in view of Ross (A first course in probability, 2014, 9th edition, pg. 75, previously cited) is withdrawn in view of the claim amendments filed 12 June 2026.
12. Claims 1-5 and 11-15 are rejected under 35 USC 103(a) as being unpatentable over Chang et al. (US 2020/0013483 A1, previously cited), in view of Carbunar et al. (Secure Data Management (SDM), 2010, vol. 6358, pp. 70-86, previously cited) and Carper et al. (PeerJ, 2020 vol. 8, No. 8534, pp. 1-18, previously cited). The italicized text corresponds to the instant claim limitations. This rejection is maintained and any newly recited portions herein are necessitated by claim amendment.
With respect to claims 1 and 11, Chang et al. discloses a non-transitory computer-readable medium that stores one or more programs, including instructions which, when executed by an electronic device including a processor, cause the device to perform any of the methods described herein (para. 0023, a computer-implemented method (claim 1); a non-transitory computer-readable medium having computer-executable instructions stored thereon that performs the actions claimed (claim 11)).
With respect to claims 1 and 11, Chang et al. disclose acquiring sequence read data representing nucleic acid sequences, a storage system to store sequence data and computer system to perform analyses (para. 0063, 0071 and 0146, receiving by a computing device, a set of first strings representing the nucleic acid sequences of the first set of nucleotide sequences).
With respect to claims 1 and 11, Chang et al. disclose a method of comparing sequence reads from an individual to a reference genome that includes one-hot encoding of known nucleotides whereby the nucleotide bases can be encoded using a full byte (8 bits) and can be expressed in binary values as follows: adenine=‘00000001’, cytosine=‘00000010’, guanine ‘00000100’, thymine=‘00001000’. Chang et al. further discloses that an unknown base can be represented by ‘00000000’ (para. 0004, 0078, determining, by the computing device, a plurality of values representing Hamming distances between the first strings and the second strings representing the second set of nucleotide sequences by performing actions comprising, for each pairing of a first string and a second string: converting any value characters in the first string and the second string to a one hot encoding and converting any unknown characters in the first string and the second string to a zero value to create a first bit representation and a second bit representation, wherein each value character represents a nucleotide in a plurality of nucleotides).
With respect to claims 1 and 11, Chang et al. discloses that in comparing numerically encoded nucleic acid sequences, a bitwise exclusive-OR (XOR) can be used to compare the reference genome file to the sequence read file, resulting in a non-zero value being returned for a mismatch between any nucleotide bases, and a zero value for matching nucleotide bases. Chang et al. further teaches that DNA string are analyzed using an active window, which is a fixed-length sliding window to restrict the regions being compared to the same lengths (para. 0091 and 0110, executing a bitwise XOR processor instruction one or more times to compare the first bit representation and the second bit representation to obtain a bitwise XOR result, wherein each execution of the bitwise XOR processor instruction simultaneously compares a plurality of encoded characters in the first bit representation to a plurality of encoded characters in the second bit representation).
With respect to claims 1 and 11, Chang et al. is silent to counting a number of non-zero bits in the bitwise XOR result. However, these limitations were known in the art before the effective filing date of the instant application, as taught by Carbunar et al.
Regarding Claims 1 and 11, Carbunar et al., discloses a method of calculating a bitwise Hamming distance (dH) by binary encoding DNA sequences, calculating bitwise XOR and counting the bits in the results. Similar to the instant application, Carbunar et al., teaches encoding the 4 nucleotide symbols as follows: A=0001, C=0010, G=0100, T=1000 prior to the XOR operation. By this method, at any given position being compared, dH has a count of 1 if the numerical values are mismatched and 0 if matched, which equivalent to the bitwise XOR description in the instant application (p. 79, para. counting a number of non-zero bits in the bitwise XOR result).
An invention would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the invention if some motivation in the prior art would have led that person to combine the prior art teachings to arrive at the claimed invention. Carbunar et al. taught that counting the number of bits in the bitwise XOR result to obtain a bitwise Hamming distance enabled evaluation of differences between bit-encoded DNA strings on remote data with privacy in un-trusted environments for forensic science and other applications requiring identity protection (Carbunar et al., p. 77, para. 5). Therefore, a person having ordinary skill in the art would have been motivated to apply the distance calculation taught by Carbunar et al. to the method to of sequence alignment and analysis taught by Chang et al. to measure differences between DNA sequences in an encoded environment to protect subject identity. Furthermore, a person having ordinary skill in the art would predict that the Hamming distance calculation taught by Carbunar et al., could be readily added to the method of Chang et al., with a reasonable expectation of success because both methods pertain to DNA sequence comparisons the calculation of Hamming distance is a simple step of addition with a predictable outcome. The invention is therefore prima facie obvious (see MPEP 2143(I)(G)).
Pertaining to claims 1 and 11, Chang et al. and Carbunar et al. are silent to multiplying the number of non-zero bits in the bitwise XOR result by two to obtain a bitcount result, but this is a simple step that would be obvious try in normalizing bitwise distance. Carbunar et al., points to two differences between bit-wise and the symbol-based Hamming distances that would motivate trying this step in order to normalize the bit-wise distance to the standard symbol-wise distance per string length. First, Carbunar et al. teaches that due to the encoding with 4 bits per nucleotide, pairs of elements with a symbol-wise distance of ‘d’ will have a ‘2d’ bit-wise Hamming distance (i.e. dnucleotide = dbit/2). Second, since there are 4 symbols (A, G, C and T), the number of bits will be 4 times the number of symbols (p. 10, para. 4, multiplying the bitwise XOR result by two to obtain a bitcount result). Therefore, the simplest approach to normalize the bit-wise hamming distance to the symbol-wise distance is to multiply the XOR result (i.e. the bit-wise distance) by two. In doing so, one mismatched nucleotide would have a bit-wise Hamming distance of 4 (per 4 bits), which is equivalent to a symbol-wise Hamming distance of 1 (per 1 nucleotide) because 4/4 = 1/1.
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to try multiplying the number of bits in the bitwise XOR result by two to normalize the bit-wise distance to the genomic distance per string length. This is one of a finite number of predictable solutions for effective normalization, which also includes dividing the symbol-wise Hamming distance by two. This application has a reasonable expectation of success because it is simple multiplication and it would effectively overcome the differences pointed out by Carbunar et al. to normalize bitwise distance to genomic distance per string length in the method taught by Chang et al. The invention is therefore prima facie obvious (see MPEP 2143(I)(E)).
Regarding claims 1 and 11, Chang et al. and Carbunar et al. are silent on adjusting the bitcount result based on unknown characters in at least one of the string sets to calculate the Hamming distance; and providing a result based on the determined plurality of values. However, this limitation was known in the art at the time of the effective filing date of the instant application, as taught by Carper et al.
In regard to claims 1 and 11, Carper et al. teaches calculating a symbol-wise Hamming distance based on comparison of two strings of nucleic acids and then adjusting the distance results based on unknown bases in at least one of the two sequences (using nucleic acid symbols including A, G, C, T and N). Carper et al. created a custom Hamming distance (termed nucleotide Hamming distance), which accommodates IUPAC nucleotide ambiguities by adjusting the distance value. For example, in a comparison of two strings of nucleotides, there is a total of one mismatch (Y-C) resulting in a symbol-wise Hamming distance of 1. However, Y is the ambiguity code representing C or T, so a Y-C pair represents a possible C-C match. Therefore, the Hamming distance is adjusted from 1 to 0 to account for the ambiguous base Y, lowering the probability of a mismatch to 0 (p. 4, para. 2, Fig. 1, adjusting the bitcount result based on unknown characters in at least one of the first string and the second string to obtain the value representing the Hamming distance).
Regarding claims 1 and 11, Carper. et al., teaches providing a result based on the determined plurality of values. Carper et al., teaches that aligned sequence reads are compared to corresponding reference genome to determine ‘support characteristics’ which include all output data (such as matched and mismatched nucleotides, the number of supporting sequence reads, alignment positions and a distribution of estimated fragment lengths for each). Carper also teaches that any of the support characteristics or other values can be output from one computer component to another and can be provided to a user (para. 0004, 0018, 0147, providing a result based on the determined plurality of values).
An invention would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention if some motivation in the prior art would have led that person to combine the prior art teachings to arrive at the claimed invention. Carper et al., taught that adjusting the bitcount result (Hamming distance) to account for unknown nucleotides in sequence comparisons avoids artificially inflating the number of differences between sequences and thus better distinguishes related organisms than unadjusted methods (p.4, para. 2). Therefore, a person having ordinary skill in the art would have been motivated to utilize the method of adjusting for unknown nucleotides in sequence alignments taught by Carper et al. to the method of calculating Hamming distance taught by Chang et al. and Carbunar et al. to avoid artificially inflating the Hamming distance due to ambiguous nucleotides in the sequences. Furthermore, a person having ordinary skill in the art would predict that the correction method taught by Carper et al. could be readily added to the distance calculation method by Chang et al. and Carbunar et al. with reasonable expectation of success because they both pertain to DNA sequence comparisons and adjusting distances based on nucleotide ambiguity can be a simple operation such as subtraction that can easily be applied in a rule-based manner to effectively account for unknown bases. The invention is therefore prima facie obvious (see MPEP 2143(I)(G)).
Regarding claims 2 and 12, Chang et al. teaches analyzing sets of nucleotide sequences from a sequencer and that any suitable sequencing-by-synthesis platform can be used to identify mutations including the Genome Sequencers from Roche/454 Life Sciences, the GENOME ANALYZER from Illumina/SOLEXA, the SOLID system from Applied BioSystems, and the HELISCOPE system from Helicos Biosciences (para. 0066, the method of claim 1 [the non-transitory computer-readable medium of claim 11]; wherein the first set of nucleotide sequences are from a sequencing device).
Regarding claims 3 and 13, Chang et al. discloses that aligned sequence reads from a sample from an individual are compared to corresponding reference genome positions (para. 0004, wherein the second set of nucleotide sequences includes at least one sequence of interest from a reference genome, a sequence of interest from a viral insertion, a sequence of a predicted protein that is not associated with a position in the reference genome; a sequence of a predicted gene that is not associated with a position in the reference genome; a partial sequence of a fusion gene as a result of a translocation; a partial sequence of a fusion gene as a result if inversion; a partial sequence of a fusion gene as a result of deletion; a complete sequence of a fusion gene as a result of translocation; a complete sequence of a fusion gene as a result of inversion; or a complete seque3nce of a fusion gene as a result of deletion).
In reference to claims 4 and 14, Chang et al. discloses that the comparison includes performing a bitwise operation to compare N bytes of the converted reference genome file to a corresponding N bytes of the converted content of the sequence read file and that the results include an alignment in which the sequence reads are aligned to a reference genome. (para. 0070, 0091 and Fig. 1 step 130; the method/medium of claim 3, wherein providing the result based on the determined plurality of values includes providing an alignment of the first set of nucleotide sequences to the at least one of the reference genome, the viral insertion, the predicted protein, the predicted gene, or the fusion gene).
Regarding claims 5 and 15, Chang et al., Carbunar et al. and Carper et al. do not explicitly teach that the value representing the Hamming distance between the first string and the second string is a value that is four times the Hamming distance. However, this is the result of multiplying the bitwise XOR result by 2, which is a simple step that would be obvious try to normalize the bitwise distance to the symbol-wise distance. Carbunar et al. points to two differences between bit-wise and the symbol-based Hamming distances that would motivate multiplying the bit-wise Hamming distance by two: 1) Carbunar et al. teaches that due to the coding (i.e. encoding with 4 bits per nucleotide), pairs of elements of symbol-wise distance d will have a 2d bit-wise Hamming distance (i.e. dnucleotide = dbit/2) and 2) Since there are 4 symbols (A, G, C and T), the number of bits will be 4 times the number of symbols (p. 10, para. 4, wherein the value representing the Hamming distance between the first string and the second string is a value that is four times the Hamming distance). These differences motivate normalizing the bitwise distance to the symbol-wise distance by multiplying the XOR result (i.e. the bit-wise distance) by two. After this transformation, a mismatched nucleotide would have a modified bit-wise Hamming distance of 4 (per 4 bits), which is equivalent to the symbol-wise Hamming distance of 1 (per 1 nucleotide) because 4/4 = 1/1.
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to try multiplying the number of bits in the bitwise XOR result by two so that the bitwise hamming is 4 times the symbol-wise hamming in order to normalize the bit-wise distance to the genomic distance per string length. There are a finite number of predictable solutions for effective normalization. This application has a reasonable expectation of success because it is simple multiplication and it would effectively overcome the differences pointed out by Carbunar et al., to normalize bitwise distance to genomic distance per string length in the method taught by Chang et al. The invention is therefore prima facie obvious (see MPEP 2143(I)(E)).
13. Claims 7, 9-10, 17 and 19-20 are rejected under 35 USC 103(a) as being unpatentable over Chang et al. (US 2020/0013483 A1, previously cited), in view of Carbunar et al. (Secure Data Management (SDM), 2010, vol. 6358, pp. 70-86, previously cited), Carper et al. (PeerJ, 2020 vol. 8, No. 8534, pp. 1-18, previously cited), as applied to claims 1-5 and 11-15 above, and further in view of Ross (A first course in probability, 2014, 9th edition, pg. 75, previously cited). The italicized text corresponds to the instant claim limitations. This rejection is maintained and any newly recited portions herein are necessitated by claim amendment.
The limitations of claims 1-5 and 11-15 have been taught by Chang et al., Carbunar et al. and Carper et al.
Pertaining to claims 7 and 17, Chang et al. teaches that the sequence read file and the reference genome can have unknown characters (para. 0078, Fig. 3D, wherein the first string and the second string include unknown character(s)).
Pertaining to claims 7 and 17, Chang et al., Carbunar et al., and Carper et al. are silent to the method of adjusting for unknown characters in both strings being compared by counting the number of unknown characters in both strings, counting the number of unknown character pairs in the alignment and adding both numbers to the bitcount result to get the Hamming distance. However, these limitations were known in the art at the time of the effective filing date of the invention, as taught by Ross.
Pertaining to claims 7 and 17, Ross teaches a well-established probability principle that when applied to the calculation of Hamming distance to account for unknown nucleotides in both the first and second strings, yields a Hamming distance equation that is equivalent to equation resulting from claims 7 and 17 of the instant application, thus making the claimed approach obvious to try. Ross teaches a principle for independent events (P(EF) = P(E)*P(F)), whereby the probability of two independent events ‘E’ and ‘F’ is the product of their probabilities. This equation can be used to estimate distances for ambiguous nucleotide pairs (N-X and N-N) based on the probability of a match assuming equal likelihood of an ambiguous nucleotide N being A, G, C or T.
To summarize, estimated fractional distances for ambiguous nucleotides using the probability principle for independent events (P(EF) = P(E)*P(F)) are shown below:
p(match) is probability of a matched known pair, and distance = 1 - p(match)
The distance for matches of known nucleotides (X-X) is 0
The distance for mismatches of known nucleotides (X-Y) is 1
The distance for an ambiguous nucleotide paired with a known nucleotide (X-N) is equal to the expected Hamming distance between a known nucleotide and a uniformly ambiguous nucleotide (N). For example, given a pair N-A, P(match) = P(N=A) * P(A=A) = ¼*1 = ¼. Therefore, the distance = 1 – P(match) = 1-¼= ¾.
The distance for an ambiguous nucleotide paired with an ambiguous nucleotide (N-N) is equal the expected distance between two uniformly ambiguous nucleotides. P(match) = P(N1=A)*P(N2=A) + P(N1=G)*P(N2=G) + P(N1=C)*P(N2=C) + P(N1=T)*P(N2=T) = 0.25*0.25 + 0.25*0.25 + 0.25*0.25 + 0.25*0.25 = 0.25. Therefore, distance = 1 – P(match) = 1 – ¼ = ¾.
Therefore, the Hamming distance equation derived using the probability principle is: distance = 1 XY + ¾ XN + ¾ NN, which is identical to the distance equation resulting from the methods described in claims 7 and 17 and disclosed in the specification of the instant application (para. 0060) (i.e., bitwise Hamming4 = 4 XY + 3 XN + 3 NN and symbol-wise Hamming = 1 XY + ¾ XN + ¾ NN) (Ross, p. 75, equation 4.1, A method of adjusting the Hamming distance calculation to account for unknown characters in both the first and second strings by: 1) counting the number of unknown characters in the first string and the second string, 2) determining the number of unknown characters pairs in the alignment and 3) adding the number of unknown characters and the number of pairs of unknown characters to the bitcount result).
At the time of the invention, there had been a recognized need in the art to adjust the Hamming distance (bitcount result) to account for unknown nucleotides in sequence comparisons to avoid artificially inflating the number of differences between sequences and thus better distinguishes related organisms (Carper et al., p.4, para. 2). There are a finite number of identified, predictable potential solutions to the need to calculate distances for ambiguous nucleotides, which includes either reducing mismatch value for pairs with ambiguous nucleotides to 0 (Carper et al. p. 4, para. 2, Fig. 1) or deriving a fractional value of expected distances based on well-grounded probability theory to calculate pairwise probability of independent events disclosed by Ross.
A person having ordinary skill in the art before the effective filing date of the instant application could have applied the probability principle for independent events taught by Ross to adjust the Hamming distance for comparisons with unknown nucleotides in both sequences taught by Chang et al., Carbunar et al., and Carper et al. A person having ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success because it involves simple algebra, counting and adding steps: counting the number of unknown characters in both strings (1 XN + 2 NN), counting the number of unknown character pairs in the alignment (1NN) and adding both numbers to the bitcount result (4XY + 2 XN) to get the Hamming distance (Hamming4 = 4 XY + 3 XN + 3 NN; Hamming = XY + ¾ XN + ¾ NN). Additionally, the steps effectively apply the well-established probability principle for independent events, which is broadly relevant to many biological applications. The invention is therefore prima facie obvious (see MPEP 2143(I)(E).
Regarding claims 9 and 19, Chang et al., Carbunar et al., Carper et al. and Ross teach that the two sequences can be read sequences. For the purposes of examination, read sequence will be interpreted to be simply a sequence fragment produced by a machine. Chang et al., teaches a method by which aligned sequence reads obtained from a subject’s sample are compared to a reference genome to determine support characteristics. It is further disclosed that the reference genome file can be sequencing data from a human subject. Therefore Chang et al., Carbunar et al., Carper et al. and Ross, teach that the two sequences can be read sequences (para. 004 and 0073, the two sequences can be read sequences).
Regarding claims 10 and 20, Chang et al., Carbunar et al., Carper et al. and Ross teach the provided results include clustering of the first set of nucleotide sequences and the second set of nucleotide sequences.
Chang et al. discloses that using the same numerical encoding for the reference genome and a plurality of sequence reads enables rapid comparison between groups of sequence-read and reference-genome nucleobases. Making and comparing different groups of sequence reads is a form of clustering the sequence reads (the first set of nucleotide sequences) and aligning each group with the reference genome (the second set of nucleotide sequences) is a form of clustering between the first and second set of nucleotide sequences. Chang et al. further discloses that nucleotide strings can be clustered or grouped based on their position in the reference genome or their position of alignment to the reference genome. Chang et al. further discloses partitioning the reference genome into a plurality of partitions, each partition comprising contiguous positions of the reference genome (para. 0005, 0017, Fig. 6A, provided results include clustering of the first set of nucleotide sequences and the second set of nucleotide sequences).
Response to 103 rejection arguments:
Applicant’s arguments filed 12 June 2026 have been fully considered. Arguments relating to claims 6, 8, 16 and 18 are persuasive, and those pertaining to claims 1-5, 7-15, 17 and 19-20 are not persuasive as described below.
Response to arguments pertaining to claims 1 and 11 relate to the hamming distance calculation, specifically that the prior art cited does not teach the same motivation for the scaling operation as in the instant application and does not teach the “adjustment” in the operation to account for unknown nucleotides.
Applicant asserts that the motivation taught in the prior art for multiplying a bitwise XOR result by 2 does not apply to the invention (remarks, p. 12, para 3).
This argument is not persuasive because obviousness rejections require an explanation as to why the invention would have been obvious (MPEP 2142) and there are several different rationales that can be utilized to do this (MPEP 2103). Whereas Rationale G (TSM) is based on a teaching, motivation or suggestion, Rationale E, which is the one applied in the rejection, is not based on such motivation.
Applicant asserts that the teaching and motivation of Carbunar et al. for calculating Hamming distance by multiplying XOR by two would only work for cases with known nucleotides (i.e. in the comparison of known nucleotides to known nucleotides) and that simply multiplying by 2 would not work for cases with unknown nucleotides in either sequence. Applicant further asserts that to calculate a Hamming distance when unknown nucleotides are included, the unknown nucleotides would need to be “adjusted” and that this adjustment was not taught by Carbunar et al. (remarks, p. 12, para. 4 – p. 13, para. 6).
This argument is not persuasive because the rejection is based on the combined teachings of Chang et al., Carbunar et al. and Carper et al. rather than Carbunar et al. alone. One cannot establish nonobviousness by arguing against references individually where the rejection is based upon the teachings of a combination of references. In re Keller, 642 F.2d 413, 425 (CCPA 1981)(see MPEP 2145(IV)). Examiner agrees that the multiplying by 2 motivated by Carbunar et al. does not apply to cases that have unknown nucleotides and that the value would need to be adjusted in those cases, but the “adjustment” is claimed as a separate operation and this limitation is taught by Carper et al. who teaches adjusting Hamming distances of matches with unknown nucleotides. Carper et al. also teaches a rationale for combining this method with the Hamming distance calculation of Chang et al. and Carbunar et al., which is that accounting for unknown nucleotides in sequence comparisons avoids artificially inflating the number of differences between sequences (see rejection of claims 1 and 11 above).
Response to arguments pertaining to claims 2-4, 6-10, 12-14 and 16-20 relate to their dependency on claims 1 and 11.
Applicant asserts that the claims should be allowed at least by virtue of their dependency from allowable independent claims (remarks, p. 14, para. 1)
This is a moot point because claims 1 and 11 are not allowable as indicated above.
Response to arguments pertaining to claims 6 and 16 regarding prior art teachings being computationally expensive
Applicant argues that with respect to claims 6 and 16, the cited references (Carver et al. and Bleasby et al.) do not teach the Hamming distance claimed because even though the Hamming distance taught yields the same values as the claimed invention, the calculation requires more steps (two division operations and a multiplication operation), thus it is computationally more expensive.
This argument is persuasive and the rejection has been withdrawn.
Response to arguments pertaining to claims 8 and 18 regarding prior art not teaching all limitations
Applicant argues that while the prior art (Chang et al.) teaches distinguishing N-N pairs verses all other nucleotide pairs using AND operation, it does not meet the requirement that N-N pairs have some value and all other pair combinations have zero value (which is required to obtain by counting bits the number of matched unknown characters) (remarks, p. 4, para. 4 – p. 15, para. 2).
This argument is persuasive and the rejection has been withdrawn.
Conclusion
14. No claims are allowed. Note that claims 6, 8, 16 and 18 would be allowable if rewritten in independent form.
Prior grounds for rejection were maintained and there were no new grounds for rejection in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
E-mail Communications Authorization
15. Per updated USPTO Internet usage policies, Applicant and/or applicant's representative is encouraged to authorize the USPTO examiner to discuss any subject matter concerning the above application via Internet e-mail communications. See MPEP 502.03. To approve such communications, Applicant must provide written authorization for e-mail communication by submitting the following statement via EFS-Web (using PTO/SB/439) or Central Fax (571-273-8300): "Recognizing that Internet communications are not secure, / hereby authorize the USPTO to communicate with the undersigned and practitioners in accordance with 37 CFR 1.33 and 37 CFR 1.34 concerning any subject matter of this application by video conferencing, instant messaging, or electronic mail. / understand that a copy of these communications will be made of record in the application file."
Written authorizations submitted to the Examiner via e-mail are NOT proper. Written authorizations must be submitted via EFS-Web (using PTO/SB/439) or Central Fax (571-273- 8300). A paper copy of e-mail correspondence will be placed in the patent application when appropriate. E-mails from the USPTO are for the sole use of the intended recipient, and may contain information subject to the confidentiality requirement set forth in 35 USC § 122. See also MPEP 502.03.
Inquiries
16. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JENNIFER J SMITH whose telephone number is (571)272-7801. The examiner can normally be reached Monday-Friday 7:30 AM - 3:30 PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Olivia Wise can be reached at (571) 272-2249. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/J.J.S./ Examiner, Art Unit 1685
/OLIVIA M. WISE/ Supervisory Patent Examiner, Art Unit 1685
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