Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
2. Applicant’s election without traverse of Group I, claims 1, 2, 4, 10, 12-15, 17, 19, 21, 22, 24, 26, 28, 29 and 32, in the reply filed on 10 December 2025 is acknowledged.
Claim Objections
3. Claim 13 is objected to because of the following informalities: There is no period at the end of the claim. Appropriate correction is required.
Claim Rejections - 35 USC § 112
4. 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.
5. Claims 4, 10, 15, 19, 22, 24, 26, 28 and 29 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.
A. Regarding claims 4, 10, 26 and 28, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
B. Claim 15 recites the limitation "said target DNA sequences" in line 1 of the claim. There is insufficient antecedent basis for this limitation in either claim 14 or in claim 1’s recitation of “target nucleotide sequences.”
C. The term “preferably” in claims 19, 22 and 24 is a relative term which renders the claim indefinite. The term “preferably” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. In claims 19, 22 and 24 the length of the nucleic acid linker, “clonal lymphoid cells,” and “one or more rearranged V, D, or J gene segment sequence characteristics,” respectively, have been rendered indefinite by this term.
D. Claim 29 is additionally rejected as being dependent from previously rejected claim 24.
Claim Rejections - 35 USC § 102
6. 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.
7. Claims 1, 10, 12-15, 17 and 19 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Hardik et al (MeFIT: merging and filtering tool for Illumina paired-end reads for 16S rRNA amplicon sequencing, BMC Bioinformatics, 17, 491, published 01 December 2016).
Regarding claim 1, Hardik teaches a method of sequencing the 16S rRNA of bacteria as a method of identifying a bacterial source (i.e., screening a nucleic acid sample; abstract and pg. 1 column 1 ¶ 1). Without further limitation regarding the claimed “target nucleotide sequences,” and nucleotide sequence within the 16S bacterial rRNA is interpreted as a target nucleotide sequence for the purpose of determining bacterial identity. Therefore any DNA template comprising 16S rRNA information inherently comprises ‘target nucleotide sequences’ localized to the region of contiguous nucleotides at the 5' and/or the 3' terminal ends of said template. Additionally, Hardik teaches sequencing using the Illumina MiSeq platform, which inherently comprises the steps of: spatially isolating on a solid support a library of individual template DNA molecules, amplifying said spatially isolated template DNA molecules to generate clusters of amplicons wherein each cluster is generated form an individual spatially isolate template DNA molecule, and bidirectionally sequencing one or more amplicons of one or more clusters. Hardik teaches that the forward and reverse sequencing reads of said amplicons do not provide a contiguous read across the full length of the amplicon (pg. 2 column 2 ¶ 1 and pg. 3 column 1 ¶ 2). Hardik teaches retaining these non-overlapping reads (in order to be retained, these reads are inherently identified) and generating a nucleic acid sequence result by linking the forward read to a nucleic acid linker and appending it to the reverse complement of the reverse read. Hardik teaches that the whole forward and reverse reads (i.e., not less than 75% of the maximal read length of the bidirectional sequencing methodology, and the same portion for all forward reads and all reverse reads), and teaches a default linker sequence of 15 Ns (i.e., the linker sequence is the same for all nucleic acid sequencing results; pg. 3 column 1 ¶ 2 and pg. 3 column 2 ¶ 1).
Regarding claim 10, Hardik teaches sequencing on the Illumina MiSeq sequencer which inherently uses a flow cell as the solid support (abstract).
Regarding claim 12, Hardik teaches that the DNA template comprises a primer sequence (i.e., a sequencing primer hybridization site; pg. 4 column 2 ¶ 1).
Regarding claims 13 and 14, as discussed above and fully incorporated here the phrase “target nucleotide sequences” is so broad as to encompass any region of 16S rRNA used for bacterial identification. Therefore, Hardik teaches that said contiguous nucleotide region of claim 1 step (i) (i.e., the region of template DNA where the target nucleotide sequences are localized) corresponds to about 80% of the maximum forward and reverse read length deliverable by the bidirectional sequencing technology when analyzing a 16S rRNA amplicon (pg. 3 column 1 ¶ 2). Hardik teaches that the full forward and reverse read sequences are linked together (i.e., the forward and reverse read portions are not less than 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82% or 83% of the maximum forward and reverse read length deliverable by the bidirectional sequencing technology; pg. 3 column 1 ¶ 2 and pg. 3 column 2 ¶ 1).
Regarding claim 15, as discussed above and fully incorporated here the phrase “target nucleotide sequences” is so broad as to encompass any region of 16S rRNA used for bacterial identification. Therefore, Hardik teaches that the target nucleotide sequences are localized to the 120 contiguous nucleotides at the 5' and/or 3' terminal ends of said template when analyzing a DNA template derived from 16S rRNA (pg. 3 column 1 ¶ 2). Hardik additionally teaches terminal primer regions of 20 base pairs (pg. 4 column 1 ¶ 4).
Regarding claim 17, Hardik teaches sequencing on the Illumina MiSeq sequencer, which inherently comprises cluster formation by bridge amplification and sequencing by synthesis using reversibly terminated labelled nucleotides.
Regarding claim 19, Hardik teaches a default nucleic acid linker length of 15 nucleotides (pg. 3 column 2 ¶ 1).
Claim Rejections - 35 USC § 103
8. 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.
9. Claims 2, 4, 22, 24 and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Hardik et al (MeFIT: merging and filtering tool for Illumina paired-end reads for 16S rRNA amplicon sequencing, BMC Bioinformatics, 17, 491, published 01 December 2016) in view of Waltari et al (5' Rapid amplification of cDNA ends and Illumina MiSeq reveals B cell receptor features in healthy adults, adults with chronic HIV-1 infection, cord blood and humanized mice, 9, 628, published 26 March 2018).
Regarding claim 2, the method of claim 1 is discussed fully above and incorporated here.
Hardik does not teach a method that comprises diagnosing, monitoring or otherwise screening for a condition in a patient, which condition is characterized by the expression of one or more target nucleotide sequences.
However, Waltari teaches the screening of patient samples (pg. 2 column 2 ¶ 2 and 3, pg. 14 column 2 ¶ 2) for mutations related to immune response to HIV-1 infection (i.e., a condition; pg. 17 column 2 ¶ 1).
It would have been obvious to one having ordinary skill in the art to have simply substituted the DNA template derived from 16S rRNA taught by Hardik with the DNA templates derived from patient samples taught by Waltari to arrive at the instantly claimed invention with a reasonable expectation of success. The ordinary artisan would have been motivated to use the sequencing method taught by Hardik to retain non-overlapping regions identified in sequencing results because Waltari specifically teaches the inclusion of non-overlapping sequencing results to recover heavy chain reads related to long CDR3s (pg. 19 column 1 ¶ 2). In addition, the ordinary artisan would have recognized that the known techniques in the cited references could have been combined with predictable results because the known techniques in the cited references predictably result in nucleic acid sequence analysis of data derived from an Illumina MiSeq sequencer.
Regarding claim 4, Waltari teaches that the nucleic acid sample of interest comprises B cell receptor DNA related to V-gene usage, somatic hypermutation, and CDR3 length (i.e., limitation (v) of claim 4; abstract).
Regarding claims 22 and 24, Waltari teaches that clonal B cells such as HIV-1 bnAb lineages are tracked by NGS (i.e., the condition is characterized by a clonal population of lymphoid/immune cells; pg. 19 column 1 ¶ 1).
Regarding claim 26, Waltari teaches that the condition is HIV-1 infection (abstract and pg. 19 column 1 ¶ 1).
10. Claim 21 is rejected under 35 U.S.C. 103 as being unpatentable over Hardik et al (MeFIT: merging and filtering tool for Illumina paired-end reads for 16S rRNA amplicon sequencing, BMC Bioinformatics, 17, 491, published 01 December 2016) in view of Jeraldo et al (IM-TORNADO: a tool for comparison of 16S reads from paired-end libraries, 9, 12, e114804, published 15 December 2024).
Regarding claim 21, the method of claim 1 is discussed fully above and incorporated here.
Hardik does not teach that the nucleic acid sequence results generated in step (iv) of claim 1 are aligned.
However, Jeraldo teaches a method of analyzing non-overlapping paired-end reads wherein the sequence results are aligned (pg. 4 column 2).
It would have been obvious to one having ordinary skill in the art to have modified the method taught by Hardik to incorporate the step of aligning the sequencing results taught by Jeraldo to arrive at the instantly claimed invention with a reasonable expectation of success. The ordinary artisan would have been motivated to make this modification in order to accurately determine the consensus sequence of the nucleic acid sequence results in order to determine the phylogeny associated with the determined 16S rRNA sequence. In addition, one having ordinary skill in the art would have recognized that the known techniques in the cited references could have been combined with predictable results because the known techniques of the cited references predictably result in the identification of bacterial species by 16S rRNA sequencing.
11. Claims 26, 28, 29 and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Hardik et al (MeFIT: merging and filtering tool for Illumina paired-end reads for 16S rRNA amplicon sequencing, BMC Bioinformatics, 17, 491, published 01 December 2016) in view of Waltari et al (5' Rapid amplification of cDNA ends and Illumina MiSeq reveals B cell receptor features in healthy adults, adults with chronic HIV-1 infection, cord blood and humanized mice, 9, 628, published 26 March 2018) as applied to claim 24 above, and further in view of Faham et al (United States Patent Application No. US20180080090, published 22 March 2018).
Regarding claims 26 and 28, the method of claim 24 is discussed fully above and incorporated here.
Waltari does not teach that the condition is a lymphoid or myeloid neoplasia.
However, Faham teaches the use of DNA sequencing to monitor lymphoid neoplasms that have undergone clonal evolution (i.e., the condition is characterized by target nucleotide sequences expressed in an immune cell; abstract). Faham specifically teaches that clonal profiling is used to identify Acute Lymphoblastic Leukemia (ALL; [0010]).
It would have been obvious to one having ordinary skill in the art to modified the method taught by Hardik in view of Waltari to have analyzed sequencing results for clonotype profiling related to lymphoid neoplasms rather than HIV infection as taught by Faham to arrive at the instantly claimed invention with a reasonable expectation of success. The ordinary artisan would have been motivated to make this modification because Faham teaches a specific need for improved method related to the prognosis and diagnosis of leukemias that have undergone clonal evolution (abstract). In addition, one having ordinary skill in the art would have recognized that the known techniques in the cited references could have been combined with predictable results because the known techniques in the cited references predictably result in the clonal analysis of lymphoid cells by sequencing on Illumina instruments.
Regarding claims 29 and 32, this rejection is based on the earlier rejection of claim 26 based on Hardik in view of Waltari. The method of claim 26 is discussed on pg. 8 of this Office Action.
Hardik in view of Waltari teach that the condition is HIV-1 but do not teach that the sequencing method is used to detect minimum residual disease.
However, Faham teaches that the sequencing of clonal lymphoid populations have utility in guiding the treatment of infections that exist in active and latent states. Faham specifically teaches the assessment of HIV viral load after treatment (i.e., the determination of residual disease and therapeutic efficacy; [0243]).
It would have been obvious to one having ordinary skill in the art to have modified the method taught by Hardik in view of Waltari for the analysis of lymphoid clonotypes related to HIV-1 to further monitor HIV viral load as taught by Faham to arrive at the instantly claimed invention with a reasonable expectation of success. The ordinary artisan would have been motivated to make this modification to monitor the state of the patient’s disease as taught by Faham ([0243]). In addition, one having ordinary skill in the art would have recognized that the known techniques in the cited references could have been combined with predictable results because the known techniques in the cited references predictably result in the analysis of HIV by lymphoid clonotypes.
Conclusion
12. No claims are allowed.
13. Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRIAN ELLIS YOUNG whose telephone number is (703)756-5397. The examiner can normally be reached M-F 0730 - 1700.
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/BRIAN ELLIS YOUNG/Examiner, Art Unit 1684
/JULIET C SWITZER/Primary Examiner, Art Unit 1682