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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 10/30/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Status of Claims
This office action is in response to Applicant's Response to Election / Restriction filed on August 4, 2026. No claims amendment is made in the response filed on August 4, 2026.
Claims 1-20 are pending, with claims 10-20 withdrawn.
Claims 1-9 are under examination. This is the first action on the merits.
Election/Restrictions
The requirements for species election for "Species of HLA locus," set forth in the office action mailed on June 04, 2026, have been withdrawn.
Applicant’s election without traverse of Group I (claims 1-9) in the reply filed on Aug 04, 2026 is acknowledged.
Claims 10-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention. Examination on the merits commences on claims 1-9.
Claim Objections
Claim 2 is objected to because of the following informalities:
In claim 2, to properly reference base claim 1, it should read:
The composition of claim 1, wherein the one or more HLA loci is selected from HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQB1, and HLA-DPB1.
Priority
The priority date of the instant claims 1-7 and 9 is 04/13/2023, filling date of the US provisional application NO. 63/495,910.
Regarding claim 8, the earliest priority is 04/10/2024, the filling date of the instant U.S. nonprovisional application, because the instant application is the first to disclose "wherein the one or more HLA primer pairs are in a separate container than the barcode primer pairs" in the recited kit.
Claim Interpretation
In evaluating the patentability of the claims presented in this application, claim terms have been given their broadest reasonable interpretation (BRI) consistent with the specification, as understood by one of ordinary skill in the art, as outlined in MPEP§ 2111.
Regarding claim 1, the terms "common forward primer sequence" and "common reverse primer sequence" are defined in the specification as follows:
"The terms “common forward primer sequence” and “common reverse primer sequence”, collectively “the common sequences”, as used herein, refer to segments of the forward and reverse primers that are not complementary to and do not hybridize with the target cDNA sequence, e.g. the HLA cDNA. The common sequences incorporate additional features which allow for the detection and/or immobilization of the primers but do not alter the basic property of the primers, that of acting as a point of initiation of DNA synthesis. " (specification, [0027])
Regarding claim 5, the term "barcode sequence" is defined in the specification as follows:
"The terms “tag” and “barcode,” are used interchangeably herein, and generally refer to a nucleic acid sequence that may be attached to a nucleic acid analyte to convey information about the analyte. For example, a barcode may be a polynucleotide sequence attached to fragments of a target polynucleotide contained within a particular partition. This barcode may then be sequenced with the fragments of the target polynucleotide. The presence of the same barcode on multiple sequences may provide information about the origin of the sequences. For example, a barcode may indicate that the sequence came from a particular subject or sample. This is particularly useful for sequence assembly when several samples are pooled before sequencing. As such, the barcode sequence is an identifiable sequence that serves as a tag for identifying the source of the amplified cDNA molecule." ([0031])
While the application's disclosure defines the term "barcode" as a nucleic acid sequence that conveys information about the analyte, such description lacks any structural features for a "barcode." Further, the disclosure lacks any structural feature for the term "barcode sequence" that would distinguish it from any sequence known in the art.
Thus, under BRI "barcode sequence" is interpreted to encompass any identifiable nucleic acid sequence.
Reasons for Lack of Rejection for Ineligible Subject Matter (35 USC 101)
The claimed invention in the claims filed on 04/10/2024 meets the criteria for patent-eligible subject matter under the guidelines set forth in MPEP § 2106.
Claim 1 recites:
A composition comprising one or more human leukocyte antigen (HLA) primer pairs, each HLA primer pair comprising:
a forward primer comprising:
a sequence that is complementary to a forward strand cDNA sequence of an HLA locus; and
a common forward primer sequence at the 5’ end of the forward primer; and
a reverse primer comprising:
a sequence that is complementary to a reverse strand cDNA sequence of the HLA locus; and
a common reverse primer sequence at the 5’ end of the reverse primer,
wherein each of the one or more primer pairs is complementary to a different HLA locus.
Therefore, the claim is directed to primers, wherein each primer comprises a "a common forward primer sequence" or "a common reverse primer sequence."
The subject matter eligibility test is below:
Step 1 - Whether the Claim is to a Statutory Category: YES. The claims are drawn to a composition, therefore to one of the four statutory categories.
Step 2A Prong 1 - Whether the Claim Recite an Abstract idea, Law of Nature, or Natural Phenomenon: No
As stated in MPEP 2106.04(b)(I), laws of nature and natural phenomena, as identified by the courts, include naturally occurring principles/relations and nature-based products that are naturally occurring or that do not have markedly different characteristics compared to what occurs in nature.
Here, the recited primers comprise markedly different characteristics compared to what occurs in nature, namely, "a common forward primer sequence at the 5’ end of the forward primer" and "a common reverse primer sequence at the 5’ end of the reverse primer."
The courts have identified that "short, synthetic, single-stranded DNA molecule[s] that bind specifically to … intended targets nucleotide sequence[s]" are products of nature because they claim the same nucleotide sequence as naturally occurring DNA. See University of Utah Research Foundation v. Ambry Genetics Corp., 774 F.3d 755, 761, 113 USPQ2d 1241, 1244 (Fed. Cir. 2014). See also MPEP 2106.
However, in this case, the primers are specifically recited as comprising common primer sequences. As expressly defined in the specification, the common primer sequences are "segments of the forward and reverse primers that are not complementary to and do not hybridize with the target cDNA sequence." (specification, [0027]). The specification further defines the common primer sequences as "incorporate additional features which allow for the detection and/or immobilization of the primers." (specification, [0027]).
Therefore, in view of the definition in specification, the claimed primers comprising the “common forward primer sequence” and “common reverse primer sequence” require intentional tagging of the primers for detection and/or immobilization, and do not claim the same nucleotide sequence as the target cDNA. A naturally occurring polynucleotide would not have such an intentionally applied tag, where the polynucleotide comprises both a sequence portion complementary to a target cDNA and a detectable tagging region that does not hybridize to the target.
Accordingly, the claimed primers are not directed to products of nature.
Claim Rejections - 35 USC § 102
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 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.
Claims 1-2, 5-6 and 8-9 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Wachter (WO2021214307A1 - Single step sample preparation for next generation sequencing; published 2021-10-28).
Regarding claim 1, Wachter teaches a composition comprising one or more human leukocyte antigen (HLA) primer pairs ([0039] “a forward target specific primer comprising a first forward adaptor sequence, and a reverse target specific primer comprising a first reverse adaptor sequence”; [0046] “target sequence is a leukocyte antigen-associated gene selected from HLA-A, HLA-B, HLA-C, HLA-E, HLA-F, HLA-G, HLA-DRAl, HLA-DRBl, HLA-DRB3/4/5, HLA-DQAl, HLA-DQBl, HLA-DPAl, or HLA-DPBl”), each HLA primer pair comprising:
a forward primer ([0039]; [0096]; [0046]) comprising:
a sequence that is complementary to a forward strand cDNA sequence of an HLA locus ([0096] lines 8-11, “The forward target specific primer advantageously comprises two sections or portions, a target specific portion and an adaptor portion. The target specific portion is complementary to a target sequence on the cDNA”; [0046]; [0094]); and
a common forward primer sequence at the 5’ end of the forward primer ([0096] lines 14-16, “The adaptor portion is located at the 5' end of the primer. It corresponds to a sequencing primer sequence and, at the same time, may be used as adaptor for binding to primers of group (c), i.e. to indexing primers”); and
a reverse primer comprising ([0039]; [0096]; [0046]): a sequence that is complementary to a reverse strand cDNA sequence of the HLA locus ([0096] lines 19-25, “The reverse target specific primer advantageously comprises two sections or portions, a target specific portion and an adaptor portion. The target specific portion is complementary to a target sequence on the cDNA-derived complementary DNA strand”); and
a common reverse primer sequence at the 5’ end of the reverse primer ([0096] lines 29-31, “The adaptor portion is located at the 5' end of the primer. It corresponds to a sequencing primer sequence and, at the same time, may be used as adaptor for binding to primers of group (c), i.e. to indexing primers”),
wherein each of the one or more primer pairs is complementary to a different HLA locus ([0096] lines 35-38, “By using target specific forward and reverse primers which bind to the cDNA sequence (and its complement) which can be obtained with the primers of group and which is unique for every target of interest, it is possible to distinguish between different targets and even allows for including an internal control.”; [0046]).
Regarding claim 2, Wachter teaches HLA-A ([0046]; [0094]).
Regarding claim 5, Wachter further teaches a barcode primer pair ([0097]), the barcode primer pair comprising:
a barcode forward primer comprising the common forward primer sequence ([0097] lines 7-9, “The forward primer of said group (c) accordingly comprises three sections of which the most 3' oriented section is a first forward adaptor sequence, which may be identical to the first forward adaptor sequence of the forward primers of group (b) and thus complementary to a corresponding portion of the enriched molecules.”); and
a barcode reverse primer comprising the common reverse primer sequence ([0098] lines 1-3, “The reverse indexing primer of said group (c) has an identical arrangement of three sections as described above for the forward indexing primer. Accordingly, it comprises a first adaptor sequence,”);
wherein at least one of the barcode forward primer and the barcode reverse primer further comprises a barcode sequence ([0097] lines 13-16, indexing sequence).
Regarding claim 6, Wachter teaches the barcode forward primer comprises the barcode sequence [0097] lines 13-16, indexing sequence).
Regarding claim 8, Wachter teaches wherein the one or more HLA primer pairs are in a separate container than the barcode primer pairs ([0142] “The components or ingredients of the kit may, according to the present invention, be comprised in one or more containers or separate entities.”; [0139] lines 14-15, kit comprising target specific primer pairs and indexing primer pairs, comprised in different containers).
Regarding claim 9, Wachter teaches wherein the kit comprises six HLA primer pairs; and wherein each of the HLA primer pairs is complementary to one of an HLA-A locus, an HLA-B locus, an HLA-C locus, an HLA-DRB1 locus, an HLA-DQB1 locus, and an HLA-DPB1 locus ([0088] “2, 3, 4, 5, 6, 7, 8, 9, 10 or more target sequences are simultaneously amplified. The mixture may accordingly comprise a corresponding number of target specific primers.”; [0094] “the target sequence is a leukocyte antigen-associated gene. Envisaged examples include HLA-A, HLA-B, HLA-C, HLA-E, HLA-F, HLA-G, HLADRA1, HLA-DRB1, HLA-DRB3/4/5, HLA-DQA1, HLA-DQBl, HlA-DPAl, or HLA-DPBl, or variants thereof.”).
Subject Matter Not Taught/Suggested in Prior Art
Claims 3-4 and 7 are objected to as being dependent upon rejected base claims 1 and 5/1, but would be allowable if rewritten to include all of the limitations of the base claim and any intervening claims.
The following subject matter is not taught or suggested in the prior art:
Claims 3-4 and 7 recite primer combinations comprising specific sequences in SEQ ID Nos: 1-16:
3. The composition of claim 1, wherein the common forward primer sequence comprises SEQ ID NO: 15 and the common reverse primer sequence comprises SEQ ID NO: 16.
4. The composition of claim 1, wherein the one or more HLA primer pairs comprise a forward primer sequence and a reverse primer sequence selected from: SEQ ID NO: 1 and SEQ ID NO: 2; SEQ ID NO: 3 and SEQ ID NO: 4; SEQ ID NO: 5 and SEQ ID NO: 6; SEQ ID NO: 7 and SEQ ID NO: 8; SEQ ID NO: 9 and SEQ ID NO: 10; and SEQ ID NO: 11 and SEQ ID NO: 12.
7. The composition of claim 5, wherein the barcode forward primer comprises SEQ ID NO: 13 and the barcode reverse primer comprises SEQ ID NO: 14.
SEQ ID Nos: 1-11 and 13-16 are searched, no prior art teach primers comprising any of these sequences. Accordingly, no prior art teach or suggest oligonucleotides that comprise the specific combination of primer sequences, as required by claims 3-4 and 7.
Prior Art
Below are relevant prior art not used in rejection but pertinent to the claims or disclosure.
Human Leukocyte Antigen (HLA) Typing via targeted amplification of cDNA using barcode primers is well-known in the art:
Johansson et al. (2021) Targeted RNA-Based Oxford Nanopore Sequencing for Typing 12 Classical HLA Genes. Front. Genet. 12:635601. doi: 10.3389/fgene.2021.635601;
Johansson et al., (2021) HLA RNA Sequencing With Unique Molecular Identifiers Reveals High Allele-Specific Variability in mRNA Expression. Front. Immunol. 12:629059. doi: 10.3389/fimmu.2021.629059;
Hosomichi et al. The impact of next-generation sequencing technologies on HLA research. J Hum Genet 60, 665–673 (2015). https://doi.org/10.1038/jhg.2015.102; see p. 666, "PCR-based HLA sequencing using NGS";
Segawa et al., HLA genotyping by next-generation sequencing of complementary DNA. BMC Genomics 18, 914 (2017). doi.org/10.1186/s12864-017-4300-7;
Matern et al., Long-Read Nanopore Sequencing Validated for Human Leukocyte Antigen Class I Typing in Routine Diagnostics. J Mol Diagn. 2020 Jul;22(7):912-919. doi: 10.1016/j.jmoldx.2020.04.001. Epub 2020 Apr 14. PMID: 32302780;
US20200354784A1-- High-throughput polynucleotide library sequencing and transcriptome analysis;
US20190316119A1 - Compositions and methods for molecular labeling;
US20220403464A1 - Methods and Compositions for Targeted Nucleic Acid Sequence Coverage; see Figure 8.
Conclusion
Claims 2-4 and 7 are objected to; claims 1-2, 5-6 and 8-9 are rejected. No claims are allowed.
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/TIAN NMN YU/Examiner , Art Unit 1681
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