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 .
Priority
This application is a continuation (CON) of 17/529,229 filled on 11/17/2021, which is a CON of 17/175,465 filed 02/12/2021 and issued patent # 11248267. Application 17/175,465 is itself a CON of 16/773,750 filed on 01/27/2020 and issued patent # 10954562. Application 16/773,750 is a CON of 16/692,631 filed 11/22/2019 and issued patent # 10793905. Application 16/692,631 is a CON of 16/426,762 filed on 05/30/2019 and issued patent # 10550429. Application 16/426,762 is a continuation in part (CIP) of application 15/933,299 filed on 03/22/2018 and awarded patent # 10480029. Application 15/933,299 is a CON of 15/720,085 filed 09/29/2017 and awarded patent # 10011872. Application 15/720,085 has provisional application 62/438,341 filed on 12/22/2016.
Claim Status
Claims 1-30 are currently pending and under examination. Claims 1 and 16 are independent claims. Claims 2-15 are dependent upon claim 1, while claims 17-30 are dependent upon claim 16.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-30 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
With respect to the limitation in claim 1 reciting “(ii) a labeling agent, wherein said labeling agent comprises an MHC-peptide complex comprising a peptide, an MHC molecule, and a reporter barcode molecule, wherein said reporter barcode molecule comprises a reporter barcode sequence that identifies said peptide,”, and claim 16 reciting “(ii) a labeling agent, wherein said labeling agent comprises a T-cell receptor molecule and a reporter barcode molecule, wherein said reporter barcode molecule comprises a reporter barcode sequence that identifies said T-cell receptor molecule,” the specification describes labeling agents that coupled to reporter oligonucleotide containing a nucleic-acid barcode. The barcode is copied/extended and read by sequencing via hybridization to an anchor oligonucleotide in the partition. The figures likewise depict nucleic-acid barcodes rather than protein/peptide barcodes.
Although the specification broadly states that “barcodes can include polynucleotide barcodes… and/or amino-acid sequences,” (see [0120]), the application does not provide any representative examples, constructs, or instructions for a reporter barcode molecule that is not a nucleic acid (e.g. peptide-based barcode) being coupled to an MHC-peptide complex nor a T-cell receptor and then detected according to the disclosed nucleic-acid sequencing workflow. The disclosure therefore does not reasonably convey possession of the full scope or “reporter barcode molecule” as claimed, nor does describe practicing non-nucleic-acid embodiments without undue experimentation.
Accordingly, to the extent the claim reads on non-nucleic-acid “reporter barcode molecules” (e.g. peptide barcodes), the specification fails to provide adequate written description and enablement for such embodiments. See MPEP §2163 and §2164
Suggested amendment to overcome: replace “reporter barcode molecule” with “reporter oligonucleotide comprising a nucleic-acid barcode sequence that identifies said peptide /T-cell receptor molecule),” aligning the claim with the disclosed and enabled embodiments.
Claims 2-15, and 17-30 are likewise rejected under 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph, as based on their dependence on claims 1 and 16 respectively.
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.
Claims 1-30 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.
Claims 1 and 16 recite “an mRNA molecule comprising a sequence encoding for a B-cell receptor or a portion thereof”. The phrase “portion thereof” renders the scope of the claim as indefinite under 35 U.S.C. 112(b) because the specification fails to provide any objective standard for determining what constitutes a “portion” of the B-cell receptor that would fall within the claim’s coverage.
The specification generically refers to nucleic acids “encoding at least a portion of VDJ sequence of an immune cell receptor” but it does not define what size, region, or functional domain qualifies as such a portion (see [0040], [0048]). A B-Cell receptor contains multiple subunits (e.g. VH, VL, CH, CL regions, transmembrane domains, and signal peptides), any of which could be considered a portion. Because the term is purely relative and the disclosure provides no measurable parameters, such as length, sequence identity, or functional limitation, a person of ordinary skill in the art cannot determine, with reasonable certainty, the boundaries of the claimed subject matter.
Absent clear guidance, “portion thereof” could encompass anything from the start codon methionine of any protein, to a short CDR motif of only a few codons, to nearly the entire B-cell receptor transcript, leading to multiple plausible interpretations. As a result, the metes and bounds of the claim cannot be ascertained with reasonable certainty, contrary to MPEP 2173.02 and Nautilus, Inc. v. Biosig Instruments, Inc., 572 U.S. 898, 910, 110 USPQ2d 1688, 1693 (2014).
Claims 2-15, and 17-30 are likewise rejected as they are dependent upon claims 1 and 16, respectively, and do not rectify the deficiencies above. While claims 4 and 19 attempt to limit the “portion thereof” by stating that the sequence “comprises a CDR1 sequence, a CDR2 sequence, and a CDR3 sequence” this does little to provide clarity as the complementarity determining regions (CDRs) are short hypervariable loops within the variable domain of an antibody and do not have any conserved sequence to enable identification of these sequences as CDR1, CDR2, or CDR3. These domains are defined by their position relative to conserved framework regions flanking the CDRs. Antibody structure reviewed by Chiu et al. (Antibodies 2019 Dec. 3;8(4):55).
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.
(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.
Claim(s) 1-30 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Abate et al. (US 2017 /0009274 Al, published Jan. 12, 2017, effective filing date Feb. 3, 2016, on IDS).
In regards to claim 1 and 15, Abate teaches a method of analyzing nucleic acids, comprising: (a) providing a partition comprising: (1) a labeled cell comprising: (i) a messenger ribonucleic acid (mRNA) molecule comprising a sequence encoding for a B-cell receptor or a portion thereof, (see para. [0276] (ii) a labeling agent, wherein said labeling agent comprises an MHC-peptide complex comprising a peptide, an MHC molecule, and a reporter barcode molecule, wherein said reporter barcode molecule comprises a reporter barcode sequence that identifies said peptide (see para. [0276],[1457]); (2) a plurality of partition nucleic acid barcode molecules, wherein a partition nucleic acid barcode molecule of said plurality of partition nucleic acid barcode molecules comprises a partition barcode sequence; (b) using a first partition nucleic acid barcode molecule of said plurality of partition nucleic acid barcode molecules and said reporter barcode molecule to generate a first barcoded nucleic acid molecule comprising (1) said partition barcode sequence or reverse complement thereof and (2) said reporter barcode sequence or reverse complement thereof, and (c) using a second partition nucleic acid barcode molecule of said plurality of partition nucleic acid barcode molecules and said mRNA molecule to generate a second barcoded nucleic acid molecule comprising (1) said partition barcode sequence or reverse complement thereof and (2) said sequence encoding for said B-cell receptor or the portion thereof, or a reverse complement of the said sequence encoding for said B-cell receptor or the portion thereof (see Fig. 26, para. [0031], [0033], [0217]- [0218])
In regards to claim 2, Abate teaches binding MHC-peptide complex to the labeled cells (see [1457]).
In regards to claim 3, Abate teaches determining the sequence of the barcoded nucleic acids including those associated with the B-cell receptors (see Abstract, Figs. 26-28, para. [0026]-[0033] and throughout).
In regards to claims 4-7, Abate teaches identifying mRNA that encode each light and heavy chains of B-cell receptors (see Abstract, Figs. 26-28, para. [0026]-[0033], [1457]-[1460], and throughout).
In regards to claims 8-14, Abate teaches partitions as droplets, and wells and teaches a solid support, including the use of beads with nucleic acid barcodes (see [0080], [0260], and throughout).
In regards to claim 16-17, and 30, Abate teaches a method of analyzing nucleic acids, comprising: (a) providing a partition comprising: (1) a labeled cell comprising: (i) a messenger ribonucleic acid (mRNA) molecule comprising a sequence encoding for a B-cell receptor or a portion thereof, (see Fig. 26, [0030], [0276]); (ii) a labeling agent, wherein said labeling agent comprises a T-cell receptor molecule and a reporter barcode molecule, wherein said reporter barcode molecule comprises a reporter barcode sequence that identifies said T-cell receptor molecule (see [0276], [0307], [1457]-[1460]) (2) a plurality of partition nucleic acid barcode molecules, wherein a partition nucleic acid barcode molecule of said plurality of partition nucleic acid barcode molecules comprises a partition barcode sequence; (b) using a first partition nucleic acid barcode molecule of said plurality of partition nucleic acid barcode molecules and said reporter barcode molecule to generate a first barcoded nucleic acid molecule comprising (1) said partition barcode sequence or reverse complement thereof and (2) said reporter barcode sequence or reverse complement thereof, and (c) using a second partition nucleic acid barcode molecule of said plurality of partition nucleic acid barcode molecules and said mRNA molecule to generate a second barcoded nucleic acid molecule comprising (1) said partition barcode sequence or reverse complement thereof and (2) said sequence encoding for said B-cell receptor or the portion thereof, or a reverse complement of the said sequence encoding for said B-cell receptor or the portion thereof (see Fig. 26, para. [0031], [0033], [0217]- [0218]).
In regards to claim 18-22, Abate teaches identifying mRNA that encode each light and heavy chains of B-cell receptors (see Abstract, Figs. 26-28, para. [0026]-[0033], [1457]-[1460], and throughout).
In regards to claims 23-29, Abate teaches partitions as droplets, and wells and teaches a solid support, including the use of beads with nucleic acid barcodes (see [0080], [0260], and throughout).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-30 are rejected on the ground of nonstatutory double patenting as being unpatentable over:
Claims 1-31 of U.S. Patent No. 10,011,872,
Claims 1-34 of U.S. Patent No. 10,480,029,
Claims 1-34 of U.S. Patent No. 10,550,429,
Claims 1-12 of U.S. Patent No. 10,954,562,
Claims 1-36 of U.S. Patent No. 11,248,267, and
Claims 1-23 of U.S. Patent No. 11,732,302,
Although the claims at issue are not identical, they are not patentably distinct from each other.
The ‘872 patent claims methods for partitioning single cells into droplets, lysing each cell, and capturing mRNA molecules on barcoded oligonucleotide-bearing beads, followed by reverse transcription and sequencing to associate sequence reads with individual cells. The present claim 1 likewise recites a partition-based composition including barcode molecules and analytes comprising mRNA molecules including those encoding immune-cell receptors such as B-cell receptors) and optionally other analytes such as labeling agents.
The only discernible difference between the subject matter of claim 1 of the instant application and the claims of the ‘872 patent is that the instant claim more narrowly specifies that the mRNA encodes “a B-cell receptor or a portion thereof” whereas the ‘872 patent generically teaches capturing and sequencing mRNA from any cell, including lymphocytes and explicitly discloses immune-receptor mRNA species as exemplary analytes. It would have been an obvious variation for one of ordinary skill in the art to apply the single-cell mRNA barcoding methods of the ‘872 patent to B-cell receptor transcripts to identify clonotypes, as this merely represents selection of a known species withing a disclosed genus.
The ’029 patent claims a method for isolating individual cells into micro-partitions (e.g. droplets), each containing at least one barcoded oligonucleotide-bearing bead, lysing the cell, and contacting the released nucleic acids with the bead-linked oligonucleotides to that each resulting cDNA molecule is uniquely tagged with a cell-specific barcode. The patent discloses that captured nucleic acids include messenger RNA molecules derived from single cells, which may be sequence to determine the transcriptome of each cell.
The instant claim 1, likewise recites a partition comprising barcode molecules and analytes such as mRNA molecules, including those encoding at least a portion of a B-cell receptor. The sole distinction is the identification of the mRNA species as an immune-receptor transcript. However, the ‘029 patent generically teaches capture and sequencing of any cellular mRNA, including transcripts from immune cells. It would have been an obvious variation for one of ordinary skill in the art to employ the single-cell RNA barcoding techniques of the ‘029 patent to analyze B-cell receptor mRNA or fragments thereof, since such transcripts are ordinary cellular mRNA species and well-known targets for single-cell sequencing at the time of filing.
The ’429 patent claims methods for partitioning single lymphocytes into droplets that each contain a barcoded oligonucleotide, lysing the cell and capturing mRNA encoding immune-cell receptor chains (e.g. B-cell or T-cell receptors) on barcoded oligo to enable recovery of V(D)J-region sequences corresponding to each individual cell. The ‘429 patent further discloses performing reverse transcription and amplification to obtain sequence information for the heavy- and light-chain variable regions of B-cell receptor transcripts.
The instant claim recites, in the relevant part, a method comprising a partition including barcode molecules and analytes such as mRNA encoding a portion thereof of a B-cell receptor. This subject matter is not patentably distinct from that claimed in the ‘429 patent because both concern the same single-cell droplet system for barcoded capture and analysis of B-cell receptor mRNA transcripts. The instant claim merely recasts the same concept, barcoded recovery of immune cell receptor mRNA in a slightly different terms. No unexpected structural or functional distinction is apparent.
Accordingly, one of ordinary skill in the art would have found it obvious to formulate or practice the claimed method of the present application a described in the ‘429 patent, since both describe the same partition-based barcoding platform and the same class of mRNA analytes (B-cell or T-cell receptor, V(D)J transcripts). The claimed invention therefore is not patentably distinct from that claimed in the ‘429 patent.
The ‘562 patent claims methods for partitioning single cells into discrete reaction volumes, such as droplets, each containing at least one barcoded oligonucleotide-bearing bead, lysing the cell and capturing released nucleic acids. On the bead-linked oligonucleotides so that the resulting products include cell-specific barcodes. The patent teaches applying these methods to analyze transcriptomes, immune-cell receptor repertoires, or other nucleic-acid analytes from individual cells.
The instant claim 1 recites a composition or system including partitions comprising barcode molecules and analytes that include mRNA encoding a portion thereof of a B-cell receptor. The subject matter of the instant claim is not patentably distinct from that claimed in the ‘562 patent because both are directed to the same single-cell microfluidic architecture and barcoded- capture strategy. The claimed distinction – identifying the capture mRNA as that encoding a B-cell / T-cell receptor – is merely the selection of a recognized species within the genus of mRNA molecules explicitly contemplated in the ’562 patent. It would have been an obvious variant for one of ordinary skill in the art to apply the ‘562 methods to B-cell receptor mRNA to analyze immune repertoires, since the ‘562 patent itself teaches that its system can be used for such analyses.
The ‘267 patent claims compositions and method comprising partitions that contain barcoded oligonucleotide molecules which are capable of hybridizing to, capturing, or extending from nucleic acid analytes, including mRNA molecules released from single cells. The patent teaches using barcoded primers, barcoded beads and partition-based methods to tag nucleic acids with a unique barcode identifying the partition or originating cell.
The instant claim 1 recites, in part, a composition including a partition that contains a plurality of barcode molecules and analytes including mRNA encoding at least a portion of a B-cell receptor. This subject matter is not patentably distinct from that claimed in the ‘267. The ‘267 patent explicitly discloses capturing any cellular mRNA using barcoded oligonucleotides in a single-cell partition, and I teaches that the analyte may include immune-receptor transcripts, such as V(D)J related species. Identifying the mRNA in the instant claim as B-cell receptor derived merely selects a species from a genus explicitly taught by the ‘267 patent. Selecting a known species within a disclosed genus does not render the claim patentably distinct.
Therefore, one of ordinary skill in the art would have found it obvious to apply the barcoded single-cell nucleic acid analysis methods of the ‘267 patent to mRNA encoding a portion of B-cell receptors, particularly since immune-receptor transcripts are specifically contemplated. Accordingly, the instant claims are not patentably distinct over the claims of the ‘267 patent.
The ‘302 patent claims compositions and methods involving partitions that contain barcoded oligonucleotide molecules capable of tagging nucleic acid analytes, including mRNA form individual cells, with partition- or cell- specific barcode sequences. The patent teaches barcoded capture of mRNA using oligonucleotide primers or beads, reverse transcription within the partition, and subsequent recovery and sequencing of the barcoded products to associate each nucleic acid product with the partition or cell of origin.
The instant claim 1 recites a composition including a partition comprising barcode molecules and analytes such as mRNA encoding at least a portion of a B-cell receptor. The claimed invention is not patentably distinct form that claimed in the ‘302 patent. The ‘302 patent expressly discloses capturing cellular mRNA, including mRNA encoding immune-cell receptor gene products., using barcoded primers within single-cell partitions. Identifying the analyte in the instant claim as B-cell receptor derived mRNA merely selects a particular species of mRNA within the genus of cellular mRNA taught in ‘302 patent. Selection of a known species encompassed by an expressly disclosed genus does not confer patentable distinctness.
Further, the microfluidic and barcoded-primer architecture recited or inherent in the instant claim is materially the same as that disclosed in the ‘302 patent. A person of ordinary skill in the art would have found it an obvious variation to apply the barcoded single-cell analysis methods of the ‘302 patent to B-cell or T-cell receptor transcripts for immune repertoire characterization, an explicitly taught application.
Accordingly, the claimed subject matter is not patentably distinct from that claimed in either ‘872, ‘029, ‘429, ‘562, ‘267, or ‘302 patents. The rejection is made provisionally, subject to withdrawal upon submission of an acceptable terminal disclaimer under 37 CFR 1.321(c) to obviate the double-patenting issues.
Conclusion
No claim is allowed.
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/MATTHEW HAROLD RAYMONDA/Examiner, Art Unit 1684
/AARON A PRIEST/Primary Examiner, Art Unit 1681