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 .
Claim Status
Claims 1-10, 12-14, 17-19, 23-24, 26, and 40 are pending.
Claims 1-10, 12-14, 17-19, 23-24, 26, and 40 were considered.
Claims 1-10, 12-14, 17-19, 23-24, 26, and 40 are rejected.
Priority
The instant application filed on 14 July 2023 is a CON of a PCT filed on 21 January 2022 and claims priority to a provisional application filed on 22 January 2021. As such, the effective filing date of the application is 22 January 2021.
Information Disclosure Statement
The IDS filed 22 November 2023 was considered by the examiner.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Drawings
The drawings are objected to because Figures 3, 4, 5, 6, 7, and 8 contain enumerated amino acid sequences without providing sequence identifiers (see above). Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-10, 12-14, 17-19, 23-24, 26, and 40 are rejected under 35 U.S.C. 101 because the claimed inventions are directed to abstract ideas without significantly more.
Step 2A, Prong 1
In accordance with MPEP § 2106, claims found to recite statutory subject matter (Step
1: YES) are then analyzed to determine if the claims recite any concepts that equate to an
abstract idea, law of nature or natural phenomenon (Step 2A, Prong 1). In the instant application,
the claims recite the following limitations that equate to abstract ideas:
Claim 1 and dependent claims 2-10 and 12-13 and claim 40 recite:
Obtaining a single cell dataset
Identifying a clonotype group
Selecting a schema
Selecting a cell of interest
Claim 14 and dependent claims 17-19, 23-24, and 26:
Obtaining a single cell dataset
Identifying a clonotype group
Selecting a schema
Claims 3 and 17 recite:
Selecting amino acids with a pre-selected frequency threshold
Claims 4 and 18 recite:
Selecting amino acids with a selected chemical identity
Claims 5 and 19 recite:
Selecting amino acids of protein motifs that encode post-translational modifications
Claim 8 recites:
Highlighting selected amino acids
Claims 9 and 23 recite:
An alignment of amino acid sequences
Claims 10 and 24 recite:
A comparison of reference sequences and amino acid sequences
Claims 12 and 26 recite:
Calculating distances on a phylogenetic tree
Claim 13 recites:
Determining distance between a constant region and a reference sequence
The limitations for the listed claims are evaluations or judgements that can be made through mental observations or mathematical calculations which fall under the “mental processes” and “mathematical concepts” groupings of abstract ideas. Under the broadest reasonable interpretation, the abstract ideas recited in the claims are determined to cover performance either in the mind (calculations by hand or pen and paper) or by mathematical operation (calculations/algorithms). See MPEP § 2106.04(a)(2), subsection III. The courts do not distinguish between mental processes that are performed entirely in the human mind and mental processes that require a human to use a physical aid (e.g., pen and paper or a slide rule) to perform the claim limitation (see, e.g., Benson, 409 U.S. at 67, 65, 175 USPQ at 674-75, 674: noting that the claimed "conversion of [binary-coded decimal] numerals to pure binary numerals can be done mentally," i.e., "as a person would do it by head and hand."); Synopsys, Inc. V. Mentor Graphics Corp., 839 F.3d 1138, 1139, 120 USPQ2d 1473, 1474 (Fed. Cir. 2016): holding that claims to a mental process of "translating a functional description of a logic circuit into a hardware component description of the logic circuit" are directed to an abstract idea, because the claims "read on an individual performing the claimed steps mentally or with pencil and paper"). Nor do the courts distinguish between claims that recite mental processes performed by humans and claims that recite mental processes performed on a computer. As the Federal Circuit has explained, "[c]ourts have examined claims that required the use of a computer and still found that the underlying, patent-ineligible invention could be performed via pen and paper or in a person's mind" (see Versata Dev. Group V. SAP Am., Inc., 793 F.3d 1306, 1335, 115 USPQ2d 1681, 1702 (Fed. Cir. 2015); Mortgage Grader, Inc. v. First Choice Loan Servs. Inc., 811 F.3d 1314, 1324, 117 USPQ2d 1693, 1699 (Fed. Cir. 2016): holding that computer-implemented method for "anonymous loan shopping" was an abstract idea because it could be "performed by
humans without a computer").
While claims 14, 17-19, 23-24, 26, and 40 recite performing aspects of the methods with “one or more data processors”, “a computing device”, “a computer-program product”, and/or “non-transitory computer readable medium”, there are no additional limitations that indicate that the processors, computing device, computer-program product, or non-transitory computer readable medium would require anything other than carrying out the recited mental process or mathematical concept in a generic computer environment. Merely reciting that a mental process is being performed in a generic computer environment does not preclude the steps from being performed practically in the human mind or with pen and paper as claimed. If a claim limitation, under its broadest reasonable interpretation, covers performance of the limitation in the mind but for the recitation on generic computer components, then it falls into the “mental processes” grouping of abstract ideas. As such, claims 1-10, 12-14, 17-19, 23-24, 26, and 40 recite abstract ideas (Step 2A, Prong 1: YES).
Step 2A, Prong 2
Claims found to recite a judicial exception under Step 2A, Prong 1 are then further
analyzed to determine if the claims as a whole integrate the recited judicial exception into a
practical application or not (Step 2A, Prong 2). This judicial exception is not integrated into a
practical application because the claims do not recite an additional element that reflects an
improvement to technology or applies or uses the recited judicial exception in some other
meaningful way. Rather, the instant claims recite additional elements that amount to mere
instructions to implement the abstract idea or insignificant extra-solution activity. Specifically,
the claims recite the following additional elements:
Claim 1 and dependent claims 2-10 and 12-13; claim 14 and dependent claims 17-19, 23-24, and 26; and claim 40 recite:
Visualizing the selected amino acids in a graphic representation
Claims 6 and 7 recite:
Displaying positions of the selected amino acids
Claims 12 and 26 recite:
Building a phylogenetic tree
Claim 14 and dependent claims 17-19, 23-24, and 26 recite:
One or more data processors
A computing device
A non-transitory computer readable storage medium
A display for rendering a visualization
Claim 40 recites:
A computer-program product
A non-transitory computer readable medium.
The limitations for defining terms describe mental processes with additional elements. This judicial exception is not integrated into a practical application because these additional
elements do not add any meaningful limitations. The claims do not include additional elements
that are sufficient to amount to significantly more than the judicial exception because they only
describe more specificity to the types of variables. As such, these limitations equate to mere
instructions to implement the abstract ideas.
There are no limitations that indicate that the processors, computing device, computer-program product, or non-transitory computer readable medium would require anything other than a generic computing system. As such, these limitations equate to mere instructions to implement the abstract ideas on a generic computer that the courts have stated do not render an abstract idea eligible in Alice Corp., 573 U.S. at 223, 110 USPQ2d at 1983. See also 573 U.S. at 224, 110 USPQ2d at 1984.
The above recited additional elements do not provide a practical application of the recited
judicial exception. As such, claims 1-10, 12-14, 17-19, 23-24, 26, and 40 are directed to an abstract idea (Step 2A, Prong 2:NO).
Step 2B
Claims found to be directed to a judicial exception are then further evaluated to determine if the claims recite an inventive concept that provides significantly more than the judicial exception itself (Step 2B). The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims recite additional elements that are known and commonly used techniques in the art and are mere instructions to apply the recited exception in a generic computing environment.
As discussed above, there are no additional limitations to indicate that the claimed
method requires more than routine use of technology. Additionally, there are no additional limitations to indicate that the program requires anything other than generic computer components in order to carry out the recited abstract ideas in the claims. Claims that amount to nothing more than an instruction to apply the abstract idea using a generic computer do not render an abstract idea eligible. Alice Corp., 573 U.S. at 223, 110 USPQ2d at 1983. See also 573 U.S. at 224, 110 USPQ2d at 1984. In addition, mere display of collected and analyzed information that could be performed by the human mind do not render an abstract idea eligible. See Electric Power Group v. Alstom, S.A., 830 F.3d 1350, 1353-54, 119 USPQ2d 1739, 1741-42 (Fed. Cir. 2016)
The additional elements do not comprise an inventive concept when considered individually or as an ordered combination that transforms the claimed judicial exception into a patent-eligible application of the judicial exception. Therefore, the claims do not amount to significantly more than the judicial exception itself (Step 2B: No). As such, claims 1-10, 12-14, 17-19, 23-24, 26, and 40 are not patent eligible.
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, 6-10, 13-14, 23-24, and 40 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Borcherding et al. (F1000Research, 15 June 2020, pages 1-17) (Herein referred to as Borcherding.)
With respect to claim 1, dependent claims 2, 4, 6-10, and 13, and claim 40, Borcherding teaches scRepertoire was built to process data for both T-cell receptor (TCR) and immunoglobulin (Ig) enrichment workflows. (Page 1, Abstract, lines 11-13) Borcherding further teaches that clonotypes can be called using CDR3 amino acid sequence and clonotypic analysis can be performed after clonotype assignment. (Page 3, Figure 1 and caption) Borcherding additionally teaches outputs from scRepertoire can be imported into a number of single-cell expression formats to visualize clonotype data. (Page 3, Figure 1 caption) Additionally, Borcherding teaches selecting a cell of interest through scRepertoire’s use of Seurat. (Page 1, Abstract; page 3, Figure 1) Seurat v3.0.0 included the CellSelector tool before the EFD of the instant application. (Rdocumentation, 12 April 2019, page 2)
With respect to claim 2, Borcherding teaches a new R package for the analysis of T-cell and B-cell clonotypes inferred from V(D)J recombination events. (Page 8, lines 12-13)
With respect to claim 4, Borcherding teaches clonotypes can be called using the
amino acid sequence of the complementary-determining region 3 (CDR3). (Page 4, left column, “Implementation” lines 4-7)
With respect to claims 6 and 7, Borcherding teaches the distribution of CDR3 nucleotide or amino acid sequences for clonotypes can be visualized with lengthContig. (Page 4, right column, lines 7-8)
With respect to claim 8, Borcherding teaches highlightClonotypes can be used to specifically highlight the individual clonotypes of interest using the sequence information. (Page 5, Figure 4D caption)
With respect to claim 9, Borcherding teaches isolation and processing of the 10x-Genomics-based single cell mRNA and V(D)J Chromium sequencing data for immune cells. (Page 4, left column, lines 1-3) Borcherding further teaches a new R package for the analysis of T-cell and B-cell clonotypes inferred from V(D)J recombination events and is designed for the analysis of data generated using the10x Genomics V(D)J kit that allows clonotypes and transcriptomes to be co-assayed in the same individual cells. (Page 8, lines 11-14) Borcherding additionally taches that with the need to add thresholding for clonotype assignment for the BCR in the context of somatic hypermutation, they have separated the combineContig() function into
combineTCR() and combineBCR() functions and kept the ability to visualize and analyze clonotypes at the amino acid, nucleotide sequence and gene level to give all users more choices. (Page 16, paragraph 6) The instant application discloses that exact subclonotypes share identical V(D)J transcripts. [0007] The instant application further discloses referencing changes that have originated from somatic hypermutation and from possible molecular biology artifacts and/or errors in V(D)J references. [0154]
With respect to claim 10, Borcherding teaches setting specific sequences of clonotypes to be visualized, with clonotype 1 referring to the amino acid sequence “CAVNGGSQGNLIF_
CSAEREDTDTQYF” and clonotype 2 for the amino acid sequence "NA_CATSATLRVVAEKLFF". (Page 6, left column, lines 3-8) Borcherding further teaches that after combining both the clonotype and expression data, interaction between categories, such as cluster label and clonotype frequency can be visualized with the alluvialClonotypes function. (Page 6, left column, lines 10-13)
With respect to claim 13, Borcherding teaches separating the combineContig() function into combineTCR() and combineBCR() functions, the latter organizing the data similarly, but
defines nucleotide sequences by the normalized Hamming Distance, with sequences
greater than >0.85 assigned to the same group. (Page 16, paragraph 6, lines 2-5) Borcherding further teaches that in the strict definition of the clonotypes in the combineBCR() the vgene is also added to both the light and heavy chains and discloses the ability to visualize and analyze clonotypes at the amino acid, nucleotide sequence and gene level. (Page 16, paragraph 6, lines 5-8)
Claims 14, 18, 23, and 24 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Borcherding.
With respect to claim 14, and dependent claims 18, 23, and 24, Borcherding teaches scRepertoire was built to process data for both T-cell receptor (TCR) and immunoglobulin (Ig) enrichment workflows. (Page 1, Abstract, lines 11-13) Borcherding further teaches that clonotypes can be called using CDR3 amino acid sequence and clonotypic analysis can be performed after clonotype assignment. (Page 3, Figure 1 and caption) Borcherding additionally teaches outputs from scRepertoire can be imported into a number of single-cell expression formats to visualize clonotype data. (Page 3, Figure 1 caption)
With respect to claim 18, Borcherding teaches clonotypes can be called using
amino acid sequence of the complementary-determining region 3 (CDR3). (Page 4, left column, “Implementation” lines 4-7)
With respect to claim 23, Borcherding teaches isolation and processing of the 10x-Genomics-based single cell mRNA and V(D)J Chromium sequencing data for immune cells. (Page 4, left column, lines 1-3) Borcherding further teaches a new R package for the analysis of T-cell and B-cell clonotypes inferred from V(D)J recombination events and is designed for the analysis of data generated using the10x Genomics V(D)J kit that allows clonotypes and transcriptomes to be co-assayed in the same individual cells. (Page 8, lines 11-14) Borcherding additionally taches that with the need to add thresholding for clonotype assignment for the BCR in the context of somatic hypermutation, they have separated the combineContig() function into
combineTCR() and combineBCR() functions and kept the ability to visualize and analyze clonotypes at the amino acid, nucleotide sequence and gene level to give all users more choices. (Page 16, paragraph 6) The instant application discloses that exact subclonotypes share identical V(D)J transcripts. [0007] The instant application further discloses referencing changes that have originated from somatic hypermutation and from possible molecular biology artifacts and/or errors in V(D)J references. [0154]
With respect to claim 24, Borcherding teaches setting specific sequences of clonotypes to be visualized, with clonotype 1 referring to the amino acid sequence “CAVNGGSQGNLIF_
CSAEREDTDTQYF” and clonotype 2 for the amino acid sequence "NA_CATSATLRVVAEKLFF". (Page 6, left column, lines 3-8) Borcherding further teaches that after combining both the clonotype and expression data, interaction between categories, such as cluster label and clonotype frequency can be visualized with the alluvialClonotypes function. (Page 6, left column, lines 10-13)
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.
Claims 3 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Borcherding in view of Richardson et al. (MABS, 11 January 2021, e1869406-1 - e1869406-14) (Herein referred to as Richardson.)
Borcherding teaches the limitations of claims 1 and 14 as described above.
Borcherding does not teach wherein the schema comprises selecting amino acids with a frequency meeting a pre-selected frequency threshold in the clonotype group.
Richardson teaches clonotypes as antibodies with the same heavy chain V and J genes, CDRH3s of the same length, and above a threshold level of amino acid identity across the CDRH3. (Page e1869406-3, left column, lines 36-39) Richardson further teaches that for clonotyping, the optimal heavy-chain only threshold is 72% CDRH3 amino acid identity. (Page e1869406-4, left column, lines 8-9) Richardson additionally teaches clonotypes were defined as groups of heavy chain sequences sharing the same V and J genes, with identical CDRH3 lengths and a number of amino acid mismatches equal to or below a threshold sequence identity. (Page e1869406-11, left column, lines 19-21)
It would have been prima facie obvious to one of ordinary skill in the art at the effective
filing date of the invention to have combined the methods of Borcherding and Richardson. Borcherding discloses analyses based on amino acid sequence and that these functions can also be used to examine the dynamics of single or multiple expanded clonotypes across the categorical variables. (Page 6, left column, lines 12-14) Borcherding also discloses that after the attachment of the expression information to a single-cell expression object, the function, expression2List() allows users generate analyses based on any categorical variable in the meta data. (Page 6, left column, lines 14-18) Richardson discloses that these defined amino acid thresholds are optimal as they maximize both precision and recall, corresponding to the “shoulder” of the precision–recall curve and that, at these optimal thresholds, clonotyping recovers binders with 83% precision and 79% recall (meaning that 21% of the binders in this data set are not related by clonotype to any other). (Page e1869406-4, left column, lines 11-16) Therefore, one of ordinary skill in the art would have been motivated to combine the cell selection methods of Borcherding with the amino acid threshold analysis of Richardson to enhance prospective repertoire mining. The invention is therefore prima facie obvious.
Claims 5 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Borcherding in view of Vletter et al. (IDS reference C11; Frontiers in Immunology, 18 February 2020, pages 1-12) (Herein referred to as Vletter.)
Borcherding teaches the limitations of claims 1 and 14 as described above.
Borcherding does not teach wherein the schema comprises selecting amino acids of protein motifs that encode post-translational modification in the clonotype group.
Vletter teaches a process primed by the presence of N-linked glycosylation motifs, which consist of an asparagine (N), followed by any amino acid but proline, followed by serine (S) or threonine (T) (N-X-S/T; X6=P). (Page 2, left column, last paragraph lines 3-8)
It would have been prima facie obvious to one of ordinary skill in the art at the effective
filing date of the invention to have combined the methods of Borcherding and Vletter. Borcherding discloses analyses based on amino acid sequence and that these functions can also be used to examine the dynamics of single or multiple expanded clonotypes across the categorical variables. (Page 6, left column, lines 12-14) Borcherding also discloses that after the attachment of the expression information to a single-cell expression object, the function, expression2List() allows users generate analyses based on any categorical variable in the meta data. (Page 6, left column, lines 14-18) Vletter discloses that N-linked glycosylation motifs are only present in the variable domain when rearrangements contain the Vsegments IGHV1-8, IGHV4-34, or the more rarely used IGHV5-10, IGKV5-2, IGLV3-12, and IGLV3-22 (34). Additional Nlinked glycosylation motifs may be found in naïve B cells when junctional diversity creates novel motifs in the complementary determining region 3 (CDR3). (Page 2, right column, last paragraph lines 4-10) Therefore, one of ordinary skill in the art would have been motivated to combine the methods of cell selection methods of Borcherding with the protein motif analysis of Vletter to assess the impact of post-translational modifications on the interactions and responses of immune cells. The invention is therefore prima facie obvious.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Borcherding in view of Dhar et al. (IDS reference C2; PLoS Computational Biology, 8 June 2020, pages 1-27) (Herein referred to as Dhar.)
Borcherding teaches the limitations of claim 1 as described above. Borcherding further teaches functions that define nucleotide sequences by the normalized Hamming Distance, with sequences greater than >0.85 assigned to the same group and in the combineBCR() the vgene is also added to both the light and heavy chains. (Page 16, paragraph 6, lines 3-6)
Borcherding does not teach building a phylogenetic tree of the clonotype group according to the schema.
Dhar teaches BCR diversity is induced by naturally occurring combinatorial “V(D)J” rearrangement, mutation, and selection processes and further describes a novel approach to Bayesian phylogenetic inference for BCR sequences that is based on a phylogenetic hidden Markov model (phylo-HMM). (Page 1, Abstract, lines 4-5 and 12-14) Dhar additionally teaches a technique that integrates a naive rearrangement model with a phylogenetic model for BCR sequence evolution and also naturally accounts for uncertainty in all unobserved variables, including the phylogenetic tree, via posterior distribution sampling. (Page 1, Abstract, lines 14-17) Dhar also discloses constructing a phylogenetic inference procedure that not only allows for easy quantification of phylogenetic and ancestral sequence uncertainty but also models the V(D)J recombination as an informative prior for the naive sequence at the root of a phylogenetic tree describing the evolution of one clonal lineage. (Page 3, lines 12-16)
It would have been prima facie obvious to one of ordinary skill in the art at the effective
filing date of the invention to have combined the cell selection methods of Borcherding with the phylogenetic tree of Dhar. Dhar discloses that before one can perform ancestral sequence inference for clonal sequences that result from the same naive rearrangement event, one must first obtain an estimate of the clonal phylogenetic tree. (Page 1, Author summary, lines 3-5) Dhar further discloses that the current standard phylogenetic inference techniques used to model the process of sequence evolution do not account for all the complexities associated with this evolutionary process. (Page 1, Author summary, lines 5-7) Dhar teaches a Bayesian approach to phylogenetic inference for clonal sequences that is based on a phylogenetic hidden Markov model. (Page 1, Author summary, lines 8-9) Dhar’s phylo-HMM models both the naive rearrangement and somatic hypermutation processes and this Bayesian framework allows one to naturally account for uncertainty in all unobserved variables, including a phylogenetic tree, via posterior distribution sampling. (Pages 1-2, Author summary, lines 9-12) Therefore, one of ordinary skill in the art would have been motivated to combine the cell selection methods of Borcherding and phylogenetic inference procedure of Dhar to allow for easy quantification of phylogenetic and ancestral sequence uncertainty and model the V(D)J recombination as an informative prior for the naive sequence at the root of a phylogenetic tree options. (Dhar, page 3, lines 12-16) The invention is therefore prima facie obvious.
Claim 26 is rejected under 35 U.S.C. 103 as being unpatentable over Borcherding in view of Dhar et al. (IDS reference C2; PLoS Computational Biology, 8 June 2020, pages 1-27) (Herein referred to as Dhar.)
Borcherding teaches the limitations of claim 1 as described above.
Borcherding does not teach building a phylogenetic tree of the clonotype group according to the schema.
Dhar teaches BCR diversity is induced by naturally occurring combinatorial “V(D)J” rearrangement, mutation, and selection processes and further describes a novel approach to Bayesian phylogenetic inference for BCR sequences that is based on a phylogenetic hidden Markov model (phylo-HMM). (Page 1, Abstract, lines 4-5 and 12-14) Dhar additionally teaches a technique that integrates a naive rearrangement model with a phylogenetic model for BCR sequence evolution and also naturally accounts for uncertainty in all unobserved variables, including the phylogenetic tree, via posterior distribution sampling. (Page 1, Abstract, lines 14-17) Dhar also discloses constructing a phylogenetic inference procedure that not only allows for easy quantification of phylogenetic and ancestral sequence uncertainty but also models the V(D)J recombination as an informative prior for the naive sequence at the root of a phylogenetic tree describing the evolution of one clonal lineage. (Page 3, lines 12-16)
It would have been prima facie obvious to one of ordinary skill in the art at the effective
filing date of the invention to have combined the cell selection methods of Borcherding with the phylogenetic tree of Dhar. Dhar discloses that before one can perform ancestral sequence inference for clonal sequences that result from the same naive rearrangement event, one must first obtain an estimate of the clonal phylogenetic tree. (Page 1, Author summary, lines 3-5) Dhar further discloses that the current standard phylogenetic inference techniques used to model the process of sequence evolution do not account for all the complexities associated with this evolutionary process. (Page 1, Author summary, lines 5-7) Dhar teaches a Bayesian approach to phylogenetic inference for clonal sequences that is based on a phylogenetic hidden Markov model. (Page 1, Author summary, lines 8-9) Dhar’s phylo-HMM models both the naive rearrangement and somatic hypermutation processes and this Bayesian framework allows one to naturally account for uncertainty in all unobserved variables, including a phylogenetic tree, via posterior distribution sampling. (Pages 1-2, Author summary, lines 9-12) Therefore, one of ordinary skill in the art would have been motivated to combine the cell selection methods of Borcherding and phylogenetic inference procedure of Dhar to allow for easy quantification of phylogenetic and ancestral sequence uncertainty and model the V(D)J recombination as an informative prior for the naive sequence at the root of a phylogenetic tree options. (Dhar, page 3, lines 12-16) The invention is therefore prima facie obvious.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Wong et al teaches obtaining a dataset of immune cells, identifying a clonotype, affordances on a display selected by the user based on amino acid sequence, visualizing selected amino acids that defines the clonotype, each contig represents a T-cell receptor chain or a B-cell chain, filtering by CDR regions, highlighting contigs that contain the entered amino acid sequence, analyzing based on the VDJ sequences, constant and variable gene segments of immune molecules, an alignment of contig consensus sequences, and defining a distance function for samples in different clusters. (IDS reference A40, US2018/0371545 A1) Stuart et al teaches an R toolkit Seurat that present a framework for the comprehensive integration of single cell data. (Cell, 13 June 2019, pages 1888–1902) Nouri and Kleinstein teach somatic hypermutation analysis for improved identification of B-cell clonal families from next-generation sequencing data. (PLOS Computational Biology, 23 June 2020, pages 1-22) Koch at al teach a T-cell repertoire model that captures the distribution of the TCR repertoire, demonstrates stability across varying sequencing depths, and permits comparative analysis across any number of sampled individuals. (PLOS Computational Biology, 28 November 2018, pages 1-18) Cakir et al teach an R package which allows users to convert their own scRNAseq datasets into a specific data format for visualization. (NAR Genomics and Bioinformatics, 29 July 2020, pages 1-6) Ni et al teach an interactive software for T-cell repertoire sequencing data analysis. (Frontiers in Genetics, 21 July 2020, pages 1-8) Clark teaches a high-throughput solution for profiling paired V(D)J transcripts from lymphocytes and, that by working on a cell-by-cell basis, it provides high resolution insights into the adaptive immune system. (10x Genomics blog post, 27 March 2017, pages 1-5)
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/S.L.G./Examiner, Art Unit 1687
/Karlheinz R. Skowronek/Supervisory Patent Examiner, Art Unit 1687
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