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 .
Priority
This application filed 08/29/2022 is a Continuation of PCT/US2021/019120, filed 02/22/2021, and claims priority from Provisional Application 62983485, filed 02/28/2020 and from Provisional Application 63011783, filed 04/17/2020. The claims are therefore examined as filed on 02/28/2020, the effective filing date. In future actions, the effective filing date of one or more claims may change, due to amendments to the claims, or further review of the priority application(s).
Claim Status
Claims 1-15, 27-28 and 43-44 are pending.
Claim 27 is objected to.
Claims 16-26, 29-42 and 45-46 are cancelled.
Claims 1-15, 27-28 and 43-44 are examined.
Claims 1-15, 27-28 and 43-44 are rejected.
Information Disclosure Statement
The Information Disclosure Statements are in compliance with the provisions of 37 CFR 1.97. Accordingly, all references have been considered.
Drawings
The drawings are objected to because the different views of Fig 6, broken up across several pages, are labelled as “FIG 6 (Cont.)”, and instead need to be labelled as Fig 6A, Fig 6B. etc. Partial views intended to form one complete view, on one or several sheets, must be identified by the same number followed by a capital letter (see MPEP 1.84).
The drawings are also objected to for not meeting the sequence listings requirements. Fig 6 (pg 7-11) includes amino acid sequence of at least 4 amino acids that do not have Seq ID Numbers in the Figures themselves, nor in the brief description of the drawings (see section on Nucleotide and/or Amino Acid Sequence Disclosures below).
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.
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 (see pg 7-11 of 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.
Claim Objections
Claim 27 is objected to because of the following informalities:
Claim 27 should read “obtaining the immune cell
Appropriate correction is required.
Claim Interpretation
The following is a quotation of 35 U.S.C. 112(f):
(f) Element in Claim for a Combination. – An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The following is a quotation of pre-AIA 35 U.S.C. 112, sixth paragraph:
An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art. The broadest reasonable interpretation of a claim element (also commonly referred to as a claim limitation) is limited by the description in the specification when 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is invoked.
As explained in MPEP § 2181, subsection I, claim limitations that meet the following three-prong test will be interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph:
(A) the claim limitation uses the term “means” or “step” or a term used as a substitute for “means” that is a generic placeholder (also called a nonce term or a non-structural term having no specific structural meaning) for performing the claimed function;
(B) the term “means” or “step” or the generic placeholder is modified by functional language, typically, but not always linked by the transition word “for” (e.g., “means for”) or another linking word or phrase, such as “configured to” or “so that”; and
(C) the term “means” or “step” or the generic placeholder is not modified by sufficient structure, material, or acts for performing the claimed function.
Use of the word “means” (or “step”) in a claim with functional language creates a rebuttable presumption that the claim limitation is to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites sufficient structure, material, or acts to entirely perform the recited function.
Absence of the word “means” (or “step”) in a claim creates a rebuttable presumption that the claim limitation is not to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is not interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites function without reciting sufficient structure, material or acts to entirely perform the recited function.
Claim limitations in this application that use the word “means” (or “step”) are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action. Conversely, claim limitations in this application that do not use the word “means” (or “step”) are not being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action.
This application includes one or more claim limitations that do not use the word “means,” but are nonetheless being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, because the claim limitation(s) uses a generic placeholder that is coupled with functional language without reciting sufficient structure to perform the recited function and the generic placeholder is not preceded by a structural modifier. Such claim limitations are: the “processing unit” in claim 14, the “comparison engine” in claims 14-15, and the “identification engine” in claim 14.
Because these claim limitations are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, they are being interpreted to cover the corresponding structure described in the specification as performing the claimed function, and equivalents thereof. The specification indicates that the structure of the “processing unit” is a processor/computer system, and that the engines are software provided on a computer system (pg 43).
If applicant does not intend to have this/these limitation(s) interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, applicant may: (1) amend the claim limitation(s) to avoid it/them being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph (e.g., by reciting sufficient structure to perform the claimed function); or (2) present a sufficient showing that the claim limitation(s) recite(s) sufficient structure to perform the claimed function so as to avoid it/them being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph.
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 1-15, 27-28 and 43-44 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea of mental processes and mathematical concepts, without significantly more.
The MPEP at MPEP 2106 sets forth steps for identifying eligible subject matter:
(1) Are the claims directed to a process, machine, manufacture or composition of matter?
(2A)(1) Do the claims recite a judicially recognized exception, i.e. a law of nature, a natural phenomenon, or an abstract idea?
(2A)(2) Do the claims recite additional elements that integrate the judicial exception into a practical application?
(2B) If the claims recite a judicial exception and do not integrate the judicial exception, do the claims recite additional elements that provide an inventive concept and amount to significantly more than the judicial exception?
With regard to step (1) (Are the claims directed to a process, machine, manufacture or composition of matter?): Yes. The claims are directed to one of the statutory classes. Claims 1-13 and 43-44 are directed to a process (a method), claims 14-15 are directed to a machine product (a system comprising a processing unit), and claims 27-28 are also directed to a product (a non-transitory computer readable medium).
With regard to step (2A)(1) (Do the claims recite a judicially recognized exception?): Yes. The claims recite the abstract ideas of processing data using mental steps and mathematical concepts. Claims that recite nothing more than abstract ideas, natural phenomena, or laws of nature are not eligible for patent protection (see MPEP 2106.04).
Abstract ideas include mathematical concepts, (mathematical formulas or equations, mathematical relationships and mathematical calculations), certain methods of organizing human activity, and mental processes (including procedures for collecting, observing, evaluating, and organizing information (See MPEP 2106.04(a)(2)). In particular, these abstract ideas include but are not limited to:
Comparing immune cell receptor sequences associated with a first immune cell and a second immune cell using a comparison protocol (mental process; the human mind is capable of comparing sequences by following a protocol; claims 1-2, 14-15, 27-28)
Identifying the first immune cell and second immune cell as members of the same clonotype if one or more immune cell receptor sequence comparison criteria is met (mental process; the human mind is capable of identifying cells based on a given criteria being met; claim 1, 14, 27)
Determining a number of shared mutations in the immune cell receptor sequences of the first and second immune cell (mental process; the human mind is capable of comparing sequences and identifying identical base changes, claims 2, 15, 28)
Calculating a probability value that the number of shared mutations occurred by chance and determining the comparison criteria is not met if the probability value exceeds a pre set threshold (mental process/mathematical concept; the human mind is capable of calculating probability and comparing a value to a threshold, calculating a probability and comparing numerical values are mathematical concepts; claim 4)
Comparing V and J segments for length and base pair differences (mental process; the human mind is capable of comparing two sequences and identifying differences in length or bases; claims 5-6)
Comparing lengths or differences of the CDRs (mental process; the human mind is capable of comparing two CDRs and identifying differences; claims 7-8)
Determining the number of CDR differences between cell members and determining that comparison criteria is not met if the number of CDR differences exceed a determined two-cell threshold (mental process/mathematical concept; the human mind is capable of counting/identifying differences and comparing the total to a threshold, counting a value and comparing it to another threshold value is a mathematical concept; claim 9)
Identifying exact subclonotypes within the identified clonotype comprising a set of immune cells having identical V, D, and J transcripts (mental process; the human mind is capable of identifying a subtype based on data/matching data to make a determination; claim 11)
Determining germline alleles by calculating shared differences between immune cells with disjoint CDR3 junction sequences within the immune cell receptor sequence dataset and shared mutations relative to a universal reference sequence (mental process/mathematical concept; the human mind is capable of calculating shared differences between sequences and a reference sequence, counting differences/performing a calculation is a mathematical concept; claims 12-13)
Dependent claims 3 and 10 further limit the abstract ideas recited in the independent claims, and do not change their characterization as abstract ideas.
Therefore, the claims recite elements that constitute one or more judicial exceptions.
With regard to step (2A)(2) (Do the claims recite additional elements that integrate the judicial exception into a practical application?): No. Claim 1 and its dependents recite the additional element of “obtaining the immune cell receptor sequence dataset from a sample”, and claim 2 further recites the additional element of “receiving a reference immune cell receptor sequence” as part of the comparison protocol. Claims 14-15 also recite the additional element of a system comprising a data source, processing unit and comparison/identification engines for performing the method of claim 1, and claims 27-28 similarly recite the additional element of a non-transitory computer readable medium for causing a computer to perform the method of claim 1, and the additional element of obtaining the immune cell receptor sequence dataset.
While the claims recite the additional element of receiving or obtaining data, such steps that only amount to necessary data gathering , without any technical details of how the data is obtained that integrate the judicial exception, are insignificant extrasolution activities that do not add a meaningful limitation to the claims (see MPEP 2106.05(g)). As a result, the judicial exception is not integrated into a practical application. In addition, while claims 14-15 and 27-28 recite additional elements related to the use of computers, they do not provide any specific details by which the computer-readable medium, computer or processing unit performs or carries out the judicial exception listed in step (2A)(1), nor do they provide any details of how specific structures of the computer are used to implement these functions. The judicial exception is therefore not integrated into a practical application because the generically recited computer elements do not add a meaningful limitation to the abstract idea, as they amount to simply implementing the abstract idea on a computer (see MPEP 2106.05(f)). Because the claims do not recite any additional elements that integrate the judicial exception into a practical application, the claims as a whole are directed to an abstract idea.
With regard to step (2B) (Do the claims recite additional elements that provide an inventive concept and amount to significantly more than the judicial exception?): No. The claims recite an abstract idea with additional elements; however, these additional elements are general computer elements added to abstract ideas, and non-particular instructions to apply the abstract idea by linking it to a field of use or extrasolution activity (see MPEP 2106.05(f-h)). General computer elements used to perform an abstract idea do not provide an inventive concept, and similarly, non-particular instructions to gather or receive data do not provide an inventive concept. Non-particular instructions to gather data using general computer elements are also considered well-understood, routine and conventional activities (see MPEP 2106.05(d), which indicates that limitations such as “Receiving or transmitting data over a network” from Symantec, 838 F.3d at 1321, 120 USPQ2d at 1362, and “Storing and retrieving information in memory” from Versata Dev. Group, Inc. v. SAP Am., Inc., 793 F.3d 1306, 1334, 115 USPQ2d 1681, 1701 (Fed. Cir. 2015); OIP Techs., 788 F.3d at 1363, 115 USPQ2d at 1092-93 are recognized as conventional activities). The claims therefore do not include additional elements that are sufficient to amount to significantly more than the judicial exception. As a result, the claims as a whole do not provide an inventive concept.
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 Rejection
Claims 1, 5-10, 14, 27 and 44 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WONG 2016 “Systems And Methods For Visualizing A Pattern In A Dataset” (US 20180225416 A1, as cited on the IDS filed 3-21-2023).
Claim Interpretation and Scope and Contents of Prior Art
Claims 1, 14, and 27 recite a method, system, and computer-readable medium, respectively, with instructions for grouping immune cells within an immune cell receptor sequence dataset, the method comprising: obtaining the immune cell receptor sequence dataset from a sample, the dataset including a plurality of full-length immune cell receptor sequences each comprised of at least one heavy chain region sequence and one light chain region sequence, wherein each immune cell receptor sequence is associated with an individual immune cell in the sample.
With respect to this limitation, WONG teaches clustering immune cells in a dataset (Abstract, [0003, 8]), involving obtaining a clonotype dataset that includes the V(D)J clonotype of the B-cell immunoglobulin receptors of B-cells, or the T-cell receptor of T-cells, from a biological sample, and immune cell receptor sequences comprising light and heavy chain sequences [0088], and where each immune receptor sequence is associated with an individual immune cell [0018, 140, 184, each first entity in the dataset is a gene and each second entity is single cell].
Claims 1, 14, and 27 also recite the limitations of comparing the immune cell receptor sequences associated with a first immune cell and a second immune cell from the sample using a comparison protocol; and identifying the first immune cell and the second immune cell as members of the same clonotype, if one or more immune cell receptor sequence comparison criteria is met.
With respect to these limitations, WONG teaches comparing the immune cell receptor sequences from different cells to identify the cells as the same clonotype using clustering methods (a comparison protocol) and by determining if comparison criteria, such as whether the cells’ receptor chains have the same corresponding CDR3 sequences, are met [088, 107, 175, 195-196].
Claim 5 recites the limitation of the comparison protocol comprising comparing V and J segments portions of the immune cell receptor sequences associated with the first immune cell and the second immune cell, wherein the comparison criteria is met when the V and J segments portions have the same length, and claim 6 recites the limitation of determining a number of base differences between the V and J segments portions associated with the first immune cell and the second immune cell, and determining that the comparison criteria is not met if the number of base differences exceed a predetermined VJ base difference threshold. With respect to this limitation, With respect to this limitation, WONG teaches comparing V and J sequence segments from different second entities (immune cells) and grouping them based on the sequences [088], and that two second entities (immune cells) are deemed to have the same clonotype (meet a comparison criteria) if their respective receptor chains have the same corresponding CDR3 sequences [0175] which spans the V gene and J gene in T-cell receptor α chains and the V, D and J genes in T-cell receptor β chains [0189] (V and J segments portions covered by the CDR3 sequence are identical and therefore have the same lengths and base pairs/meet a threshold).
Claim 7 recites the limitation of the comparison protocol comprising comparing lengths of the complementarity-determining regions (CDRs) associated with the first immune cell and the second immune cell, and determining that the comparison criteria is met when the CDRs have the same length. With respect to this limitation, WONG teaches comparing CDR sequences associated with the immune cells [0048, 88] and that two cells are deemed to have the same clonotype if their receptor chains have the same corresponding CDR3 sequences [0175] and therefore the same length.
Claim 8 recites the limitation of determining the number of differences in the CDRs associated with the first immune cell and the second immune cell, and determining that the comparison criteria is not met when the number of differences exceeds a predetermined CDR threshold. With respect to this limitation, WONG teaches applying a filter to cluster the cell data based on CDR bases or by a specific CDR sequence [0178] which is equivalent to determining the criteria for including a cell or sequence in a clonotype is not met because the number of differences exceeds a threshold.
Claim 9 recites the limitation wherein the first immune cell and the second immune cell are cell members of a two-cell clonotype, the method further comprising: determining the number of CDR differences between the cell members; determining that the comparison criteria is not met if the number of CDR differences exceed a determined two-cell threshold. With respect to this limitation, WONG teaches comparing CDR sequences associated with the immune cells [0048, 88] and that two cells are deemed to have the same clonotype if their receptor chains have the same corresponding CDR3 sequences [0175].
Claim 10 recites the limitation wherein the two-cell threshold has a value dependent on the number of shared mutations. With respect to this limitation, WONG teaches that two cells are deemed to have the same clonotype if their receptor chains have the same corresponding CDR3 sequences [0175], and as such, would have the same number of shared mutations.
Claim 44 recites the limitation of the comparison protocol comprising comparing D segments portions of the immune cell receptor sequences associated with the first immune cell and the second immune cell, wherein the comparison criteria is met when the D segments portions have the same length. With respect to this limitation, WONG teaches comparing CDR3 sequences (which includes the D segment) associated with the immune cells [0048, 88] and that two cells are deemed to have the same clonotype if their receptor chains have the same corresponding CDR3 sequences [0175, 0189] such that the CDR3 segments and the D segment portions also inherently have the same length.
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.
Claim Rejection
Claims 2-4 , 11-13, 15, 28, and 43 are rejected under 35 U.S.C. 103 as being unpatentable over WONG as applied to claims 1, 5-10, 14, 27 and 44 above, and further in view of SOTO 2019 “High frequency of shared clonotypes in human B cell receptor repertoires.”
Claim Interpretation and Scope and Contents of Prior Art
WONG teaches the limitations of claims 1, 5-10, 14, 27 and 44 above.
Claims 2, 15, and 28 recite the limitations of the comparison protocol including: receiving a reference immune cell receptor sequence; comparing the immune cell receptor sequences of the first immune cell and the second immune cell to the reference immune cell receptor sequence; and determining a number of shared mutations in the immune cell receptor sequences of the first immune cell and the second immune cell. With respect to these limitations, WONG teaches that the clonotype dataset includes or is associated with a VDJ chain reference sequence table with the reference sequence of all the V and J genes in a genome or those represented by the clonotype dataset [0089] and that the reference sequence is compared or aligned to the database cell receptor sequences [096-97]. WONG further teaches that the genes can share variations [0133], and that cells have the same clonotype if they have the same CDR3 sequence ( and therefore shared mutations) [0194-196].
WONG does not specifically teach determining a number of shared mutations in the immune cell receptor sequences of the first immune cell and the second immune cell. However, SOTO teaches determining somatic variants ( clones with mutations) and clustering clonotypes that had 80% sequence identity in the HCDR3 region (pg 3 par 1) and also teaches grouping somatic variants associated with each V3J clonotype by requiring the corresponding CDR1 and CDR2 amino acid sequences to be identical (pg 4 par 3), therefore having identical mutations.
Claim 3 recites the limitation wherein the comparison criteria is met when the immune cell receptor sequences of the first immune cell and the second immune cell share a pre- set number of mutations. With respect to this limitation, WONG teaches comparing cell receptor sequences by specific CDR3 sequences or bases [0178] and that two cells are deemed to have the same clonotype if their receptor chains have the same corresponding CDR3 sequences [0175, 0189], and therefore an identical number of shared mutations. SOTO also teaches clustering clonotypes with 80% sequence identity in the HCDR3 region (pg 3 par 1) which is a result of the number of identical bases/mutations meeting a threshold equal to 80% similarity.
Claim 4 recites the limitation of calculating a probability value that the number of shared mutations occurred by chance; and determining the comparison criteria as not being met if the probability value exceeds a pre- set probability threshold. With respect to this limitation, WONG teaches that its method constructs a probability distribution so that entity vectors with similar discrete attribute values are picked over entity vectors with dissimilar values [0140], and SOTO also teaches determining that the presence of overlapping clonotypes did not occur by chance alone (pg 3 last par, pg 4 par 1-2).
Claim 11 recites the limitation of identifying exact subclonotypes within the identified clonotype, wherein the exact subclonotype comprises a non- zero set of immune cells having identical V, D, and J transcripts. With respect to this limitation, WONG teaches identifying immune cells with a specific CDR3 nucleic acid sequence as a clonotype [0175-178] but does not teach identifying exact subclonotypes within them. However, SOTO teaches further grouping sequences with matching V, D, and J genes (pg 7 par 2) which would result in subclonotypes.
Claim 12 recites the limitation of determining germline alleles for a donor V segments portion sequence. With respect to this limitation, WONG teaches determining germline alleles of VDJ regions [088, 0185] but does not teach determining them for donor sequences. However, SOTO teaches determining germline alleles to assess clonotype sharing between donors (pg 7 par 2, pg 8 par 4).
Claim 13 recites the limitation wherein determining the germline alleles for the donor V segments portion sequence comprises calculating shared differences between immune cells with disjoint CDR3 junction sequences within the immune cell receptor sequence dataset and shared mutations relative to a universal reference sequence, and wherein the determination of shared differences are representative of germline mutations. With respect to this limitation, WONG teaches determining differences between CDR3 sequences in the immune cell dataset relative to a reference sequence [0089, 0175] that can include germline VDJ sequences [088, 0185], and SOTO teaches determining shared motifs between CDR3 sequences as part of determining germline alleles from donor segments (pg 4 par 2-4).
Claim 43 recites the limitation of joining singletons, wherein the singletons can be joined to obtain a more frequent exact subclonotype if the sequences of the singletons are identical. With respect to this limitation, SOTO teaches increasing the frequency of clonotypes by grouping together V3J clonotypes sharing identical V and J germline gene assignments with CDR3 amino acid sequences sharing 80% or greater sequence identity (pg 7 par 2) which can be applied to singletons with identical sequences in creating subclonotypes.
Resolving Ordinary Skill in the Art and Obviousness Rationale
A teaching, suggestion, or motivation in the prior art would have led one of ordinary skill in the art to modify or combine the prior art to arrive at the claimed invention. Specifically, a person of ordinary skill in determining clonotypes would have been motivated to combine the teachings of WONG with the teachings of SOTO, in order to achieve the claimed invention, because clonotypes (and subclonotypes) are determined based on sequence similarity (pg 2 par 1) and because mutations/somatic variations can cause new clonotypes/subclonotypes (Abstract) by decreasing similarities; further, determining germline alleles allows for more accurate/high confidence determination of clonotypes and determining clonotype sharing between donors(pg 7 par 2-3). A person of ordinary skill would reasonably expect success from combining these teachings, as both WONG and SOTO teach methods of determining clonotypes and grouping cells into clonotypes. Therefore, the claims at issue would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention as there is both a reason to modify or combine the prior art, and a reasonable expectation of success (see MPEP 2143.02 (I)).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARY C LEVERETT whose telephone number is (571)272-5494. The examiner can normally be reached 8:00am - 5:00pm M-Th.
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/MARY C LEVERETT/Examiner, Art Unit 1687