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 .
Applicant cancels claims 8-9, 11, 14-15, 17-18, 20, 25, 28-29, 31-38, 40-41, 50-61, 63-68, 71-74 and 76-80. Claims 1-7, 10, 12-13, 16, 19, 21-24, 26-27, 30, 39, 42, 49, 62, 69-70 and 75 currently pending and under examination.
Information Disclosure Statement
The Information Disclosure Statement filed September 13, 2024 has been considered.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (see Page 14, [0047]). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The use of the terms Triton® X-100, Tween® 20, Sarcosyl® (see Page 67, [0197]), which are trade names or a marks used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claims 13 and 16 are objected to because of the following informalities:
In claim 13, lines 2-3, the terms “a capture sequence configured to couple to the capture handle”, should read “ a capture sequence that couples to the capture handle”.
In claim 13, lines 4-5, the terms “a capture sequence configured to couple to an mRNA or DNA analyte”, should read “a capture sequence that couples to an mRNA or DNA analyte”
In claim 16, lines 2-3, the terms “a capture sequence configured to couple to the capture handle” should read “ a capture sequence that couples to the capture handle”.
In claim 16, lines 4-5, the terms “a capture sequence configured to couple to non-templated nucleotides” should read “ a capture sequence that couples to non-templated nucleotides”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 1-7, 10, 12-13, 16, 19, 21-24, 26-27, 30, 39, 42, 49, 62, 69-70 and 75 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.
Claim 1 is considered vague and definite for the following reasons:
Claim 1 recites the limitation "the plurality of variant antibodies" in lines 10 and 13. There is insufficient antecedent basis for this limitation in the claim.
Claims 5-7, 10, 12-13, 16, 19, 21-24, 26-27, 39, 62, 69-70 and 75 depend from claim 1 and are therefore included in this rejection.
Claim 2 is considered vague and definite for the following reasons:
Claim 2 recites the limitation "the plurality of variant antibodies" in lines 10 and 13. There is insufficient antecedent basis for this limitation in the claim.
Claim 3 is considered vague and definite for the following reasons:
Claim 3 recites the limitation "the plurality of variant antibodies" in lines 10 and 13. There is insufficient antecedent basis for this limitation in the claim.
Claim 4 is considered vague and definite for the following reasons:
Claim 4 recites the limitation "the plurality of variant antibodies" in lines 10 and 13. There is insufficient antecedent basis for this limitation in the claim.
Claim 30 is considered vague and definite for the following reasons:
Claim 30 recites the limitation "the plurality of variant antibodies" in lines 10 and 12-13. There is insufficient antecedent basis for this limitation in the claim.
Claim 49 depends from claim 30 and is therefore included in this rejection.
Claim 42 is considered vague and definite for the following reasons:
Claim 42 recites the limitation "the first reporter" in line 9. There is insufficient antecedent basis for this limitation in the claim.
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.
Claims 1-7, 10, 12-13, 16, 19, 21-24, 26-27, 30, 39, 42, 49, 62, 69-70 and 75 are rejected under 35 U.S.C. 102 (a)(1) and (a)(2) as being anticipated by Belgrader et al. (U.S. Patent Application Publication US 2020/0002764 A1, published January 02, 2020).
Regarding claim 1, Belgrader teaches a method of engineering an antigen-binding site of an antibody, or antigen-binding fragment thereof, to comprise an altered characteristic (Page 25, [0270], Pages 30-31, [0304]-[0305], Page 31, [0308]-[0309], Pages 44-45, [0380]-[0381], Page 57, [0468], Page 71, [0543]-[0544], Page 72, [0559] and Page 90, [0681]-[0682]). Belgrader teaches providing a nucleic acid sequence encoding a selected antibody, or selected antigen-binding fragment thereof, wherein the selected antibody, or selected antigen-binding fragment thereof, binds a target antigen (Page 2, [0012], Page 3, [0021] and [0030], Page 4, [0031] and [0040], Pages 21-22, [0251], Pages 21-22, [0249]-[0252], Page 28, [0289], Pages 44-45, [0380]-[0381], Page 49, [0420], Pages 49-50, [0425]-[0426] and Page 94, [0707]). Belgrader teaches amplifying the nucleic acid sequence in an error-prone amplification reaction to produce a plurality of polynucleotides encoding variant antibodies, or variant antigen-binding fragments thereof and expressing the plurality of variant antibodies, or variant antigen-binding fragments thereof, in a plurality of cells, as well as a cell of the plurality of cells expresses a variant antibody, or variant antigen- binding fragment thereof, of the plurality of variant antibodies, or variant antigen- binding fragments thereof (Page 13, [0186], Page 30, [0297], Page 31, [0305]-[0308], Page 41, [0357]-[0358], Pages 42-43, [0368] and Page 86, [0653]-[0654]). Belgrader teaches incubating the plurality of cells in a reaction mixture further comprising the target antigen (Page 2, [0012], Page 3, [0021] and [0030], Page 4, [0031] and [0040], Pages 21-22, [0251], Pages 21-22, [0249]-[0252], Page 28, [0289]-[0292], Page 44, [0378], Pages 44-45, [0380]-[0384], Page 49, [0420], Pages 49-50, [0425]-[0426] and Page 94, [0707]). Belgrader teaches the target antigen is coupled to a reporter oligonucleotide (Page 21, [0249], Page 28, [0289]-[0290], Page 45, [0382] and [0384]). Belgrader teaches partitioning the reaction mixture into a plurality of partitions and a partition of the plurality of partitions comprises a partitioned cell bound to the target antigen (Page 2, [0012], Page 3, [0021] and [0030], Page 4, [0031] and [0040], Pages 21-22, [0251], Pages 21-22, [0249]-[0252], Page 28, [0289], Pages 44-45, [0380]-[0381], Page 49, [0420], Pages 49-50, [0425]-[0426] and Page 94, [0707]). Belgrader teaches a plurality of nucleic acid barcode molecules comprising a partition-specific barcode sequence (Page 61, [0491]-[0492]). Belgrader teaches in the partition, generating barcoded nucleic acid molecules (Page 1, [0006], Page 2, [0015], Pages 6-7, [0061]-[0062] and Page 22, [0253]). Belgrader teaches the barcoded nucleic acid molecules comprise a first barcoded nucleic acid molecule comprising a sequence of the reporter oligonucleotide or a reverse complement thereof and the partition-specific barcode sequence or reverse complement thereof (Page 1, [0006], Page 2, [0015], Pages 6-7, [0061]-[0062], Page 18, [0229], Page 22, [0253], Page 28, [0291]-[0292], Page 61, [0491]-[0492] and Page 70, [0535]). Belgrader teaches a second barcoded nucleic acid molecule comprising a nucleic acid sequence encoding the variant antibody, or variant antigen-binding fragment thereof, expressed by the cell or reverse complement thereof and the partition-specific barcode sequence or reverse complement thereof (Page 3, [0024] and [0028], Pages 6-7, [0061]-[0062], Page 21, [0249]-[0250], Page 21, [0291]-[0292], Page 30, [0299]-[0302] and Page 61, [0491]-[0492]). Belgrader teaches identifying the variant antibody, or variant antigen-binding fragment thereof, as engineered to comprise the altered characteristic based on the generated first barcoded nucleic acid molecule (Pages 21-22, [0249]-[0252], Page 25, [0270], Pages 30-31, [0297]-[0309], Page 41, [0358], Pages 44-45, [0380]-[0381], Page 45, [0388], Page 47, [0406], Page 57, [0468], Page 71, [0543]-[0544], Page 72, [0559], Page 86, [0650] and Page 90, [0681]-[0682]).
Regarding claim 2, Belgrader teaches a method of preparing a library of variant antibodies, or variant antigen-binding fragments thereof, comprising an altered characteristic (Page 10, [0146]-[0149], Pages 12-13, [0183]-[0185], Page 25, [0270], Page 28, [0290], Pages 30-31, [0304]-[0305], Page 31, [0308]-[0309], Pages 44-45, [0380]-[0381], Page 57, [0468], Page 71, [0543]-[0544], Page 72, [0559] and Page 90, [0681]-[0682]). Belgrader teaches providing a nucleic acid sequence encoding a selected antibody, or selected antigen-binding fragment thereof, wherein the selected antibody, or selected antigen-binding fragment thereof, binds a target antigen (Page 2, [0012], Page 3, [0021] and [0030], Page 4, [0031] and [0040], Pages 21-22, [0251], Pages 21-22, [0249]-[0252], Page 28, [0289], Pages 44-45, [0380]-[0381], Page 49, [0420], Pages 49-50, [0425]-[0426] and Page 94, [0707]). Belgrader teaches amplifying the nucleic acid sequence in an error-prone amplification reaction to produce a plurality of polynucleotides encoding variant antibodies, or variant antigen-binding fragments thereof and expressing the plurality of variant antibodies, or variant antigen-binding fragments thereof, in a plurality of cells, a cell of the plurality of cells expresses a variant antibody, or variant antigen- binding fragment thereof, of the plurality of variant antibodies, or variant antigen- binding fragments thereof (Page 13, [0186], Page 30, [0297], Page 31, [0305]-[0308], Page 41, [0357]-[0358], Pages 42-43, [0368] and Page 86, [0653]-[0654]). Belgrader teaches incubating the plurality of cells in a reaction mixture further comprising the target antigen Page 2, [0012], Page 3, [0021] and [0030], Page 4, [0031] and [0040], Pages 21-22, [0251], Pages 21-22, [0249]-[0252], Page 28, [0289]-[0292], Page 44, [0378], Pages 44-45, [0380]-[0384], Page 49, [0420], Pages 49-50, [0425]-[0426] and Page 94, [0707]). Belgrader teaches the target antigen is coupled to a reporter oligonucleotide (Page 21, [0249], Page 28, [0289]-[0290], Page 45, [0382] and [0384]). Belgrader teaches partitioning the reaction mixture into a plurality of partitions, and a partition of the plurality of partitions comprises a partitioned cell bound to the target antigen (Page 2, [0012], Page 3, [0021] and [0030], Page 4, [0031] and [0040], Pages 21-22, [0251], Pages 21-22, [0249]-[0252], Page 28, [0289], Pages 44-45, [0380]-[0381], Page 49, [0420], Pages 49-50, [0425]-[0426] and Page 94, [0707]). Belgrader teaches a plurality of nucleic acid barcode molecules comprising a partition-specific barcode sequence (Page 61, [0491]-[0492]). Belgrader teaches in the partition, generating barcoded nucleic acid molecules (Page 1, [0006], Page 2, [0015], Pages 6-7, [0061]-[0062] and Page 22, [0253]). Belgrader teaches the barcoded nucleic acid molecules comprise a first barcoded nucleic acid molecule comprising a sequence of the reporter oligonucleotide or a reverse complement thereof and the partition-specific barcode sequence or reverse complement thereof (Page 1, [0006], Page 2, [0015], Pages 6-7, [0061]-[0062], Page 18, [0229], Page 22, [0253], Page 28, [0291]-[0292], Page 61, [0491]-[0492] and Page 70, [0535]). Belgrader teaches a second barcoded nucleic acid molecule comprising a nucleic acid sequence encoding the variant antibody, or variant antigen-binding fragment thereof, expressed by the cell or reverse complement thereof and the partition-specific barcode sequence or reverse complement thereof (Page 3, [0024] and [0028], Pages 6-7, [0061]-[0062], Page 21, [0249]-[0250], Page 21, [0291]-[0292], Page 30, [0299]-[0302] and Page 61, [0491]-[0492]). Belgrader teaches identifying the variant antibody, or variant antigen-binding fragment thereof, for inclusion in the library based on the generated first barcoded nucleic acid molecule (Pages 21-22, [0249]-[0252], Page 23, [0257], Page 25, [0270], Page 28, [0290], Pages 30-31, [0297]-[0309], Page 41, [0358], Pages 44-45, [0380]-[0381], Page 45, [0388], Page 47, [0406], Page 57, [0468], Page 71, [0543]-[0544], Page 72, [0559], Page 86, [0650] and Page 90, [0681]-[0682]).
Regarding claim 3, Belgrader teaches a method of engineering an antigen-binding site of an antibody, or antigen-binding fragment thereof, to comprise an altered characteristic (Page 25, [0270], Pages 30-31, [0304]-[0305], Page 31, [0308]-[0309], Pages 44-45, [0380]-[0381], Page 57, [0468], Page 71, [0543]-[0544], Page 72, [0559] and Page 90, [0681]-[0682]). Belgrader teaches providing a nucleic acid sequence encoding a selected antibody, or selected antigen-binding fragment thereof, wherein the selected antibody, or selected antigen-binding fragment thereof, binds a target antigen (Page 2, [0012], Page 3, [0021] and [0030], Page 4, [0031] and [0040], Pages 21-22, [0251], Pages 21-22, [0249]-[0252], Page 28, [0289], Pages 44-45, [0380]-[0381], Page 49, [0420], Pages 49-50, [0425]-[0426] and Page 94, [0707]). Belgrader teaches amplifying the nucleic acid sequence in an error-prone amplification reaction to produce a plurality of polynucleotides encoding variant antibodies, or variant antigen-binding fragments thereof and expressing the plurality of variant antibodies, or variant antigen-binding fragments thereof, in a plurality of cells, as well as a cell of the plurality of cells expresses a variant antibody, or variant antigen- binding fragment thereof, of the plurality of variant antibodies, or variant antigen- binding fragments thereof (Page 13, [0186], Page 30, [0297], Page 31, [0305]-[0308], Page 41, [0357]-[0358], Pages 42-43, [0368] and Page 86, [0653]-[0654]). Belgrader teaches incubating the plurality of cells in a reaction mixture further comprising the target antigen (Page 2, [0012], Page 3, [0021] and [0030], Page 4, [0031] and [0040], Pages 21-22, [0251], Pages 21-22, [0249]-[0252], Page 28, [0289]-[0292], Page 44, [0378], Pages 44-45, [0380]-[0384], Page 49, [0420], Pages 49-50, [0425]-[0426] and Page 94, [0707]). Belgrader teaches the target antigen is coupled to a reporter oligonucleotide (Page 21, [0249], Page 28, [0289]-[0290], Page 45, [0382] and [0384]). Belgrader teaches partitioning the reaction mixture into a plurality of partitions and a partition of the plurality of partitions comprises a partitioned cell bound to the target antigen (Page 2, [0012], Page 3, [0021] and [0030], Page 4, [0031] and [0040], Pages 21-22, [0251], Pages 21-22, [0249]-[0252], Page 28, [0289], Pages 44-45, [0380]-[0381], Page 49, [0420], Pages 49-50, [0425]-[0426] and Page 94, [0707]). Belgrader teaches a plurality of nucleic acid barcode molecules comprising a partition-specific barcode sequence (Page 61, [0491]-[0492]). Belgrader teaches generating barcoded nucleic acid molecules (Page 1, [0006], Page 2, [0015], Pages 6-7, [0061]-[0062] and Page 22, [0253]). Belgrader teaches the barcoded nucleic acid molecules comprise a first barcoded nucleic acid molecule comprising a sequence of the reporter oligonucleotide or a reverse complement thereof and the partition-specific barcode sequence or reverse complement thereof (Page 1, [0006], Page 2, [0015], Pages 6-7, [0061]-[0062], Page 18, [0229], Page 22, [0253], Page 28, [0291]-[0292], Page 61, [0491]-[0492] and Page 70, [0535]). Belgrader teaches a second barcoded nucleic acid molecule comprising a nucleic acid sequence encoding the variant antibody, or variant antigen-binding fragment thereof, expressed by the cell or reverse complement thereof and the partition-specific barcode sequence or reverse complement thereof (Page 3, [0024] and [0028], Pages 6-7, [0061]-[0062], Page 21, [0249]-[0250], Page 21, [0291]-[0292], Page 30, [0299]-[0302] and Page 61, [0491]-[0492]). Belgrader teaches identifying the variant antibody, or variant antigen-binding fragment thereof, as engineered to comprise the altered characteristic based on the generated first barcoded nucleic acid molecule (Pages 21-22, [0249]-[0252], Page 25, [0270], Pages 30-31, [0297]-[0309], Page 41, [0358], Pages 44-45, [0380]-[0381], Page 45, [0388], Page 47, [0406], Page 57, [0468], Page 71, [0543]-[0544], Page 72, [0559], Page 86, [0650] and Page 90, [0681]-[0682]).
Regarding claim 4, Belgrader teaches a method of preparing a library of variant antibodies, or variant antigen-binding fragments thereof, comprising an altered characteristic (Page 10, [0146]-[0149], Pages 12-13, [0183]-[0185], Page 25, [0270], Page 28, [0290], Pages 30-31, [0304]-[0305], Page 31, [0308]-[0309], Pages 44-45, [0380]-[0381], Page 57, [0468], Page 71, [0543]-[0544], Page 72, [0559] and Page 90, [0681]-[0682]). Belgrader teaches providing a nucleic acid sequence encoding a selected antibody, or selected antigen-binding fragment thereof, wherein the selected antibody, or selected antigen-binding fragment thereof, binds a target antigen (Page 2, [0012], Page 3, [0021] and [0030], Page 4, [0031] and [0040], Pages 21-22, [0251], Pages 21-22, [0249]-[0252], Page 28, [0289], Pages 44-45, [0380]-[0381], Page 49, [0420], Pages 49-50, [0425]-[0426] and Page 94, [0707]). Belgrader teaches amplifying the nucleic acid sequence in an error-prone amplification reaction to produce a plurality of polynucleotides encoding variant antibodies, or variant antigen-binding fragments thereof and expressing the plurality of variant antibodies, or variant antigen-binding fragments thereof, in a plurality of cells, a cell of the plurality of cells expresses a variant antibody, or variant antigen- binding fragment thereof, of the plurality of variant antibodies, or variant antigen- binding fragments thereof (Page 13, [0186], Page 30, [0297], Page 31, [0305]-[0308], Page 41, [0357]-[0358], Pages 42-43, [0368] and Page 86, [0653]-[0654]). Belgrader teaches incubating the plurality of cells in a reaction mixture further comprising the target antigen Page 2, [0012], Page 3, [0021] and [0030], Page 4, [0031] and [0040], Pages 21-22, [0251], Pages 21-22, [0249]-[0252], Page 28, [0289]-[0292], Page 44, [0378], Pages 44-45, [0380]-[0384], Page 49, [0420], Pages 49-50, [0425]-[0426] and Page 94, [0707]). Belgrader teaches the target antigen is coupled to a reporter oligonucleotide (Page 21, [0249], Page 28, [0289]-[0290], Page 45, [0382] and [0384]). Belgrader teaches partitioning the reaction mixture into a plurality of partitions, and a partition of the plurality of partitions comprises a partitioned cell bound to the target antigen (Page 2, [0012], Page 3, [0021] and [0030], Page 4, [0031] and [0040], Pages 21-22, [0251], Pages 21-22, [0249]-[0252], Page 28, [0289], Pages 44-45, [0380]-[0381], Page 49, [0420], Pages 49-50, [0425]-[0426] and Page 94, [0707]). Belgrader teaches a plurality of nucleic acid barcode molecules comprising a partition-specific barcode sequence (Page 61, [0491]-[0492]). Belgrader teaches generating barcoded nucleic acid molecules (Page 1, [0006], Page 2, [0015], Pages 6-7, [0061]-[0062] and Page 22, [0253]). Belgrader teaches the barcoded nucleic acid molecules comprise a first barcoded nucleic acid molecule comprising a sequence of the reporter oligonucleotide or a reverse complement thereof and the partition-specific barcode sequence or reverse complement thereof (Page 1, [0006], Page 2, [0015], Pages 6-7, [0061]-[0062], Page 18, [0229], Page 22, [0253], Page 28, [0291]-[0292], Page 61, [0491]-[0492] and Page 70, [0535]). Belgrader teaches a second barcoded nucleic acid molecule comprising a nucleic acid sequence encoding the variant antibody, or variant antigen-binding fragment thereof, expressed by the cell or reverse complement thereof and the partition-specific barcode sequence or reverse complement thereof (Page 3, [0024] and [0028], Pages 6-7, [0061]-[0062], Page 21, [0249]-[0250], Page 21, [0291]-[0292], Page 30, [0299]-[0302] and Page 61, [0491]-[0492]). Belgrader teaches identifying the variant antibody, or variant antigen-binding fragment thereof, for inclusion in the library based on the generated first barcoded nucleic acid molecule (Pages 21-22, [0249]-[0252], Page 23, [0257], Page 25, [0270], Page 28, [0290], Pages 30-31, [0297]-[0309], Page 41, [0358], Pages 44-45, [0380]-[0381], Page 45, [0388], Page 47, [0406], Page 57, [0468], Page 71, [0543]-[0544], Page 72, [0559], Page 86, [0650] and Page 90, [0681]-[0682]).
Regarding claim 5, Belgrader teaches the provided nucleic acid sequence encoding the selected antibody, or selected antigen-binding fragment thereof, is of a plurality of nucleic acid sequences encoding a plurality of selected antibodies, or selected antigen-binding fragments thereof, that bind the target antigen (Page 2, [0012], Page 3, [0021], [0024] and [0030], Page 4, [0031] and [0040], Pages 21-22, [0249]-[0253], Page 28, [0289], Pages 44-45, [0379]-[0381], Page 48, [0418], Page 49, [0420], Pages 49-50, [0425]-[0426] and Page 94, [0707]).
Regarding claim 6, Belgrader teaches the selected antibody, or selected antigen-binding fragment thereof, comprises a human antibody, or antigen-binding fragment thereof (Page 11, [0170], Page 13, [0186], Pages 55-56, [0461], Page 56, [0465]-[0466] and Page 93, [0701]).
Regarding claim 7, Belgrader teaches the provided nucleic acid sequence encoding the selected antibody, or selected antigen-binding fragment thereof, is derived from nucleic acids of a cell of a human donor or a combination of cells from multiple human donors (Page 11, [0170], Page 13, [0186], Pages 55-56, [0461], Page 56, [0465]-[0466] and Page 93, [0701]).
Regarding claim 10, Belgrader teaches the provided nucleic acid sequence encoding the selected antibody, or selected antigen-binding fragment thereof, is derived from nucleic acids of a cell of a mouse, wherein the mouse is a transgenic mouse (genetically altered) (Page 11, [0170], Page 65, [0515], Page 72, [0559] and Page 88, [0664]).
Regarding claim 12, Belgrader teaches the reporter oligonucleotide comprises a reporter barcode sequence and a capture handle sequence (Page 1, [0006]-[0008], Page 2, [0015], Page 18, [0229], Page 26, [0279]-[0280], Page 48, [0418], Pages 54-55, [0456]-[0459], Page 60, [0479]-[0480], Page 95, [0710]-[0711] and Fig. 87).
Regarding claim 13, Belgrader teaches a first nucleic acid barcode molecule of the plurality of barcode molecules further comprises a capture sequence configured to couple to the capture handle sequence, and a second nucleic acid barcode molecule of the plurality of nucleic acid barcode molecules further comprises a capture sequence configured to couple to an mRNA or DNA analyte (Page 1, [0006]-[0008], Page 2, [0015], Page 18, [0229], Page 26, [0279]-[0280], Page 48, [0418], Pages 54-55, [0456]-[0459], Page 56, [0462], Page 60, [0479]-[0481], Page 95, [0710]-[0711] and Fig. 87).
Regarding claim 16, Belgrader teaches a first nucleic acid barcode molecule of the plurality of barcode molecules further comprises a capture sequence configured to couple to the capture handle sequence, and a second nucleic acid barcode molecule of the plurality of nucleic acid barcode molecules further comprises a capture sequence configured to couple to non-templated nucleotides appended to a cDNA reverse transcribed from an mRNA analyte (Page 1, [0006]-[0008], Page 2, [0015], Page 4, [0040], Page 18, [0229], Page 26, [0279]-[0280], Page 32-33, [0314]-[0318], Page 34, [0322], Page 48, [0418], Pages 54-55, [0456]-[0459], Page 56, [0462], Page 60, [0478]-[0481], Page 95, [0710]-[0711] and Fig. 87). Belgrader teaches optionally the second nucleic acid barcode molecule further comprises a template switch oligonucleotide (TSO) (Page 72, [0548], Page 74, [0571] and Page 95, [0711])
Regarding claim 19, Belgrader teaches the target antigen coupled to the reporter oligonucleotide comprises a detectable label (i.e., fluorescence; Page 9, [0113], Pages 44-45, [0381]-[0382], Page 56, [0465], Page 57, [0470], Page 88, [0664] and Page 90, [0681]).
Regarding claim 21, Belgrader teaches the first and/or second barcoded nucleic molecule further comprises a UMI sequence (Page 22, [0252] and Page 52, [0444]).
Regarding claim 22, Belgrader teaches comprising determining sequences of the first and the second barcoded nucleic acid molecule (Page 3, [0024]-[0025], Page 6, [0054], Page 10, [0147]-[0149] and Page 11, [0173]).
Regarding claim 23, Belgrader teaches assessing affinity of the variant antibody, or variant antigen binding fragment thereof, based on the generated quantity of the first barcoded nucleic acid molecule (Page 12, [0181], (Page 25, [0270], Pages 30-31, [0304]-[0305], Page 31, [0308]-[0309], Pages 43-44, [0375], Pages 44-45, [0380]-[0381], Page 57, [0468], Page 71, [0543]-[0544], Page 72, [0559] and Page 90, [0681]-[0682]).
Regarding claim 24, Belgrader teaches the reaction mixture further comprises an antigen not bound by the selected antibody, or selected antigen-binding fragment thereof, wherein the antigen not bound by the selected antibody, or selected antigen-binding fragment thereof, is coupled to a second reporter oligonucleotide (Page , [0012], Page , [0021], Page [0030], Page [0249], Page 29, [0289]-[0290] and Pages 43-44, [0375]-[0376]).
Regarding claim 26, Belgrader teaches a second partition of the plurality of partitions comprises a second cell expressing the selected antibody, or selected antigen-binding fragment thereof, bound to the target antigen, and the plurality of nucleic acid barcode molecules comprising the partition-specific barcode sequence (Page 2, [0012], Page 3, [0021], [0024] and [0030], Page 4, [0031] and [0040], Page 6, [0058], Pages 6-7, [0061]-[0062], Page 19, [0234], Pages 21-22, [0249]-[0253], Page 28, [0289], Pages 44-45, [0379]-[0381], Page 48, [0418], Page 49, [0420], Pages 49-50, [0425]-[0426], Page 56, [0462], Pages 61-62, [0492] and Page 94, [0707]).
Regarding claim 27, Belgrader teaches the cell is a mammalian cell, an insect cell or a yeast cell (Page 20, [0243] and Pages 41-42, [0359]).
Regarding claim 30, Belgrader teaches a method of preparing a library of variant antibodies, or variant antigen-binding fragments thereof, comprising an altered characteristic or characteristics (Page 10, [0146]-[0149], Pages 12-13, [0183]-[0185], Page 25, [0270], Page 28, [0290], Pages 30-31, [0304]-[0305], Page 31, [0308]-[0309], Pages 44-45, [0380]-[0381], Page 57, [0468], Page 71, [0543]-[0544], Page 72, [0559] and Page 90, [0681]-[0682]). Belgrader teaches providing a nucleic acid sequence encoding a selected antibody derived from nucleic acids of a cell of a human donor, or selected antigen-binding fragment thereof, wherein the selected human antibody, or selected antigen-binding fragment thereof, binds a target antigen (Page 11, [0170], Page 13, [0186], Pages 55-56, [0461], Page 56, [0465]-[0466] and Page 93, [0701], Page 2, [0012], Page 3, [0021] and [0030], Page 4, [0031] and [0040], Pages 21-22, [0251], Pages 21-22, [0249]-[0252], Page 28, [0289], Pages 44-45, [0380]-[0381], Page 49, [0420], Pages 49-50, [0425]-[0426] and Page 94, [0707]). Belgrader teaches amplifying the nucleic acid sequence in an error-prone amplification reaction to produce a plurality of polynucleotides encoding variant antibodies, or variant antigen-binding fragments thereof and expressing the plurality of variant antibodies, or variant antigen-binding fragments thereof, in a plurality of mammalian cells (Page 20, [0243], Pages 41-42, [0359], Page 13, [0186], Page 30, [0297], Page 31, [0305]-[0308], Page 41, [0357]-[0358], Pages 42-43, [0368] and Page 86, [0653]-[0654]). Belgrader teaches a mammalian cell of the plurality of mammalian cells expresses a variant antibody, or variant antigen-binding fragment thereof, of the plurality of variant antibodies or variant antigen-binding fragments thereof; and identifying the variant antibody, or variant antigen-binding fragment thereof, for inclusion in the library if it comprises an altered characteristic or characteristics (Page 20, [0243], Pages 41-42, [0359], Page 13, [0185]-[0186], Page 30, [0297], Page 31, [0305]-[0308], Page 41, [0357]-[0358], Pages 42-43, [0368], Pages 43-44, [0375], Page 57, [0468], Page 86, [0653]-[0654] and Page 90, [0681]-[0682]).
Regarding claim 39, Belgrader teaches the target antigen is a pathogen selected from a virus or a bacterial cell (Page 21, [0250]).
Regarding claim 42, Belgrader teaches a system for engineering an antigen-binding site of an antibody, or antigen-binding fragment thereof, to comprise an improved characteristic (Page 25, [0270], Pages 30-31, [0304]-[0305], Page 31, [0308]-[0309], Pages 44-45, [0380]-[0381], Page 57, [0468], Page 71, [0543]-[0544], Page 72, [0559] and Page 90, [0681]-[0682]). Belgrader teaches reagents for performing error-prone amplification and a target antigen coupled to a reporter oligonucleotide (Page 13, [0186], Page 30, [0297], Page 31, [0305]-[0308], Page 41, [0357]-[0358], Pages 42-43, [0368], Page 86, [0653]-[0654], Page 21, [0249], Page 28, [0289]-[0290], Page 45, [0382] and [0384]). Belgrader teaches a plurality of nucleic acid barcode molecules comprising a partition-specific barcode sequence (Page 61, [0491]-[0492]). Belgrader teaches reagents for generating a plurality barcoded nucleic acid molecules formed by complementary base pairing of a capture sequence of the plurality of nucleic acid barcode molecules and a capture handle sequence of the first reporter oligonucleotide (Page 1, [0006]-[0008], Page 2, [0015], Page 18, [0229], Page 26, [0279]-[0280], Page 48, [0418], Pages 54-55, [0456]-[0459], Page 60, [0478]-[0480], Page 90, [0692], Page 95, [0710]-[0711] and Fig. 87).
Regarding claim 49, Belgrader teaches the cell of the human donor is identified as expressing the selected antibody, or selected antigen-binding fragment thereof (Page 11, [0170], Page 13, [0186], Pages 55-56, [0461], Page 56, [0465]-[0466] and Page 93, [0701]). Belgrader teaches the nucleic acid sequence encoding the selected antibody, or antigen-binding fragment thereof, is prepared for the providing, incubating the cell of the human donor with the target antigen (Page 13, [0186], Page 2, [0012], Page 3, [0021] and [0030], Page 4, [0031] and [0040], Pages 21-22, [0251], Pages 21-22, [0249]-[0252], Page 28, [0289]-[0292], Page 44, [0378], Pages 44-45, [0380]-[0384], Page 49, [0420], Pages 49-50, [0425]-[0426] and Page 94, [0707]). Belgrader teaches the target antigen is coupled to a reporter oligonucleotide (Page 21, [0249], Page 28, [0289]-[0290], Page 45, [0382] and [0384]). Belgrader teaches partitioning the cell of the human donor bound to the target antigen in a partition further comprising a plurality of nucleic acid barcode molecules comprising a partition-specific barcode sequence (Page 13, [0186], Page 2, [0012], Page 3, [0021] and [0030], Page 4, [0031] and [0040], Pages 21-22, [0251], Pages 21-22, [0249]-[0252], Page 28, [0289], Pages 44-45, [0380]-[0381], Page 49, [0420], Pages 49-50, [0425]-[0426], Page 61, [0491]-[0492] and Page 94, [0707]). Belgrader teaches in the partition, generating barcoded nucleic acid molecules (Page 1, [0006], Page 2, [0015], Pages 6-7, [0061]-[0062] and Page 22, [0253]). Belgrader teaches the barcoded nucleic acid molecules comprise a first barcoded nucleic acid molecule comprising the sequence of the reporter oligonucleotide or a reverse complement thereof and the partition-specific barcode sequence or reverse complement thereof (Page 1, [0006], Page 2, [0015], Pages 6-7, [0061]-[0062], Page 18, [0229], Page 22, [0253], Page 28, [0291]-[0292], Page 61, [0491]-[0492] and Page 70, [0535]). Belgrader teaches detection of the first barcoded nucleic acid molecule identifies the cell of the human donor as expressing the selected antibody, or the selected antigen- binding fragment thereof (Page 13, [0186], Page 7, [0063], Pages 31, [0307]-[0308], Page 46, [0396] and Page 49, [0424]-[0425]) Belgrader teaches a second barcoded nucleic acid molecule comprising the nucleic acid sequence encoding the selected antibody, or selected antigen-binding fragment thereof, for the providing (Page 3, [0024] and [0028], Pages 6-7, [0061]-[0062], Page 21, [0249]-[0250], Page 21, [0291]-[0292], Page 30, [0299]-[0302] and Page 61, [0491]-[0492]).
Regarding claim 62, Belgrader teaches the first and/or second barcoded nucleic molecule further comprises a UMI sequence (Page 22, [0252] and Page 52, [0444]).
Regarding claim 69, Belgrader teaches the variant antibody, or variant antigen-binding fragment thereof, comprises at least one, at least three, or at least five amino acid substitution relative to the selected antibody or antigen binding fragment thereof (Pages 44-45, [0381] and Page 74, [0569]).
Regarding claim 70, Belgrader teaches the altered characteristic comprises altered affinity, an altered association constant, an altered dissociation constant, altered specificity for the target antigen and optionally when the altered characteristic is altered affinity it is a higher affinity (Page 12, [0181], (Page 25, [0270], Pages 30-31, [0304]-[0305], Page 31, [0308]-[0309], Pages 44-45, [0380]-[0381], Page 57, [0468], Page 71, [0543]-[0544], Page 72, [0559] and Page 90, [0681]-[0682]).
Regarding claim 75, Belgrader teaches the antibody is a secreted antibody or an antigen binding fragment thereof (Pages 11-12, [0176], Pages 30-31, [0304] and Page 71, [0543]).
Belgrader teaches every limitation of claims 1-7, 10, 12-13, 16, 19, 21-24, 26-27, 30, 39, 42, 49, 62, 69-70 and 75, and therefore Belgrader anticipates claims 1-7, 10, 12-13, 16, 19, 21-24, 26-27, 30, 39, 42, 49, 62, 69-70 and 75.
Conclusion
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/JESSICA D PARISI/Examiner, Art Unit 1684
/HEATHER CALAMITA/Supervisory Patent Examiner, Art Unit 1684
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