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 .
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-7 and 21-31 in the reply filed on 01/26/26 is acknowledged.
Claims Status
Claims 1-7 and 21-31 are pending.
Claims 8-20 are canceled.
Claims 1-7 and 21-31 are currently under examination.
Priority
This application claims the benefit of U.S. Provisional Application No. 63/497,554, filed April 21, 2023, which claims the benefit of U.S. Provisional Application No. 63/354,846, filed June 23, 2022. Accordingly, the priority date of claim set filed on 01/26/2026, is determined to be June 23, 2022.
Specification
Applicant is reminded of the proper content of an abstract of the disclosure.
A patent abstract is a concise statement of the technical disclosure of the patent and should include that which is new in the art to which the invention pertains. The abstract should not refer to purported merits or speculative applications of the invention and should not compare the invention with the prior art.
If the patent is of a basic nature, the entire technical disclosure may be new in the art, and the abstract should be directed to the entire disclosure. If the patent is in the nature of an improvement in an old apparatus, process, product, or composition, the abstract should include the technical disclosure of the improvement. The abstract should also mention by way of example any preferred modifications or alternatives.
Where applicable, the abstract should include the following: (1) if a machine or apparatus, its organization and operation; (2) if an article, its method of making; (3) if a chemical compound, its identity and use; (4) if a mixture, its ingredients; (5) if a process, the steps.
Extensive mechanical and design details of an apparatus should not be included in the abstract. The abstract should be in narrative form and generally limited to a single paragraph within the range of 50 to 150 words in length.
See MPEP § 608.01(b) for guidelines for the preparation of patent abstracts.
The abstract of the disclosure is objected to because the abstract should be in narrative form and generally limited to a single paragraph within the range of 50 to 150 words in length. Furthermore, the abstract lacks details of the following: (1) if a machine or apparatus, its organization and operation; (2) if an article, its method of making; (3) if a chemical compound, its identity and use; (4) if a mixture, its ingredients; (5) if a process, the steps. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
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 21-25 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 21-25 are indefinite over “a second internal cleavable site” (ln 3 and ln 8). Claim 21, requires an “internal cleavable site” in the second oligonucleotide and the first extended oligonucleotide. It is not clear if there is a first internal cleavable site. Claims 22-25 depend on the indefinite claim 21.
Claim Rejections - 35 USC § 103
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.
Claims 1-7 and 21-31 are rejected under 35 U.S.C. 103 as being unpatentable over Patterson et al. (“Patterson”; Patent App. Pub. US 20210230681 A1, Jul 29, 2021).
Patterson discloses “The present disclosure provides methods and compositions for detecting and spatially locating analyte interactions and gene expression in a biological sample. For example, provided herein are methods of determining a location of at least one analyte in a biological sample using analyte-binding moieties, proximity ligation, and an array including capture probes.” (Abstract).
Regarding claim 1, Patterson teaches a method comprising “method for determining abundance of an interaction between a first analyte and a second analyte in a biological sample. The first oligonucleotide 1401 that is bound to the first analyte-binding moiety 1402 at its 5′ end includes from 5′ to 3′ a functional sequence 1403, a first barcode 1404, and a first bridge sequence 1405. The first bridge sequence includes a sequence that is substantially complementary to the second bridge sequence. The second oligonucleotide 1406 that is bound to the second analyte-binding moiety 1407 at its 5′ end includes from 5′ to 3′ a complement of a capture probe capture domain sequence 1408, a second barcode (or complement thereof) 1409, and a second bridge sequence 1410. The second bridge sequence includes a sequence that is substantially complementary to the first bridge sequence… After attaching the first analyte-binding moiety to the first analyte and the second analyte-binding moiety to the second analyte, the first bridge sequence 1405 hybridizes to the second bridge sequence 1410 thereby generating a hybridized proximity oligonucleotide. The first oligonucleotide is extended 1413 using the second oligonucleotide as a template, and the second oligonucleotide is extended 1414 using the first oligonucleotide as a template, thereby creating a double stranded hybridized proximity oligonucleotide 1415.” (Para. 361-362, Example 7, Fig. 14 see below). Patterson teaches a method comprising “the functional sequence is a primer binding sequence.”(Para. 251). Patterson teaches a method comprising “In some embodiments, the second oligonucleotide comprises a primer-binding sequence” (Para. 199) and “capture domain sequence can include a sequence that is at least partially complementary to a sequence” (Para. 255). Furthermore, Patterson teaches a method comprising “In some embodiments, a second oligonucleotide includes from 5′ to 3′: a functional sequence (e.g., any of the exemplary functional sequences described herein; e.g., a primer binding sequence), a second barcode, and a second bridge sequence. The “bridge sequence” reads on a probe sequence. The “capture domain sequence” reads on a primer binding sequence.
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Thus, Patterson teaches A method of forming an oligonucleotide comprising two barcode sequences, said method comprising: a) contacting a first biomolecule with a first proximity probe, wherein the first proximity probe comprises a first oligonucleotide comprising, from 5' to 3', a first primer binding sequence, a first barcode sequence, and a first probe sequence; b) contacting a second biomolecule with a second proximity probe, wherein the second proximity probe comprises a second oligonucleotide comprising, from 5' to 3', a second primer binding sequence, a second barcode sequence, and a second probe sequence; c) hybridizing the first probe sequence of said first oligonucleotide to the second probe sequence of said second oligonucleotide and extending the first probe sequence with a polymerase to form a first extended oligonucleotide comprising, from 5' to 3', the first primer binding sequence, the first barcode sequence, the first probe sequence, a complement of the second barcode sequence, and a complement of the second primer binding sequence.
Furthermore, Patterson teaches the limitations of dependent claims 2-7 and 21-31 which depend on claim 1.
Regarding claims 2-4, Ref teaches a method wherein “The first oligonucleotide is bound to the first analyte-binding moiety via a first cleavable linker 1411, and the second oligonucleotide is bound to the second analyte-binding moiety via a second cleavable linker 1412. (Para. 361; Fig. 14 see above).Thus, Patterson teaches a method wherein the first oligonucleotide and the second oligonucleotide comprise a first cleavable site; wherein the first cleavable site of the first oligonucleotide is 5' of the first primer binding sequence, and wherein the first cleavable site of the second oligonucleotide is 5' of the second primer binding sequence; and wherein the second oligonucleotide comprises a first cleavable site.
Regarding claim 5, Patterson teaches a method wherein “In some embodiments, the determining step includes amplifying … all or part of the hybridized proximity oligonucleotide” (Para.41). Patterson teaches a method wherein “In some embodiments, the determining step includes sequencing.” (Para. 43). Thus, Patterson suggests a method further comprising cleaving the first cleavable site, amplifying the first extended oligonucleotide to form amplification products, and sequencing the amplification products.
Regarding claim 6, Patterson teaches a method wherein “In some embodiments, the releasing includes removing the second oligonucleotide from the second analyte-binding moiety.” (Para. 37). Patterson teaches a method wherein “in some embodiments, product is cleaved from the analyte binding moieties. In some instances, the … product is then dissociated into a single-stranded molecules... Dissociation can be performed using methods known in the art (i.e., increase in temperature, chemical means)”. (Para. 245) Thus, Patterson suggests a method further comprising cleaving the first cleavable site and removing the second oligonucleotide.
Regarding claim 7, Patterson teaches a method wherein “a “padlock oligonucleotide” refers to an oligonucleotide that has at its 5′ and 3′ ends, sequences (e.g., a first sequence at the 5′ end and a second sequence at the 3′ end) that are complementary to a portion of the first oligonucleotide… and a portion of the second oligonucleotide” (Para. 260). Patterson teaches a method wherein “In some embodiments, an additional oligonucleotide includes a capture probe capture domain sequence and a priming sequence. In some embodiments, an additional oligonucleotide includes from 5′ to 3′ a priming sequence and a capture probe capture domain sequence.” (Para. 259). Patterson teaches a method wherein “comprising a first barcode sequence” and “comprising a second barcode sequence” (Para. 259). Patterson teaches a method wherein “In some instances, a polymerase (e.g., a DNA polymerase) can extend one of the oligonucleotides prior to ligation.” (Para. 123). Patterson teaches a method wherein “In some embodiments, the circularizing step comprises ligating the first sequence of the padlock oligonucleotide to the second sequence of the padlock oligonucleotide to create a circularized padlock oligonucleotide.” (Para. 259). The “capture probe capture domain sequence” reads on a primer binding sequence. Thus, Patterson suggests a method further comprising hybridizing an oligonucleotide primer to the first extended oligonucleotide, wherein the oligonucleotide primer comprises, from 5' to 3', a first sequence complementary to the first primer binding sequence and a second sequence complementary to the complement of the second primer binding sequence, extending the second sequence along the first extended oligonucleotide to generate a complementary sequence, and ligating the complementary sequence to the first sequence of the oligonucleotide primer to form a circular oligonucleotide comprising the complement of the first barcode sequence and the second barcode sequence.
Regarding claim 21, Patterson further teaches a method wherein “In some embodiments, the capture probe comprises one or more additional functional sequences” (Para. 102). Patterson teaches a method wherein “In some embodiments, a bridge sequence can include a sequence that is at least partially complementary to one or more additional sequences (e.g., a third oligonucleotide, one or more additional oligonucleotides, a proximity probe, or a padlock oligonucleotide)” (Para. 181). Patterson teaches a method wherein “In some embodiments, the third functional sequence is a cleavage domain (e.g., any of the exemplary cleavage domains described herein (Para. 221)”. Thus, Patterson suggests a method wherein: the second oligonucleotide comprises, from 5' to 3', a second primer binding sequence, a second internal cleavable site, a third probe sequence, a second barcode sequence, and a second probe sequence, and the first extended oligonucleotide comprises, from 5' to 3', the first primer binding sequence, the first barcode sequence, the first probe sequence, a complement of the second barcode sequence, a complement of the third probe sequence, a cleavable complement of the second internal cleavable site, and a complement of the second primer binding sequence.
Regarding claims 22 and 24, Patterson teaches a method wherein “cleavage of the cleavage domain occurs” (Para.221) and “product is cleaved from the analyte binding moieties. In some instances, the… product is then dissociated into a single-stranded molecules” (Para. 245). Thus, Patterson suggests a method further comprising: d) cleaving the second internal cleavable site of said second oligonucleotide and the cleavable complement of the second internal cleavable site of said first extended oligonucleotide, thereby forming a cleaved second oligonucleotide and a cleaved first extended oligonucleotide, and removing said cleaved second oligonucleotide; and further comprising cleaving the second internal cleavable site of said second extended oligonucleotide and the cleavable complement of the second internal cleavable site of said first extended oligonucleotide, thereby forming a cleaved second extended oligonucleotide and a cleaved first extended oligonucleotide, and removing said cleaved second extended oligonucleotide.
Regarding claim 23, Patterson teaches a method wherein “In some instances, a polymerase (e.g., a DNA polymerase) can extend one of the oligonucleotides prior to ligation.” (Para. 123). Thus, Patterson suggests a method further comprising: d) extending the second oligonucleotide with a polymerase to form a second extended oligonucleotide comprising, from 5' to 3', the second primer binding sequence, the second internal cleavable site, the third probe sequence, the second barcode sequence, the second probe sequence, a complement of the first barcode sequence, and the second primer binding sequence.
Regarding claim 25, Patterson further teaches a method wherein “In some embodiments, the capture probe comprises one or more additional functional sequences” (Para. 102). Patterson teaches a method wherein “In some embodiments, a bridge sequence can include a sequence that is at least partially complementary to one or more additional sequences (e.g., a third oligonucleotide, one or more additional oligonucleotides, a proximity probe, or a padlock oligonucleotide)” (Para. 181). Thus, Patterson suggests a method wherein the cleaved first extended oligonucleotide comprises, from 5' to 3', the first primer binding sequence, the first barcode sequence, the first probe sequence, a complement of the second barcode sequence, and the complement of the third probe sequence.
Regarding claim 26, Patterson teaches a method wherein “In some embodiments, the amplifying step comprises: hybridizing one or more amplification primers to the padlock oligonucleotide; and amplifying the padlock oligonucleotide with a polymerase.” (Para. 259). Patterson teaches a method wherein “In some embodiments, the polymerase has strand displacement activity.” (Para. 259). Patterson teaches a method wherein “RCA, or rolling circle amplification, is well known in the art and includes a process by which circularized nucleic acid molecules are amplified with a DNA polymerase with strand displacement capabilities (and other necessary reagents for amplification to occur), thereby creating multiple concatenated copies of the circularized nucleic acid molecules.” (Para. 263). Thus, Patterson suggests a method further comprising amplifying the circular oligonucleotide by extending an amplification primer hybridized to the circular oligonucleotide with a strand-displacing polymerase, wherein the amplification primer extension generates an extension product comprising multiple complements of the circular oligonucleotide.
Regarding claims 27-28, Patterson teaches a method wherein “In some embodiments, the determining step includes sequencing.” (Para. 43). Thus, Patterson suggests a method further comprising sequencing the circular oligonucleotide; and further comprising sequencing the extension product.
Regarding claim 29, Patterson teaches a method wherein “the oligonucleotide is bound to the first analyte-binding moiety via a first linker” (Para. 179). Patterson teaches a method wherein “the oligonucleotide is bound to the second analyte-binding moiety via a second linker” (Para. 195) and “In some embodiments, the second linker is a second cleavable linker” (Para. 195). Thus, Patterson suggests a method wherein said first oligonucleotide is attached to the first proximity probe via a linker, and wherein said second oligonucleotide is attached to the second proximity probe via a cleavable linker.
Regarding claim 30, Patterson teaches a method wherein “enzyme-cleavable linker” (Para. 27). The “enzyme-cleavable linkers” read on cleavable linkers comprising polypeptide. Thus, Patterson suggests a method wherein said cleavable linker comprises a polynucleotide or a polypeptide sequence.
Regarding claim 31, Ref teaches a method wherein “the first analyte-binding moiety is a first protein. In some embodiments, the first protein is a first antibody. In some embodiments, the first antibody is a monoclonal antibody, recombinant antibody, synthetic antibody, a single domain antibody, a single-chain variable fragment (scFv), and or an antigen-binding fragment (Fab). In some embodiments, the first analyte-binding moiety is a nucleic acid aptamer.” (Para. 21-22) and “the second analyte-binding moiety is a second protein. In some embodiments, the second protein is a second antibody. In some embodiments, the second antibody is a monoclonal antibody, recombinant antibody, synthetic antibody, a single domain antibody, a single-chain variable fragment (scFv), and or an antigen-binding fragment (Fab). In some embodiments, the second analyte-binding moiety is a nucleic acid aptamer.” (Para. 25-26). Thus, Patterson suggests a method wherein the first proximity probe and the second proximity probe are an antibody, an antibody fragment, an affimer, an aptamer, or a nucleic acid.
Therefore, the invention as recited in claims 1-7 and 21-31 are prima facie obvious over the prior art Patterson et al. One of ordinary skill in the art would have had a reasonable expectation of success given the obviousness of the limitations. These claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of forming proximity oligonucleotide with two barcodes. It would have been obvious to provide a method of forming an oligonucleotide comprising two barcode sequences according to the limitations of the instant application claims 1-7 and 21-31 based on Patterson et al. (Patent App. Pub. US 20210230681 A1).
Conclusion
No claims are in condition for allowance.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KENDRA R VANN-OJUEKAIYE whose telephone number is (571)270-7529. The examiner can normally be reached M-F 9:00 AM- 5:00 PM.
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/KENDRA R VANN-OJUEKAIYE/Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682
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