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 .
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on August 17th, 2022, December 27th, 2024, and May 28th, 2025 are acknowledged. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements have been considered by the examiner.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-13, in the reply filed on August 4th, 2025 is acknowledged.
Claims 14-16, 23, 24, 29, and 32 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on August 4th, 2025.
Claim Summary
Claims 17-22, 25-28, 30-31, and 33-41 have been canceled. Claims 1-16, 23-24, 29, and 32 are pending. Claims 14-16, 23, 24, 29, and 32 are withdrawn from consideration as being drawn to a non-elected invention/species. Claims 1-13 are under examination and discussed in this Office action.
Claim Interpretation
Claim 1 recites the limitation “wherein said sample sequence comprising a distinguishable sequence from other sample sequences of other sample nucleic acids in said cell”. “Distinguishable sequence” appears to mean a sequence additional to the sequence of the sample nucleic acid based on the description provided in the instant specification at paragraphs [00069], [00083], and [00084], and Examples 1 and 2. Therefore, “distinguishable sequence” is interpreted to mean a sequence additional to the sequence of the sample nucleic acid in the sample sequence. This interpretation applies to all following rejections.
Claim Objections
Claims 1 and 9-11 are objected to because of the following informalities:
Claim 1 recites “wherein said sample sequence comprising a distinguishable sequence”. This is grammatically incorrect. “Comprising” should instead read “comprises”.
Claims 9, 10, and 11 recite “an unique”. This is grammatically incorrect. “An unique” should instead read “a unique”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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 1-13 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 recites the limitation "the barcoded polynucleotide" in line 6 of the claim. There is insufficient antecedent basis for this limitation in the claim. There is no earlier introduction of “a barcoded polynucleotide”. Instead, “a plurality of barcoded polynucleotides” is introduced. Claims 2-13 are also rejected here for depending from claim 1 and not further clarifying the insufficient basis.
Claim 10 recites the limitation “wherein at least 80 percent of said sample sequences with the distinguishable sequence comprise an unique sequence different from other sample sequences in said cell”. It is unclear from this recitation what aspects of the sample sequences are different from other sample sequences. One interpretation is that the distinguishable sequence is meant to be the unique sequence different from other sample sequences. For example, the distinguishable sequence is another barcode or a unique molecular identifier that is a sequence additional to the sequence of the sample nucleic acid in the sample sequence, as has been interpreted above. However, as currently written, it appears multiple sample sequences have a single distinguishable sequence. If the distinguishable sequence is meant to be the unique sequence different from other sample sequences, it is unclear how at least 80 percent could be different if there are many sample sequences with the same distinguishable sequence. Another interpretation is that the sample sequence originating from the sample nucleic acids is meant to be the unique sequence different from other sample sequences. For the purpose of compact prosecution, the recitation of “wherein at least 80 percent of said sample sequences with the distinguishable sequence comprise an unique sequence different from other sample sequences in said cell” is interpreted to mean the distinguishable sequence is different for each sample sequence, and at least 80 percent of the distinguishable sequences are unique.
Claim 10 also has insufficient antecedent basis for the limitation “said sample sequences with the distinguishable sequence”. Claim 1, from which claim 10 depends, introduces a “sample sequence”, but not a plurality of sample sequences.
The same clarity and antecedent basis issues noted for claim 10 are also noted for claim 11, substituting at least 90 percent for at least 80 percent. The same interpretation is applied for claim 11 as identified for claim 10, substituting at least 90 percent for at least 80 percent (e.g. “wherein at least 90 percent of said sample sequences with the distinguishable sequence comprise an unique sequence different from other sample sequences in said cell” is interpreted to mean the distinguishable sequence is different for each sample sequence, and at least 90 percent of the distinguishable sequences are unique).
Claim 13 recites the limitation “wherein said cells consist essentially nuclei isolated from the cells”. It is unclear from this recitation how cells can consist essentially nuclei isolated from the cells. A nucleus is an organelle of a cell, while a cell also consists of many organelles in addition to a nucleus, such as mitochondria, ribosomes, endoplasmic reticulum, etc. Given these aspects of a cell, it is clear that a cell consists of more than just a nucleus. For the purpose of compact prosecution, “wherein said cells consist essentially nuclei isolated from the cells” is interpreted to mean wherein the sample comprises a nucleus within a plurality of nuclei isolated from cells.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-13 are rejected under 35 U.S.C. 103 as being unpatentable over Belhocine (US 20180340171 A1; cited on the IDS filed December 26th, 2024).
Regarding instant claim 1, Belhocine teaches a method of analyzing and/or counting nucleic acids from single cells comprising: a. providing a sample comprising a cell within a plurality of cells, wherein the cell comprises a plurality of sample nucleic acids (Pages 8-9, paragraph [0086]); b. generating a plurality of barcoded polynucleotides from the plurality of sample nucleic acids of said cell (Page 36, paragraph [0299]), wherein the barcoded polynucleotide comprises: i. a barcode sequence configured to distinguish said sample nucleic acid from other sample nucleic acids in other cells (Page 14, paragraph [0119]; Page 14, paragraph [0126]; Page 13, paragraph [0187] and [0188]; Page 36, paragraph [0299]); ii. a sample sequence from the sample nucleic acid in the cell (Page 36, paragraphs [0299] and [0300]); c. sequencing said barcoded polynucleotide to determine the sample sequence and the barcode sequence (Page 36, paragraph [0300]).
Belhocine does not directly teach that the sample sequences of the cited barcoded polynucleotides comprise a distinguishable sequence from other sample sequences. As set forth above, “distinguishable sequence” is interpreted to mean a sequence additional to the sequence of the sample nucleic acid in the sample sequence. Given this interpretation, Belhocine teaches that a barcode carrying bead that is co-partitioned and intended to be hybridized with a biological particle of interest (the example used in this instance is mRNA) may include a unique molecular identifying sequence that is different for different mRNA molecules (e.g. distinguishable sequence) (Pages 16-17, paragraph [0142]; Page 17, paragraph [0143]). Therefore, while Belhocine does not explicitly teach all of the elements of the claim in a single embodiment, the addition of a distinguishable sequence to the sample sequences would have been obvious to one of ordinary skill in the art. One of ordinary skill in the art would have been motivated to add a distinguishable sequence to allow quantitation of the number of original biological particles of interest (Pages 16-17, paragraph [0142]). There would be a strong expectation of success as the combination of these methods amounts to applying a known technique to a known method to yield predictable results (See MPEP 2141(III)).
Belhocine also does not directly teach that the cited sequenced barcoded polynucleotides are analyzed and/or counted. However, Belhocine teaches on a computer system that may be used for sequencing analysis (Pages 28-29, paragraph [0232]). Therefore, while Belhocine does not explicitly teach all of the elements of the claim in a single embodiment, the addition of analyzing and/or counting sample nucleic acids in said cell with said barcode sequence and sample sequence information would have been obvious to one of ordinary skill in the art. One of ordinary skill in the art would have been motivated to analyze and/or count sample nucleic acids to determine areas of accessible chromatin (Pages 28-29, paragraph [0232]; Page 30, paragraph [0242]). There would be a strong expectation of success as the combination of these methods amounts to applying a known technique to a known method to yield predictable results (See MPEP 2141(III)).
Regarding instant claim 2, Belhocine teaches the method of claim 1, further comprising generating a plurality of compartments wherein the cells are sequestered individually in the compartments prior to step (b) or in step (b) (Page 36, paragraph [0299]).
Regarding instant claim 3, Belhocine teaches the method of claim 1, further comprising amplifying said barcoded polynucleotide to generate a plurality of amplified barcoded polynucleotides prior to step (c) (Page 36, paragraph [0299] and [0300]).
Regarding instant claim 4, Belhocine teaches the method of claim 2, wherein said compartments comprise a form of droplet (Page 36, paragraph [0299]).
Regarding instant claim 5, Belhocine teaches the method of claim 1, wherein said sample nucleic acids are total DNA in said cell (Pages 8-9, paragraphs [0086]-[0088]).
Regarding instant claim 6, Belhocine teaches the method of claim 1, wherein said plurality of barcoded polynucleotides are generated through amplification (Page 36, paragraph [0300]).
Regarding instant claim 7, Belhocine teaches the method of claim 1, wherein said sample nucleic acids in the cell are pretreated in situ for tagmentation before step (b) (Page 35, paragraph [0290]; Page 36, paragraph [0298]).
Regarding instant claim 8, Belhocine teaches the method of claim 1, wherein said sample sequence with the distinguishable sequence is generated by tagmentation (Page 35, paragraph [0290]; Page 36, paragraph [0298]; see claim 1 for analysis regarding distinguishable sequence).
Regarding instant claim 9, Belhocine teaches the method of claim 1, wherein said sample sequence with the distinguishable sequence is used as an unique molecular identifier for the sample nucleic acid (Pages 16-17, paragraph [0142]; Page 17, paragraph [0143]; see claim 1 for analysis regarding unique molecular identifiers).
Regarding instant claim 10, Belhocine teaches the method of claim 1. Belhocine does not directly teach wherein at least 80 percent of said sample sequences with the distinguishable sequence comprise an unique sequence different from other sample sequences in said cell. However, Belhocine does teach that respective barcodes for individual nucleic acid molecules can comprise both common sequence segments and unique sequence segments between different individual nucleic acid molecules coupled to a barcode carrying bead (Pages 16-17, paragraph [0142]). This bead is co-partitioned with a biological particle of interest, where the coupled nucleic acid molecules are released and allowed to individually hybridize with individual sample nucleic acids (Page 17, paragraph [0143]). The teaching of unique sequence segments between different individual nucleic acid molecules that are each intended to hybridize with a single sample nucleic acid inherently teaches that all of the sample sequences comprise a unique sequence different from other sample sequences, therefore meeting the at least 80 percent threshold as claimed (see 112(b) claim interpretation).
Regarding instant claim 11, Belhocine teaches the method of claim 1. Belhocine does not directly teach wherein at least 90 percent of said sample sequences with the distinguishable sequence comprise an unique sequence different from other sample sequences in said cell. However, Belhocine does teach that respective barcodes for individual nucleic acid molecules can comprise both common sequence segments and unique sequence segments between different individual nucleic acid molecules coupled to a barcode carrying bead (Pages 16-17, paragraph [0142]). This bead is co-partitioned with a biological particle of interest, where the coupled nucleic acid molecules are released and allowed to individually hybridize with individual sample nucleic acids (Page 17, paragraph [0143]). The teaching of unique sequence segments between different individual nucleic acid molecules that are each intended to hybridize with a single sample nucleic acid inherently teaches that all of the sample sequences comprise a unique sequence different from other sample sequences, therefore meeting the at least 90 percent threshold as claimed (see 112(b) claim interpretation).
Regarding instant claim 12, Belhocine teaches The method of claim 1, wherein step (d) further comprises using said barcode sequence to identify a cellular origin of the sample nucleic acid (Page 14, paragraph [0119]; Page 14, paragraph [0126]; Page 13, paragraph [0187] and [0188]; Page 36, paragraph [0299]) and using said sample sequence to determine a uniqueness of the sample nucleic acid from other sample nucleic acids in the cell (Pages 16-17, paragraph [0142]; Page 17, paragraph [0143]; see claim 1 for analysis regarding unique molecular identifiers).
Regarding instant claim 13, Belhocine teaches the method of claim 1, wherein said cells consist essentially nuclei isolated from the cells (Page 36, paragraph [0298]).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-13 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 55-71 and 73-76 of copending Application No. 17596182 (reference application), in view of Belhocine (US 20180340171 A1; cited on the IDS filed December 26th, 2024).
Although the claims at issue are not identical, they are not patentably distinct from each other because both the ‘182 application and the instant application claim methods comprising providing samples that are cells, generating barcoded polynucleotides, sequencing the barcoding polynucleotides, and analyzing the barcoded polynucleotides. The methods also both include sequestering single cells in compartments for specific barcoding, and amplifying barcoded polynucleotides. While the claims of the ‘182 application have more specific detail, what is claimed is reasonably within the scope of the instant claims.
The ‘182 application claims do not require a sample sequence from the sample nucleic acid in the cell, wherein said sample sequence comprising a distinguishable sequence from other sample sequences of other sample nucleic acids in said cell. However, Belhocine teaches the claimed limitation as discussed in the above 103 rejections, obviating this variation to the claims of the ‘182 application. Any additional limitations of the claims of Application No. 17596182 are encompassed by the open claim language “comprising” found in the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-13 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 19058949 in view of in view of Belhocine (US 20180340171 A1; cited on the IDS filed December 26th, 2024).
Although the claims at issue are not identical, they are not patentably distinct from each other because both the ‘949 application and the instant application claim methods comprising providing samples that are cells, generating barcoded polynucleotides, sequencing the barcoding polynucleotides, and analyzing the barcoded polynucleotides. The methods also both include sequestering single cells in compartments for specific barcoding, and amplifying barcoded polynucleotides. While the claims of the ‘949 application have more specific detail, what is claimed is reasonably within the scope of the instant claims.
The ‘949 application claims do not require a sample sequence from the sample nucleic acid in the cell, wherein said sample sequence comprising a distinguishable sequence from other sample sequences of other sample nucleic acids in said cell. However, Belhocine teaches the claimed limitation as discussed in the above 103 rejections, obviating this variation to the claims of the ‘949 application. Any additional limitations of the claims of Application No. 19058949 are encompassed by the open claim language “comprising” found in the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
All claims are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Allison E Schloop whose telephone number is (703)756-4597. The examiner can normally be reached Monday-Friday 8:30-5 ET.
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/ALLISON E SCHLOOP/ Examiner, Art Unit 1683
/ANNE M. GUSSOW/ Supervisory Patent Examiner, Art Unit 1683