DETAILED ACTION
The present Office Action is responsive to the Amendment received on March 3, 2026.
Priority
The effective filing date (herein, “EFD”) of the instant application has been determined to be based on the PCT application, PCT/US/12/30039, filed March 22, 2012. The provisional applications, 61/583,787 and 61/467,037 do not provide any support for tagging of cDNA molecules having a sample-specific tag (i.e., sample barcode). Rather, these applications only provide molecule counter tags (i.e., copy number tags) which are physically and functionally different.
The EFD, therefore has been established as March 22, 2012.
Claim Interpretation
The term, “barcode distance” is discussed on pages 9-10 of the instant specification:
“barcodes are designed or selected such that they are not within a certain distance and are sufficient to maintain uniqueness should a barcode sequence be altered during the amplification and sequencing methods or other enzymatic reactions … For a given barcode length and number of barcodes in a set, the ‘distance’ refers to the number of times a barcode can change a nucleotide before becoming identical to another barcode in the set. For example, for a two member barcode set of AAA and AAT, the distance would be 1 because AAT need change only 1 nucleotide, i.e., the T to an A, to become identical with AAA … if the selected distance were 9, then the members of the optimized set would have a distance greater than 9, as a barcode with a distance of 9, if 9 nucleic acids were changed, would result in creation of a barcode identical to another member of the set” (pages 9 to 10)
Claim Rejections - 35 USC § 112
The rejection of claims 1-20 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particularly point out and distinctly claim the subject matter, made in the Office Action mailed on December 3, 2025 is withdrawn in view of the Amendment received on March 3, 2026.
Rejection – New Grounds, Necessitated by Amendment
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 13 and 14 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 13 and 14 depend from claim 1 and 11, respectively.
Claims 1 and 11 have been amended to actively require a sequencing step that utilizes a plurality of tagged cDNA molecules are sequenced.
Claims 13 and 14 recite the step of preparing a sequencing library configured for a massively parallel DNA sequencing. This is confusing because it is unclear whether the preparation of the sequencing library is utilized in the sequencing step of parent claims 1 and 11 as the sequencing step of the parent claims do not recite that massively parallel DNA sequencing is being performed.
For the purpose of prosecution, the library preparation step of claims 13 and 14 are the steps of claims 1 and 11 (respectively) with the added requirement of “pooling”, and that the sequencing step (of claims 1 and 11) are further limited as being massively parallel.
Double Patenting – Statutory Double Patenting Rejection
The statutory double-patenting rejection of claims 1-20 under 35 U.S.C. 101 as claiming the same invention as that of claims 1-20 of prior U.S. Patent No. 11,834,712 (herein, “the ‘712 patent”), made in the Office Action mailed on December 3, 2025 is withdrawn in view of the Amendment received on March 3, 2026.
Non-statutory Obviousness-type Double Patenting Rejection
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.
The rejection of claims 1-20 on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of U.S. Patent No. 11,608,527 (here, “the ‘527 patent”), made in the Office Action mailed on December 3, 2025 is maintained for the reasons of record.
Applicants’ Amendment received on March 3, 2026 does not contain a Terminal Disclaimer or any arguments directed to the rejection.
Therefore, the rejection is maintained for the reasons already of record.
The Rejection:
Although the claims at issue are not identical, they are not patentably distinct from each other for the following reasons.
With regard to instant independent claim 1, claims of the ‘527 patent also claims a method of quantitatively measuring a plurality of different RNA species in a cell (see claim 1, preamble), comprising:
isolating a plurality of single cells, each cell being isolated in a separate reaction vessel (see claim 1, 1st step);
releasing RNA from the isolated single cells while the cells are in the separate reaction vessels, the RNA comprising a plurality of distinct RNA species (see claim 1, 2nd step);
generating tagged cDNA from the released RNA, wherein the tagged cDNA comprises
a sample barcode sequence corresponding to the single cell and
a copy number barcode sequence; and
pooling the target cDNA from the separate reaction vessels (see claim 1, 3rd step and sub-steps (i) and (ii)), and step afterwards).
With regard to instant independent claim 15, claims of the ‘527 patent also claims a method of quantitatively measuring a plurality of different RNA species in a plurality of isolated single cells (see claim 12, preamble), comprising:
physically isolating a plurality of single cells to produce isolated single cells (see claim 12, 1st step);
releasing RNA from the isolated single cells, wherein the released RNA is physically separated from RNA released from other single cells, the RNA comprising a plurality of distinct RNA species (see claim 12, 2nd step);
forming tagged cDNA from the released RNA, wherein the tagged cDNA comprises
a sample barcode sequence corresponding to the single cell and
a copy number barcode sequence, and
pooling the tagged cDNA derived from the different isolated single cells (see 3rd step, sub-steps (i), and (ii), and the immediately following step).
With regard to instant claims 2 and 16, claims 3 and 14 of the ‘527 patent are verbatim.
With regard to instant claims 3-9 and claims 17-20, claims 4-10 claims 15-20 are verbatim.
With regard to instant claim 11-14, the latter steps of independent claims 1 and 12 and claims 11 and 22-24 of the ‘527 patent render obvious for the following reasons.
The claims of the ‘527 patent, like the instant claims, claims a method which tags a plurality of distinct RNA molecules form a plurality of single cells, wherein the tagging each RNA within the same cell with the same sample tag, and unique counter tag, allows pooling of the tagged cDNAs during sequencing. Because all of the RNA molecules derived from the same sample comprises the same sample tag, these RNA molecules can be “back tracked” to from which sample the RNA molecules came from, while the unique counter tags allow the “counting”, thus quantitating the number of these RNA molecules which were originally present in each of the sample.
Therefore, placing such tags during the cDNA synthesis via a primer would have been obvious to one of ordinary skill in the art, as well as using them as a sequence library which is clearly recited in the latter portion of claims 1 and 12 of the ‘527 patent.
Therefore, the invention as claimed is deemed prima facie obvious over the cited references.
The rejection of claims 1-20 on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No. 12,448,649 (here, “the ‘649 patent”), made in the Office Action mailed on December 3, 2025 is maintained for the reasons of record.
Applicants’ Amendment received on March 3, 2026 does not contain a Terminal Disclaimer or any arguments directed to the rejection.
Therefore, the rejection is maintained for the reasons already of record.
The Rejection:
With regard to instant claim 1, claims of the ‘649 patent also claims a method of quantitatively measuring a plurality of different RNA species in a cell (see claim 1 preamble), comprising the steps of:
isolating a plurality of single cells, each cell being isolated in a separate reaction vessel (see claim 1, “physically isolating a plurality of single cells to produce isolated single cells”, also claim 12, “isolating a plurality of single cells, each cell being isolated in a separate reaction vessel”),
releasing RNA from the isolated single cells while the cells are in the separate reaction vessels, the RNA comprising a plurality of distinct RNA species (see claim 12, “releasing RNA from the isolated single cells, the RNA comprising a plurality of distinct RNA species”);
generating tagged cDNA from the released RNA, wherein the tagged cDNA comprises (i) a sample barcode sequence corresponding to the single cell and (ii) a copy number barcode sequence (see claim 12, “generating tagged cDNA molecules from the released RNA, wherein the cDNA molecules comprise: (i) a sample barcode sequence corresponding to the isolated single cells … (ii) a copy number barcode sequence”, also claim 1 latter steps); and
pooling the tagged cDNA from the separate reaction vessels (see claim 1, “pooling the tagged cDNA derived from the isolated single cells”).
With regard to instant claim 15, claims of the ‘649 patent also claims a method of quantitatively measuring a plurality of different RNA species in a plurality of isolated single cells (see claim 1), comprising:
physically isolating a plurality of single cells to produce isolated single cells (see claim 1, “physically isolating a plurality of single cells to produce isolated single cells”);
releasing RNA from the isolated single cells, wherein the released RNA is physically separated from RNA released from other single cells, the RNA comprising a plurality of distinct RNA species (see claim 1, “releasing RNA from the isolated single cells, the RNA comprising a plurality of distinct RNA species”, also “isolating a plurality of single cells, each cell being isolated in a separate reaction vessel … releasing RNA from the isolated single cells” see claim 12);
forming tagged cDNA from the released RNA, wherein the tagged cDNA comprises (i) a sample barcode sequence; and (ii) a copy number barcode sequence (see claim 1, “forming tagged cDNA from the released RNA, wherein the tagged cDNA comprises: (i) a sample barcode sequence corresponding to the isolated single cells … a copy number barcode sequence”); and
pooling the tagged cDNA derived from the different isolated single cells (see claim 1, “pooling the tagged cDNA derived from the isolated single cells”).
With regard to instant claims 2 and 16, claims 3, 14, and 20 are verbatim).
With regard to instant claims 3-4 and 17-18, the ‘649 patent’s claims 4-5 are verbatim, and claims 15 and 21 also claims the same length range of the copy number barcode.
With regard to instant claims 7-8, claims 6-7, 16-17, and 22-23 of the ‘649 patent are verbatim.
With regard to instant claims 6 and 20, claim 10 of the ‘649 patent recites that the copy number barcode is random.
With regard to instant claims 9-10, claim 8 of the ‘649 patent recites that the primers can hybridize to a polyA tail of an mRNA molecule. While the claim does not explicitly recite that the primers comprise a polyT sequence for this, one of ordinary skill in the art would have known the conventional practice of using primers comprising polyT sequence in initiating a reverse transcription reaction of mRNA molecules, wherein the polyT sequence of the primers anneal to the polyA tail of the mRNA molecules.
With regard to instant claim 11, claim 9 of the ‘649 patent is verbatim.
With regard to instant claim 12, the sample barcodes from the same cell are identical to each other (see claim 13, “cDNA molecules derived from the same RNA species and having the same sample barcode sequence”).
Claims of the ‘649 patent do not explicitly claim that the copy number barcode are of identical length (claims 5 and 19), or that a sequence library is prepared for massively parallel DNA sequencer (claims 13 and 14).
However, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to combine the claims of the ‘649 patent with the conventional knowledge in the art, thereby arriving at the invention as claimed for the following reasons.
While claims of the ‘649 patent do not explicitly teach that a sequencing “library” is created, the method as claimed in the ‘649 patent is intended for sequencing RNA molecules from single cells, wherein the counting tags allow for the RNA molecules to be quantified and the sample tags allow for pooling of RNA molecules of different samples to be pooled and analyzed in massively parallel sequencing reactions. Therefore, one of ordinary skill in the art at the time the invention was made would have been motivated to take the method of the ‘649 patent and prepare a sequencing library and analyze them on any of well-known and commercially available next-generation sequencing platforms such as Illumina®.
As to the length of the copy number barcodes (or counting tags) having the same length sequence, doing so would have involved an obvious consideration so long as the sequence of the copy number barcodes were unique and different from one another, allowing for the quantitation of the mRNA molecules preset in the single cells.
For these reasons, the invention as claimed is deemed prima facie obvious over claims of the ‘649 patent.
The following obviousness-type double patenting rejections are also made based on the rationale provided above, but have not been reiterated herein for the sake of reducing redundant rejections.
The rejections are as follows:
The rejection of claims 1-20 on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 11,352,669, made in the Office Action mailed on December 3, 2025 is maintained for the reasons of record.
Applicants’ Amendment received on March 3, 2026 does not contain a Terminal Disclaimer or any arguments directed to the rejection.
Therefore, the rejection is maintained for the reasons already of record.
Rejection – New Grounds, Necessitated by Amendment
Claims 1-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. U.S. Patent No. 11,834,712 (herein, “the ‘712 patent”)
Although the claims at issue are not identical, they are not patentably distinct from each other for the same reasons discussed above. While the claims of the ‘712 patent do not explicitly recite that a sequencing reaction is performed, the method is directed to a method of producing a sequencing library produced from a plurality of RNA species, wherein each of the RNA species are produced in an isolated reaction vessel. Because it is conventional and customary to perform a sequencing reaction from a sequence library for identifying the sequences, one of ordinary skill in the art would have been motivated to take the claims of the ‘712 patent and perform a sequencing reaction, utilizing the copy tag and sample tag, so as to sequence the RNA sequences from the library as well as quantifying (via copy number barcode) and identifying the source (via sample barcode) from which the RNA sequence was produced.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Inquiries
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to Young J. Kim whose telephone number is (571) 272-0785. The Examiner can best be reached from 7:30 a.m. to 4:00 p.m (M-F). The Examiner can also be reached via e-mail to Young.Kim@uspto.gov. However, the office cannot guarantee security through the e-mail system nor should official papers be transmitted through this route.
If attempts to reach the Examiner by telephone are unsuccessful, the Examiner's supervisor, Gary Benzion, can be reached at (571) 272-0782.
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/YOUNG J KIM/Primary Examiner
Art Unit 1637 February 2, 2018
/YJK/