Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Status of the Claims
Claims 164, 167-168, 177-182 and 186-189 are pending. Claims 164, 167-168 and 186-189 are the subject of this FINAL Office Action.
Claim 164 requires “the unique identifier sequence is situated between the target specific sequence and the universal PCR primer sequence,” and in the product-by-process step “wherein each of the plurality of first labeled double-stranded DNA molecules is produced by nested PCR using the universal PCR primer sequence and a gene-specific primer.” This encompasses the following minimal structure:
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“Gene-specific primer” encompasses any sequence, whether random or otherwise, that hybridizes to a sequence within a genome. Primer mixtures of random sequences are designed to target genome sequences randomly. For example, a primer mixture of random 10-mers will include primers that are specific to sequences in a genome. Thus, any prior art that teaches random primer sequences meets this “gene-specific primer” limitation in the claimed product.
Furthermore, although one end of the claimed “double-stranded DNA molecules” must contain added oligo-dT, identifier sequence and universal primer sequence, yet the other end can have a similar addition, or none. This is because the claims are open-ended (“wherein each of the plurality of first labeled double-stranded DNA molecules comprises: . . .”). In other words, Applicants’ claims are much broader than their arguments warrant.
Priority
Claims 164 and its dependents receive a priority date of 12/21/2012 because the priority document filed on that date (61/745385) is the first priority document to nested PCR.
Previous Response to Arguments
The priority is maintained because Figure 39 of US provisional application number 61/603,921, which is the only disclosure of nested PCR in the provisional, does not provide any context. As explained in Novozymes A/S v. DuPont Nutrition Biosciences APS, 723 F.3d 1336, 1349 (Fed. Cir. 2013),
For example, in Hyatt v. Dudas, 492 F.3d 1365, 1371, 83 USPQ2d 1373, 1376-1377 (Fed. Cir. 2007), the examiner made a prima facie case by clearly and specifically explaining why applicant’s specification did not support the particular claimed combination of elements, even though applicant’s specification listed each and every element in the claimed combination. The court found the "examiner was explicit that while each element may be individually described in the specification, the deficiency was lack of adequate description of their combination" and, thus, "[t]he burden was then properly shifted to [inventor] to cite to the examiner where adequate written description could be found or to make an amendment to address the deficiency." Id.; see also Stored Value Solutions, Inc. v. Card Activation Techs., 499 Fed.App’x 5, 13-14 (Fed. Cir. 2012) (non-precedential) (Finding inadequate written support for claims drawn to a method of processing debit purchase transactions requiring three separate authorization codes because "the written description [did] not contain a method that include[d] all three codes" and "[e]ach authorization code is an important claim limitation, and the presence of multiple authorization codes in [the claim] was essential".)
Thus, Appellant has not demonstrated sufficiently how the Specification supports the particular combination of limitations identified by the Examiner recited in the selected claims. See Novozymes A/S v. DuPont Nutrition Biosciences APS, 723 F.3d 1336, 1349 (Fed. Cir. 2013) (explaining that each claim must be taken “as an integrated whole rather than as a collection of independent limitations”); see also Hyatt v. Dudas, 492 F.3d at 1371 (upholding examiner's rejection when the examiner stated that “while each element may be individually described in the specification, the deficiency was the lack of adequate description of their combination”); see also Flash-Control, LLC v. Intel Corp., -- Fed. Appx. --, 2021 WL 2944592, *4 (Fed. Cir. July 14, 2021) (“A patent owner cannot show written description support by picking and choosing claim elements from different embodiments that are never linked together in the specification.”).
Taking each claim—as we must—as an integrated whole rather than as a collection of independent limitations, one searches the 2000 application in vain for the disclosure of even a single species that falls within the claims or for any “blaze marks” that would lead an ordinarily skilled investigator toward such a species among a slew of competing possibilities. “Working backward from a knowledge of [the claims], that is by hindsight,” Novozymes seeks to derive written description support from an amalgam of disclosures plucked selectively from the 2000 application. Ruschig, 379 F.2d at 995. Indeed, Novozymes' expert, Dr. Arnold, in effect admitted that her testimony suffered from this flaw when she “point[ed] to [a] part of the claim” and told the judge she was “going back and finding if there's a written description for that” in the specification. With such an approach “it is all very clear what route one would travel through the forest of the specification to arrive at [the claimed invention].” Ruschig, 379 F.2d at 995. However, viewing the matter from the proper vantage point “of one with no foreknowledge of the specific compound,” we agree with the district court that the particular variants claimed in the ′23 patent lack meaningful support in the written description of the 2000 application. Id.
Specifically, the specification of 61/603,921 is completely silent as to Figure 39 or nested PCR, or yielding the following claimed characteristics: “wherein the unique identifier sequence uniquely identifies occurrences of the first mRNA target molecule, and wherein the number of different unique identifier sequences of the plurality of first labeled double-stranded DNA molecules indicates the number of occurrences of the first mRNA target”; much less in the context of single cells (claims 188-189); or Trachipleistophora anthropophthera (claim 190). At best, Figure 39 states “A collection of predetermined or random sequence label tags (depicted in green).” However, “unique identifier sequences” is never used, much less described. It is unclear if the “predetermined or random sequence label tags” of Figure 39 are the same as the claimed “unique identifier sequences.” Furthermore, at best, Figure 39 states “Step 3. Detection of the amplified labeled cDNA molecules[.] Absolute quantitation of mRNA molecules occurs by the detection and counting of different labels.” However, it is not clear that “[a]bsolute quantitation of mRNA molecules . . . by the detection and counting [] different labels” in Figure 39 is the same as “number of different unique identifier sequences of the plurality of first labeled double-stranded DNA molecules indicates the number of occurrences of the first mRNA target.” “Absolute quantitation” by “counting [] different labels” is not necessarily the same as “indicates the number of occurrences” by “number of different unique identifier sequences.”
The priority is maintained until Applicants can prove that Figure 39 in fact discloses the “particular combination” of claimed subject matter.
Claim Rejection - 35 USC § 103 - Maintained
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 may not be obtained though the invention is not identically disclosed or described as set forth in section 102 , if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
Claims 164, 167-168 and 186-189 are rejected under 35 U.S.C. § 103(a) as being unpatentable over SAMUELS (US 2012/0220494), in view of PROCKOP (US 6265157) as evidenced by Scotto-Lavino et al, 3′ End cDNA amplification using classic RACE, Nature Protocols volume 1, pages2742–2745 (2006).
SAMUELS teaches single-cell transcriptomics of thousands of molecularly-barcoded mRNA by sequencing which includes a composition of cDNA generated with RT primers that have 5’-universal primer-random barcodes/molecular barcodes-poly dT-3’ (Figs. 23-25).
Although SAMUELS does not specify a 3’-end mRNA technique using primer hybridized to RT primer universal primer sequence and mRNA-specific primer, yet this is familiar in the art to allow characterization of 3’-end information. For example, PROCKOP teaches a 3’-RACE technique that uses primer hybridized to RT primer universal primer sequence and mRNA-specific primer (“3′-RACE analyses”). As evidenced by Scotto-Lavino, a skilled artisan would have been motivated to sequence the 3’-end “because the non-coding terminal region can contain signals that regulate the stability or subcellular localization of the mRNA” and “some messages use alternative genomic sites for cleavage and polyadenylation that can alter the above properties, or change the encoded protein” (Abstract). Furthermore, it is well-known in sequencing art that sequence reads are generally short (e.g. 100-200 bases; see e.g. SAMUELS). In other words, a skilled artisan desiring 3’ mRNA information would have been motivated to apply familiar methods compatible with short-read sequencing to glean information about the 3’ ends of mRNA. One well-known method was 3’-RACE.
Previous Response to Arguments
The rejection is maintained because SAMUELS in facts contemplates barcodes equivalent to the “unique molecular identifier,” which can be 100 or more different barcodes. For example, paragraph 0302 describes “Sequencing reveals the type and number of each barcode present” and “The type and number of each barcode corresponds to the type and number of biomarkers present on each individual cell.” Paragraphs 0321-25 describe “binder barcodes” in addition to sample barcodes. These “binder barcodes” allow determination of type and number of biomarkers. Paragraphs 0233-34 describe Figure 7 (of which Figures 23-25 are iterations), and include a description of “multiple molecules co-localized in a single droplet, a digitally readable oligonucleotide barcode is attached to the target molecule's sequence” to allow one to “determine the sequence and count the number of templates traceable to each original droplet.” This is further described as “molecular barcoding in droplets, providing a large excess of unique identifying barcodes . . . compared to the number of sample objects or molecules contained in the droplets, thus allowing digital quantification of many targets of interest.” From a holistic reading of SAMUELS, it is clear that this reference contemplates barcodes equivalent to the “unique molecular identifier,” which can be 100 or more different barcodes.
Response to Arguments
The rejection is maintained because SAMUELS teaches that barcodes can be 2-25 nucleotides, or about 5 to about 10 nucleotides (para. 0211; see also para. 0217 (discussing altering barcode length depending on the application)).
Applicants also argue that SAMUELS fails to teach a single barcode that acts as a unique identifier sequence. First, the Examiner points out that nothing in the claims requires any particular sequence of the “unique identifier sequence.” Furthermore, this sequence need only be anywhere between the oligo-dT sequence and the universal primer sequence. To this end, SAMUELS, in the portions cited above in the previous reply, clearly discloses that barcode regions can be used to identify a molecule such as a single mRNA. For example, in Figures 7, 9 and 31, barcode region 1a/2a identifies a cell, while barcode regions 1, 2, n identify a molecule such as mRNA.
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Again, Applicants claim a composition with 100 or more dsDNA each comprising “unique molecular identifier” between oligo-dT and universal primer sequence, each “unique molecular identifier” different from every other. SAMUELS, in view of the cited prior art teaching oligo-dT to amplify/extend mRNA suggested in SAMUELS meet this broad claim.
Double Patenting- Obvious Type - Maintained
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 obviousness-type 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); and 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 a nonstatutory double patenting ground provided the conflicting application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement.
Effective January 1, 1994, a registered attorney or agent of record may sign a terminal disclaimer. A terminal disclaimer signed by the assignee must fully comply with 37 CFR 3.73(b).
Instant claims 164-168 and 186-189 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over conflicting claims 1-10 of U.S. 10,941,396.
The instant claims are obvious over the conflicting claims because the conflicting claims anticipate the instant claims. The conflicting claims teach a method of making the claimed labelled dsDNA (emphasis added):
1. A method for the absolute quantification of copies of mRNA molecules in a sample, comprising:
(a) stochastically labeling mRNA copies of each of two or more genes of interest in a sample with a plurality of oligonucleotide tags to produce a plurality of labelled-mRNA copies, wherein:
(i) the number of mRNA copies of each of the two or more genes of interest is at least one;
(ii) the plurality of oligonucleotide tags each comprises an oligodT sequence, a universal primer binding site, and an identifier region;
(iii) the plurality of oligonucleotide tags comprises at least 1000 oligonucleotide tags having identifier regions of different sequences for determining the number of mRNA copies of each of the two or more genes of interest;
(iv) a number of oligonucleotide tags having identifier regions of different sequences in the plurality of oligonucleotide tags is at least 5 times greater than the number of mRNA copies of any of the two or more genes of interest; and
(v) wherein stochastically labeling mRNA copies comprises attaching the oligonucleotide tags to the mRNA copies by hybridization;
(b) conducting a first strand synthesis reaction by contacting the plurality of labelled-mRNA copies with a reverse transcriptase enzyme to produce a plurality of single-stranded labelled-cDNA molecules, wherein the first strand synthesis reaction is not performed on a solid surface;
(c) amplifying the plurality of single-stranded labelled-cDNA molecules to produce a plurality of double-stranded labelled-cDNA molecules, wherein the amplifying comprises annealing a first universal primer to the universal primer binding site of the single-stranded labelled-cDNA molecules and annealing a first target-specific primer to the single-stranded labelled-cDNA molecules;
(d) conducting a nested PCR reaction on the plurality of double-stranded labelled-cDNA molecules to produce a plurality of nested PCR labelled-amplicons, wherein conducting the nested PCR reaction comprises annealing a second universal primer to the universal primer binding site of the double-stranded labelled-cDNA molecules and annealing a second target-specific primer to the double-stranded labelled-cDNA molecules, wherein the second target-specific primer anneals downstream of the first target-specific primer; and
(e) detecting at least a portion of amplicons of the nested PCR labelled-amplicons to count the number of different identifier regions associated with each of the labeled mRNA copies, thereby counting the absolute number of mRNA copies of each of the two or more genes of interest in the sample.
Thus, the conflicting claims anticipate the instant claims.
Response to Arguments
The Office is not persuaded of error by Applicants’ arguments because only “objections or requirements as to form not necessary to further consideration of the claims” may be held in abeyance. MPEP § 714.02.
Prior Art and Other Pertinent Documents
The following prior art is also pertinent to the claimed “labeled double-stranded DNA molecules”: US 20190185936 (and related Natera applications and patents); US 20050170373; US 20090163366; US 20110257031; WO 2011142836; US 20150087535; US 20130303461; US8691509; US 20180216163; US 20140256568.
The following IPRs are also relevant: IPR2023-00958; IPR2023-00876; IPR2023-00955.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Aaron Priest whose telephone number is (571)270-1095. The examiner can normally be reached 8am-6pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Gary Benzion can be reached at (571) 272-0782. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/AARON A PRIEST/Primary Examiner, Art Unit 1681
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