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 (IDS) submitted on 3/30/2024 and 10/21/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner, except where noted.
The information disclosure statement filed 3/30/2024 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. Specifically, no copy of foreign patent document no. 720 has been provided, and so this reference has not been considered.
Drawings
The drawings are objected to as failing to comply with 37 CFR 1.84(p)(5) because they include the following reference character(s) not mentioned in the description: reference character 108 in Figure 1. This element refers to a barcoded bead that appears to be referred to as reference character 105 in para. 70 of the instant specification. Corrected drawing sheets in compliance with 37 CFR 1.121(d), or amendment to the specification to add the reference character(s) in the description in compliance with 37 CFR 1.121(b) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claim 21 is objected to because of the following informalities: in the description of the oligonucleotide barcodes in lines 3-4 of the contacting step, it is recommended to amend “a target-binding region capable of hybridizing to the copies of the nucleic acid targets,” to read “a target-binding region capable of hybridizing to a nucleic acid target of the plurality of nucleic acid targets,” if it is Applicant’s intention that each oligonucleotide barcode be capable of hybridizing to all of the copies of a single nucleic acid target within the plurality of targets. Additionally, in the extending step, lines 1-2 read “hybridized to copies of a plurality of” but should read “hybridized to copies of the plurality of.” Finally, in the amplifying step, line 3 reads “of hybridizing the second universal sequence,” but should read “of hybridizing to the second universal sequence.” Appropriate correction is required.
Claim 22 is objected to because of the following informality: in line 3, “primers capable of hybridizing the second universal sequence,” should read “primers capable of hybridizing to the second universal sequence.” Appropriate correction is required.
Claim 23 is objected to because of the following informality: in line 2, “plurality of target nucleic acid species in the sample” should be amended to read “plurality of nucleic acid targets in the sample,” as this better aligns with the language used in claim 21, from which this claim depends, to describe the nucleic acids directly associated with the sample. The “target nucleic acid species” language is not used until the amplification step of claim 21. Appropriate correction is required.
Claim 27 is objected to because of the following informalities: in line 2, “species comprise” should read “species comprises.” Additionally, in the final line, the comma after “about 1000” should be removed. Appropriate correction is required.
Claim 28 is objected to because of the following informality: in line 2, “species comprise” should read “species comprises.” Appropriate correction is required.
Claim 29 is objected to because of the following informality: in the penultimate line, the comma after “about 1000” should be removed. Appropriate correction is required.
Claim 33 is objected to because of the following informalities: in the description of the oligonucleotide barcodes in lines 3-4 of the contacting step, it is recommended to amend “a target-binding region capable of hybridizing to the copies of the nucleic acid targets,” to read “a target-binding region capable of hybridizing to a nucleic acid target of the plurality of nucleic acid targets,” if it is Applicant’s intention that each oligonucleotide barcode be capable of hybridizing to all of the copies of a single nucleic acid target within the plurality of targets. Additionally, in the extending step, lines 1-2 read “hybridized to copies of a plurality of” but should read “hybridized to copies of the plurality of.” Finally, in each of the amplifying steps, line 3 reads “of hybridizing the second universal sequence,” but should read “of hybridizing to the second universal sequence.” Appropriate correction is required.
Claim 35 is objected to because of the following informality: in line 2, “plurality of target nucleic acid species in the sample” should be amended to read “plurality of nucleic acid targets in the sample,” as this better aligns with the language used in claim 33, from which this claim depends, to describe the nucleic acids directly associated with the sample. The “target nucleic acid species” language is not used until the second amplification step of claim 33. Appropriate correction is required.
Claim 38 is objected to because of the following informality: in the final line, the comma after “about 1000” should be removed. Appropriate correction is required.
Claim 39 is objected to because of the following informality: in line 2, “species comprise” should read “species comprises.” 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 27-28, 30, and 38-39 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 27 recites the limitation "the different gene targets" in line 2. There is insufficient antecedent basis for this limitation in the claim, as gene targets of any kind are not described earlier in the claim, nor in claim 21, from which this claim depends.
Claims 28 and 30 both recite the limitation "the same gene target" in line 2. There is insufficient antecedent basis for this limitation in the claims, as gene targets of any kind are not described earlier in the claims, nor in claim 21, from which these claims depend.
In claim 30 in particular, the gene target is not even clearly linked to the plurality of target nucleic acid species. However, it will be interpreted as though said plurality of target nucleic acid species includes the described gene targets.
Claim 38 recites the limitation "the different gene targets" in line 2. There is insufficient antecedent basis for this limitation in the claim, as gene targets of any kind are not described earlier in the claim, nor in claim 33, from which this claim depends.
Claim 39 recites the limitation "the same gene target" in line 2. There is insufficient antecedent basis for this limitation in the claim, as gene targets of any kind are not described earlier in the claim, nor in claim 33, from which this claim depends.
Claim Rejections - 35 USC § 103
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 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 21, 24-33, and 36-40 are rejected under 35 U.S.C. 103 as being unpatentable over Love et al. (US 2019/0218607 A1) in view of Wimberger et al. (US 2014/0087955 A1).
Love teaches methods for single cell analyses (Abstract). Para. 5 describes one such method for analysis, involving contacting nucleic acids with capture oligonucleotides, where each capture oligonucleotide has a 5’ universal primer site, a barcode, and a 3’ target binding site that is complementary to a specific nucleic acid. This capture oligonucleotide is thus analogous to the claimed oligonucleotide barcodes. The capture oligonucleotides are then extended with the target nucleic acids as a template. The products are then contacted with second strand priming oligonucleotides, where these second strands comprise a 5’ universal primer site and a 3’ target binding sequence. The target binding sequences can include both random sequences and sequences complementary to specific sequences in the first strand nucleic acids (para. 9). Thus, these second strand priming oligonucleotides are analogous to the claimed random primers. These second strand priming oligonucleotides are then extended, using the first extension product as a template.
Para. 8 notes that the input nucleic acids can be derived from multiple (2-1,000) cells, and therefore said input would contain nucleic acids that are copies of one another. These copies would then go through the method described by Love above.
In paras. 130-131, Love discusses amplification of nucleic acids, and notes that labeling nucleic acids with universal primers allows them to be amplified and sequenced with relatively similar efficiency, because the primers can hybridize to the universal sequences. Paras. 133-135 then describe a method that is the same as that described above in para. 5 of Love using mRNA and the creation of second strand cDNA specifically (which would be equivalent to the claimed plurality of extension products and the extended second strand priming oligonucleotides of Love described above). Para. 137 states that these products (which are still from a plurality of cells), which would have universal sequences on their 5’ and 3’ ends, may be amplified via these universal labels using universal primers. Because the unput nucleic acids are from a variety of cells, the resulting amplification products would contain multiple target nucleic acid species, thus meeting the amplification limitation of instant claim 1.
Para. 142 of Love states that second strands of cDNA may be separated from the first strands “prior to subsequent manipulations,” and notes that this can be accomplished “by any means,” but does not provide examples that involve the use of capture oligonucleotides. It is noted that if the second strands of cDNA are separated from the first, Love suggests keeping the first strands for sample banking (para. 142).
Wimberger teaches a device and methods for binding nucleic acids to an array, specifically for selecting target molecules (Abstract). The device of Wimberger has multiple zones that allow for the separation of sense and antisense strands, particularly through them being placed into different zones of the device, where either the sense or antisense strand may be placed in the capture zone (paras. 10-12). Para. 68 notes that the different zones of the device are specifically separable or removable, further separating the sense and antisense strands. The capture zone of the device is where capture molecules are immobilized, though capture molecules can also be present in reaction zones (paras. 10-12). The capture molecules can be nucleic acid sequences and are designed to capture specific sequences (paras. 18, 55, 69 ). The capture molecules may be specifically fixed on a substrate (paras. 58-59). Para. 85 of the reference notes that any suitable molecule can be a target for capture, particularly cDNA or mRNA, or amplified DNA/RNA products. Wimberger also teaches that their methods may be used on samples derived from cells (paras. 86 and 88). Para. 85 teaches that targets may have common sequences. The reference notes that the strand separation and capture of their invention drastically enhances capture efficiency (para. 11), and generally decreases required hybridization time between targets and capture molecules (para. 130).
Prior to the effective filing date of the claimed invention, it would have been prima facie obvious for one of ordinary skill in the art to combine the teachings of Love and Wimberger to arrive at the methods of instant claims 21 and 24-25, and specifically, to use the teachings of Wimberger as a separation method for the second strand cDNA of Love. By using the device of Wimberger, this would separate the second strand cDNA from the first strand cDNA via capture with the capture molecules, which would free them for potential downstream application, while still maintaining the first strand cDNA in a separate zone of the device that can be completely removed from the capture zone. This would ensure that sample banking, as suggested by Love, can still occur. As Wimberger suggests that their methods are particularly advantageous for efficient and quick capture, the ordinary artisan would be motivated to use the device suggested by the reference, particularly in view of the fact that the separation methods suggested by Love are not particularly limited. MPEP 2143 I (A) states, “The rationale to support a conclusion that the claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art.” Neither the second strand cDNA synthesis and amplification, nor the device of Wimberger, would be altered by this combination, and as described above, their combination would result in predictable separation of the first and second cDNA strands described by Love. Additionally, it is noted that none of the methods described by Love or Wimberger require the elements prohibited by instant claim 24.
Thus, claims 21 and 24-25 are prima facie obvious over Love in view of Wimberger.
Regarding claim 26, Wimberger teaches that the capture molecules can be immobilized to the support via a chemical immobilization (para. 80). This can involve the addition of functional groups, or the chemical modification of the existing capture molecule to include such groups. Such a functional group is specifically noted to be an amine group, where the substrate can comprise a molecule capable of binding to this amine group. As the substrate and capture molecules of Wimberger are used in Love in view of Wimberger described above, it would be prima facie obvious to attach the capture molecules to the substrate in Love in view of Wimberger via the methodology described by Wimberger.
Thus, claim 26 is prima facie obvious over Love in view of Wimberger.
Regarding claim 27, the methods described above in the rejection of claim 21 concern the use of multiple cells. Para. 157 of Love also states that, “Nucleic acid sources are sources comprising nucleic acids of interest. These include cells, viruses, nuclei, exosomes, bodily fluids and precipitates thereof, and the like. Virtually any source of nucleic acid may be used in the methods provided herein.” Para. 4 of Love states that transcriptional profiles and gene expression levels for cells can be analyzed with their methods. Para. 98 explains Figure 2C, which shows the number of unique transcripts and genes acquired from different cell types analyzed via second strand cDNA tagging. Para. 141 notes that the number of transcripts shown in this figure is represented by the rUMI axis. Up to 8,000 genes were examined. Figure 9B-C also shows transcripts and genes that were examined per cell (see para. 105), where over 3,000 genes per cell and nearly 16,000 transcripts per cell were examined for live cells. Thus, the samples of Love comprise the samples of instant claim 27. It would be prima facie obvious to use the specific samples described by Love, which have been shown to be successfully manipulated and analyzed by the method of Love, in the method of Love in view of Wimberger described above.
Thus, claim 27 is prima facie obvious over Love in view of Wimberger.
Regarding claim 28, Love teaches that the cDNA generated from their methods may be from mRNA (paras. 3, 121, 134, and 136), and thus contains exon material. Para. 129 of the reference discusses increasing transcript yield from groups of cells, and para. 137 discusses analyzing transcripts from different cells . As noted in Figure 9B-C, the number of transcripts detected can exceed the number of genes detected per cell, and thus multiple transcripts would exist for the same gene. Thus, different transcript variants exist per gene. Love also states that analyzing transcriptomes is a goal of their invention, particularly in the context of gene expression (para. 4). In Wimberger, coverage over 1x for specific sequences can be captured by using multiple of the same capture molecule to target a particular sequence (para. 55). Similarly, the capture molecule may be slightly varied to capture different versions of the same sequence (para. 55). Wimberger also teaches that multiple species of capture molecule can be used (paras. 8-9, 58, 61, and 75-76). The one or more species can have different nucleic acid sequences (para. 83), and the one or more species of capture molecules can be placed in different capture zones, which may also comprise capture molecules with different nucleic acids (paras. 76 and 83).
Prior to the effective filing date of the claimed invention, it would have been prima facie obvious for one of ordinary skill in the art to use the capture molecules of Love in view of Wimberger to capture the entirety of the transcriptome of the multiple cell samples used in Love in view of Wimberger, as that is a focus of the invention of Love, and Wimberger can be used with cell samples (paras. 86 and 88). The ordinary artisan would also recognize that gene expression data for multiple cells could provide valuable information about particular mutations of interest that can indicate a particular disease or condition. As Wimberger teaches that the same gene can be covered multiple times (and also teaches that mRNA/cDNA from multiple cells can be analyzed, paras. 85-86), and that capture molecules can include slight variations for a particular sequence, as well as particular species and zones for targeting different sequences, the capture molecules of Wimberger would be capable of capturing exon variants with a reasonable expectation of success. Para. 71 of Wimberger also teaches that target nucleic acids can specifically be those for which a derived transcript is known, adding to this expectation.
Thus, claim 28 is prima facie obvious over Love in view of Wimberger.
Regarding claim 29, Wimberger teaches that multiple species of capture molecule can be used (paras. 8-9, 58, 61, and 75-76). The one or more species can have different nucleic acid sequences (para. 83), and the one or more species of capture molecules can be placed in different capture zones, which may also comprise capture molecules with different nucleic acids (paras. 76 and 83). Para. 66 notes that 10 or more capture zones may be used. Thus, even if only a single species of capture molecule is used in each capture zone, at least 10 different nucleic acids can be captured with the array of Wimberger. In Love in view of Wimberger, as the substrate and capture molecules of Wimberger are used, at least 10 different target nucleic acid species produced by the method of Love could thus be captured, with the potential for more to be captured, depending on how many species are in each capture zone and how many specific capture zones are used. Because the substrate and capture molecules of Wimberger are used in the method of Love in view of Wimberger, it would be prima facie obvious to use the specific capture molecule/zone layout taught by Wimberger in the method of Love in view of Wimberger.
Thus, claim 29 is prima facie obvious over Love in view of Wimberger.
Regarding claim 30, as noted above in the rejection of claim 29, Wimberger teaches that one or more species of capture molecules may be used in a capture zone. In para. 76, the capture molecules in a capture zone are specifically noted to specifically capture/bind to a “part of a single stranded target molecule,” where complementarily may only exist over a portion of the entirety of said target. This paragraph goes on to note that a capture molecule may have variable length, ranging from at least 10 to at least 60 nucleotides. The one or more species of capture molecule used may partially overlap in sequence, and may cover a discrete number of genes (para. 83). Thus, the teachings of Wimberger encompass capture molecules that may slightly overlap in sequence and target the same gene, thereby binding to different regions of the same gene target.
Wimberger also states that the target molecules of their invention may be allelic variants that may be associated with particular mutants or disease associated forms, or may be used for forensic identification (para. 85). As Love teaches that their samples may be multiple cells, and also teaches the use of bodily fluid samples (para. 157), combined with the teachings of Wimberger, it would be prima facie obvious that Love in view of Wimberger could be used to analyze a collection of cells from a subject to determine if a particular disease or mutation is present. Then, the ordinary artisan would be motivated to use the embodiment of the capture molecules of Wimberger described above, where particular species of capture molecules can be used to target slightly different regions of the same gene. In a sample that contains nucleic acids from multiple cells, such capture molecules would be able to detect particular mutations that may be present in some, but not all, of the cells of the sample, which could indicate a particular disease or condition, and would aid in diagnosing a subject. As such capture molecules are encompassed by Wimberger, and Love in view of Wimberger specifically uses the capture molecules of Wimberger, there would be a reasonable expectation of success.
Thus, claim 30 is prima facie obvious over Love in view of Wimberger.
Regarding claim 31, Wimberger teaches that a capture molecule is also specifically defined by the reference as a molecule that allows a “specific interaction” with a target molecule (para. 69). In defining the specific capturing of the target molecule, for nucleic acid-nucleic acid interactions, this can indicate full complementarity over the entire length of the target (para. 84). Thus, this specific binding would include the capture molecule binding to the entire length of the target nucleic acid. As the capture oligonucleotides of Wimberger are used in the method of Love in view of Wimberger, it would be prima facie obvious that any capture nucleic acid encompassed by Wimberger could be used in the method of Love in view of Wimberger, as these capture nucleic acids would naturally have a reasonable expectation of success with their use.
Thus, claim 31 is prima facie obvious over Love in view of Wimberger.
Regarding claim 32, Wimberger teaches that their capture molecules can be nucleic acids (para. 69), and teaches that nucleic acids can include non-natural portions, such as in the case of PNAs or ANAs (para. 70). Thus, the reference encompasses using capture molecules with non-natural nucleotides. As the capture oligonucleotides of Wimberger are used in the method of Love in view of Wimberger, it would be prima facie obvious that any capture nucleic acid encompassed by Wimberger could be used in the method of Love in view of Wimberger, as these capture nucleic acids would naturally have a reasonable expectation of success with their use.
Thus, claim 32 is prima facie obvious over Love in view of Wimberger.
Regarding claim 33, this claim differs from claim 21 in that it recites two amplification steps. Both of these amplification steps involve the use of primers that hybridize to the first and second universal sequences. The type or length of amplification used is not specified. Love teaches that the amplification used in their method (described above in the rejection of claim 21) can be PCR (e.g. para. 138). Even if said PCR amplification was the smallest number of cycles recited by Love (8 cycles, see paras. 483, 514, 525, and 599 for example), this single PCR alone would read on the two amplification steps recited by the claim. After the first PCR cycle (where the primers would bind to the first and second universal sequences of the second strand cDNA, as described by Love and recited above), copies of the second strand cDNA would be generated. These alone would read on the claimed “first plurality of barcoded amplicons.” Then, as the PCR cycles continued, again using the same primers, said first plurality of barcoded amplicons would be amplified, creating the claimed target nucleic acid species. This PCR amplification is still amplifying target nucleic acids from a group of cells, and so would consist of a plurality of target species.
Thus, the teachings of Love capture the differences between instant claims 21 and 33. For the remaining limitations of claim 33, the teachings of Love in view of Wimberger described above in the rejection of claim 21 still apply.
Therefore, claim 33 is prima facie obvious over Love in view of Wimberger.
Claims 36-37 contain the same language as instant claims 24-25, respectively, and so are also prima facie obvious over Love in view of Wimberger for the reasons described above for claims 21, 24-25, and 33.
Claim 38 contains the same language as instant claim 27, and so is prima facie obvious over Love in view of Wimberger for the reasons described above for claims 21, 27, and 33.
Claim 39 contains the same language as instant claim 28, and so is prima facie obvious over Love in view of Wimberger for the reasons described above for claims 21, 28, and 33.
Claim 40 contains the same language as instant claim 32, and so is prima facie obvious over Love in view of Wimberger for the reasons described above for claims 21, 32, and 33.
Claims 22-23 and 34-35 are rejected under 35 U.S.C. 103 as being unpatentable over Love et al. (US 2019/0218607 A1), in view of Wimberger et al. (US 2014/0087955 A1), and further in view of Shum et al. (US 2020/0263169 A1).
Love in view of Wimberger teaches the methods of claims 21, 24-33, and 36-40, as described above.
Love teaches that their generated cDNA can be sequenced after amplification (paras. 131, 138, 373), and specifically notes that the universal sequences described in the reference can also facilitate such analyses (para. 131). Wimberger teaches that their device can be used with sequencing technologies (para. 146). Specifically, bound targets can be released from the array and subsequently prepared (para. 146). Though para. 146 mentions this occurring with targets in the reaction zone of the device, para. 11 teaches that captured molecules may generally be used for sequencing activities. Para. 146 also lists various sequencing methodologies that may be used, such as that of Illumina.
However, neither reference teaches that sequencing or sequencing preparation can involve an amplification that incorporates sequences associated with sequencing primers or adaptors into the second strand cDNA sequences.
Shum teaches methods for cDNA sequencing library preparation (Abstract). Paras. 216-217 and 220 and Figure 4 describe a general method where second strand cDNA is generated and amplified, and before sequencing preparation, random primers are used. This generates cDNA sequences with two universal sequences, one at each end. During sequencing library preparation, an additional amplification occurs, using library primers that attach to the universal sequences, while also adding sequencing adaptors to each end of the sequence. The final product (reference character 460) can then be sequenced. Para. 220 notes that these sequencing adaptors can be associated with sequencing methods of particular systems (e.g. P5 and P7 sequences, noted to be associated with Illumina in paras. 5 and 166).
Prior to the effective filing date of the claimed invention, it would have been prima facie obvious for one of ordinary skill in the art to use the guidance provided by Shum to perform Illumina sequencing on the captured second strand cDNA targets of Love in view of Wimberger, and to specifically use the library preparation for such sequencing described by Shum. Shum teaches products before library preparation that are cDNA sequences with two universal sequences on their ends, which are similar to the products captured on the device of Wimberger in Love in view of Wimberger. Love in view of Wimberger also suggests performing sequencing utilizing the universal sequences on their cDNA products, as well as the use of Illumina sequencing. Shum then provides the specific preparation methods to ready such a product for Illumina sequencing, as well as the knowledge of how such sequencing would generally operate. MPEP 2143 I (A) states, “The rationale to support a conclusion that the claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art.” The library primers and Illumina sequencing taught by Shum would be unchanged in this combination, and as Wimberger teaches that to perform sequencing (such as Illumina sequencing), captured targets can be removed from their device/array, the method of Love in view of Wimberger would proceed as described above in the rejection of claim 21, the targets would be removed, and then undergo the preparation and sequencing described by Shum. No change to either method would be required, and the results would be predictable, as sequencing data would be generated.
Thus, claim 22 is prima facie obvious over Love, in view of Wimberger, and further in view of Shum.
Regarding claim 23, Love teaches that the barcodes of their invention can be used to distinguish nucleic acids from a population of cells, and that is barcode is a unique identifier (para. 132). Thus, each distinct capture oligonucleotide would have its own barcode. As Love also teaches that this barcode is retained throughout creation of the second strand cDNA (para. 132), it would be present in sequencing products, and thus it would be prima facie obvious to use the barcodes for their designed purpose during sequencing analysis, and to use them to group nucleic acids within the multicellular sample in the method of Love, in view of Wimberger, and further in view of Shum. Para. 152 further notes that these barcodes can identify sets of sequences, and in particular sets of sequences that may be associated with particular treatments, conditions, or manipulations. Therefore it would be prima facie obvious for the ordinary artisan to note the size of the sets for each barcode, as this could provide information about the abundance of particular nucleic acids associated with particular treatments, conditions, or manipulations, which has many implications for research (e.g. gene expression data and disease treatment).
Thus, claim 23 is prima facie obvious over Love, in view of Wimberger, and further in view of Shum.
Regarding claim 34, this requires that the second amplification of claim 33 incorporate a sequence related to a sequencing primer or adaptor into the first amplification products. As noted above in the rejection of claim 22, Wimberger teaches that sequencing preparation may occur off of the array/device. However, the reference also teaches that sequencing can be perform in situ (i.e. on the device; para. 146).
In claim 33, the method of Love in view of Wimberger alone was considered to read on the limitations of the claim. However, this method is not sufficient to read instant claim 34. Nevertheless, given the teachings of Love, Wimberger, and Shum, prior to the effective filing date of the claimed invention, it would have been prima facie obvious for one of ordinary skill in the art to perform the method of Love, in view of Wimberger, and further in view of Shum, but to actually perform the sequencing method on the device/array of Wimberger. Specifically, Love in view of Wimberger would result in amplified sequences that are then captured and isolated on the device/array of Wimberger. Then, the sequencing library preparation (with amplification) of Shum, as described in the rejection of claim 22, would occur. Shum does not specify where their sequencing reactions must occur, and the ordinary artisan would recognize that with the library preparation steps taught by the reference, there would be several reagents in solution (excess library primers, dNTPs, etc.) that it would be beneficial to separate from the sequences being targeted for sequencing. Thus, the ordinary artisan would be motivated to capture the fully prepared library sequences with the device/array of Wimberger, and perform Illumina sequencing on said device/array. This would also prevent the need for the use or design of an additional array/solid support. Wimberger teaches that capture molecules can also be present in reaction zones on the array (para. 8-9, 11), and that multiple reaction zones can be used (para. 66). Thus, capturing the fully prepared products would not interfere with any earlier capturing performed on the device (e.g. capturing and separating the initial cDNA strands). As Wimberger teaches that sequencing may be performed on their device/array, and specifically mentions Illumina techniques, there would be a reasonable expectation of success.
In reading this combination in the context of instant claim 33, it is noted that a first isolating step would be performed after the first amplification step, and the amplification of Shum is being used to read on the second amplification step. As the claimed method comprises the listed steps, an additional isolation step can be included in said claimed method.
Thus, claim 34 is prima facie obvious over Love, in view of Wimberger, and further in view of Shum.
Regarding claim 35, Love teaches that the barcodes of their invention can be used to distinguish nucleic acids from a population of cells, and that is barcode is a unique identifier (para. 132). Thus, each distinct capture oligonucleotide would have its own barcode. As Love also teaches that this barcode is retained throughout creation of the second strand cDNA (para. 132), it would be present in sequencing products, and thus it would be prima facie obvious to use the barcodes for their designed purpose during sequencing analysis, and to use them to group nucleic acids within the multicellular sample in the method of Love, in view of Wimberger, and further in view of Shum. Para. 152 further notes that these barcodes can identify sets of sequences, and in particular sets of sequences that may be associated with particular treatments, conditions, or manipulations. Therefore it would be prima facie obvious for the ordinary artisan to note the size of the sets for each barcode, as this could provide information about the abundance of particular nucleic acids associated with particular treatments, conditions, or manipulations, which has many implications for research (e.g. gene expression data and disease treatment).
Thus, claim 35 is prima facie obvious over Love, in view of Wimberger, and further in view of Shum.
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 21-24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 and 6-7 of U.S. Patent No. 11,932,901 B2 in view of Love et al. (US 2019/0218607 A1).
Claim 1 of the ‘901 patent contains the same steps as instant claim 21, with the exception of not including the amplification step described in the instant claim. However, such a step would be obvious to perform over Love et al. (US 2019/0218607 A1), which teaches a method involving a barcode oligonucleotide and a random primer with the same structure as that claimed (see the rejection of claim 21 above). This reference also teaches amplification of nucleic acids in para. 130-131, and notes that labeling nucleic acids with universal primers allows them to be amplified and sequenced with relatively similar efficiency, because primers can hybridize to the universal sequences. Para. 137 states that products that have been extended with both the barcoded oligonucleotide and the random primer would have universal sequences on their 5’ and 3’ ends, and may be amplified via these identical labels using universal primers. Thus, in order to increase the number of copies of the labeled nucleic acids present, the ordinary artisan would be motivated to perform an amplification reaction as described in Love.
Thus, the ‘901 patent in view of Love reads on instant claim 21.
Claim 2 of the ‘901 patent contains the same language as instant claim 22, and so reads on this claim in view of the teachings of Love described above.
Claim 6 of the ’901 patent contains the same language as instant claim 23, and so reads on this claim in view of the teachings of Love described above. It is noted that claim 6 depends on claims 2 and 4 of the patent, and so includes additional steps (presented in claim 4) relative to instant claims 21-23, but such steps are not precluded by the instant claims (i.e. the instant claims comprise the listed steps).
Claim 7 of the ‘901 patent contains the same language as instant claim 24, and so reads on this claim in view of the teachings of Love described above.
Conclusion
No claims are currently allowable.
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/FRANCESCA FILIPPA GIAMMONA/Examiner, Art Unit 1681
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