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 .
Status of Claims
Claims 1, 2, 8 and 19-28 are currently pending. Claims 1, 8, 21 and 22 have been amended by Applicants’ amendment filed 10-30-2025. Claims 23-28 have been added or canceled by Applicants’ amendment filed 10-30-2025. Claims 5 and 10 have been canceled by Applicants’ amendment filed 10-30-2025.
Applicant's election without traverse of Group I, claims 1-5 and 19, directed to method for preparing an RNA library; and the election with traverse of:
Species (A): wherein the method of claim 1 comprises method (b) extracting RNA (claim 1).
Species (B) and (C): Applicant did not elect a species, in the reply filed on June 26, 2024 was previously acknowledged.
Regarding newly submitted claims 23-28, the claims are directed to an invention that is independent or distinct from the invention originally claimed for the following reasons: Newly submitted claim 23 is directed to a method for preparing a cDNA library, comprising: (i) extracting total RNA; (ii) modifying the extracted RNA, then adding a poly(A) or poly(U) tail; (iii) ligating an adaptor to the 5’ end of the tailed products; (iv) removing the rRNA from the hybrids; and (v) performing reverse transcription and PCR amplification after the rRNA has been removed (claim 23). Newly submitted claim 28 is directed to a method for preparing a cDNA library, comprising: (i) extracting total RNA; (ii) modifying the extracted RNA, then adding a poly(A) or poly(U) tail; (iii) ligating an adaptor to the 5’ end of the tailed products; (iv) removing the rRNA from the hybrids; and (v) performing reverse transcription and PCR amplification on the target RNA fragments (claim 28). Claim 1 of the claims filed September 8, 2021 was directed to a method for preparing an RNA library, comprising: (i)(a) extracting RNA and performing fragmentation; or (b) extracting RNA; (ii) adding a tail to the 3’ end; (iii) ligating an adaptor to the 5’ end, and hybridizing with a DNA probe mixture; (iv) removing RNA from the hybrid and removing DNA; and (v) performing reverse transcription and PCR amplification to obtain a library solution (clam 1). Thus, newly submitted claims 23-28 require a search and examination beyond the claims as originally presented, and constructively elected. The different species of method and composition would require a different field of search; the prior art applicable to one species would not likely be applicable to another species; and/or the species are likely to raise different non-prior art issues under 35 U.S.C. 101 and/or 35 U.S.C. 112(a). For example, the limitations of newly submitted claims 23 and 28 recite different method steps to obtain different amplified libraries as compared to instant claim 1 of the claims filed September 28, 2021.
As noted in MPEP 818.02(a), wherein subsequently presented claims to an invention other than that acted upon should be treated as provided in MPEP § 821.03. As recited in MPEP 821.04 (¶ 8.04), since applicant has received an action on the merits for the originally presented invention, this invention has been constructively elected by original presentation for prosecution on the merits.
Accordingly, newly submitted claims 23-28 are withdrawn from consideration as being directed to a non-elected invention. See 37 CFR 1.142(b) and MPEP § 821.03.
Claims 8, 10 and 20 were previously withdrawn, and claims 23-28 are newly withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on June 26, 2024.
Claims 2-4 were previously withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected species, there being no allowable generic or linking claim.
The restriction requirement was deemed proper and was made FINAL.
A complete reply to the final rejection must include cancellation of nonelected claims or other appropriate action (37 CFR 1.144) See MPEP § 821.01.
Therefore, claims 1, 19, 21 and 22 are under consideration to which the following grounds of rejection are applicable.
Priority
The present application filed March 5, 2021 is a 35 U.S.C. 371 national stage filing of International Application No. PCT/CN2018/104143, filed on September 5, 2018.
Acknowledgment is made of applicant's claim for foreign priority based on an application filed in the China. It is noted, however, Applicant has not filed a certified copy of the Chinese Application No.
PCT/CN2018/104143 application as required by 37 CFR 1.55.
Although Applicant filed an English Translation with a Verification Statement on October 30, 2025, Applicant has not provided a certified English Translation of the foreign priority document. A certified English Translation requires the following: (i) a signed affidavit confirming that the translation is a complete and accurate representation of the original document; (ii) the translator’s printed name, signature, address, and date; (iii) a certification that the translator is fluent in both the source and target (English) languages; and (iv) that it specifically identify the document being translated (e.g., the PCT application number, title) (See; MPEP 2304.01(c) and 37 CFR 41.154(b) and 41.202(e)).
Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e).
Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Response to Remarks
Applicant’s remarks filed October 30, 2025 have been fully considered but they are not persuasive. Applicants essentially assert that: (a) Applicant states that a certified English Translation is
already on file (Applicant Remarks, pg. 6, Priority).
Regarding (a), the Examiner respectfully requests that Applicant indicate where the previously filed certified English Translation can be found.
Withdrawn Objections/Rejections
Applicants’ amendment and arguments filed October 30, 2025 are acknowledged and have been fully considered. The Examiner has re-weighed all the evidence of record. Any rejection and/or objection not specifically addressed below are herein withdrawn.
Maintained Objections/Rejections
Claim Rejections - 35 USC § 112(b)
The rejection of claims 1, 19, 21 and 22 is maintained under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
Claims 1 and 21 are indefinite for the recitation of the term “a DNA probe mixture that comprises DNA probes that are reverse complementary” such as recited in claim 1, line 8 because the as-filed Specification does not teach that the ‘DNA probe mixture comprises DNA probes’. Instead, the as-filed Specification teaches that “the DNA probe mixture is composed of several DNA probes that are reverse complementary” (pg. 2, lines 3-4 and 11-12; pg. 3, lines 5-6; and pg. 6, line 10), where MPEP 2111.03(IV) states that the transitional phrase “composed of” is interpreted in the same manner as either "consisting of" or "consisting essentially of," depending on the facts of the particular case (See; AFG Industries, Inc. v. Cardinal IG Company, 239 F.3d 1239, 1245, 57 USPQ2d 1776, 1780-81 (Fed. Cir. 2001)). Moreover, the term “compose” means ‘to make up a whole’, while the term ”comprise” means ‘to contain parts’ (e.g., includes) as evidenced by Vocabulary.com (pg. 1) and Shea (pg. 1), such that the term “comprises” as recited in claim 1 is broader than provided for in the as-filed Specification and, thus, the metes and bounds of the claim cannot be determined.
Claims 19 and 23 are indefinite insofar as they ultimately depend from instant claim 1.
Claim Rejections - 35 USC § 102
The rejection of claims 1, 19, 21 and 22 is maintained under 35 U.S.C. 102(a1)/(a2) as being anticipated by Yang et. al. (hereinafter “Yang”) (bioRxiv, July 2019, 1-23).
Regarding claim 1, Yang teaches PolyAdenylation Ligation Mediated-Seq (PALM-Seq) of cell-free RNA (cfRNA), an integrated sequencing method for cell-free long and small RNA, wherein terminal modification and addition of 3’ polyadenylation and 5’ adaptor, mRNA, long non-coding RNA, microRNA, tRNA, piRNA and other RNAs are provided in a single library, and that with target RNA depletion, all these RNAs could be sequenced with relatively low depth (pg. 2, first full paragraph, lines 3-8). Yang teaches using PALM-Seq to identify pregnant-related mRNAs, long non-coding RNAs and microRNAs in female plasma, amniotic fluids, leukocytes and placentas wherein several of the authors collected samples and extracted plasma (interpreted as extracting RNA, claim 1) (pg. 2, first full paragraph, lines 8-11; and pg, 12, Author Contributions). Yang teaches that in the first step - the terminal modification of cfRNA was different, however T4 Polynucleotide Kinase (T4 PNK) could make most part of them to 5’ end phosphorylated and 3’ end hydroxyl (interpreted as treating RNA with T4 PNK; 5’ phosphate group; and 3’ hydroxyl, claim 1) (pg. 4, first full paragraph, lines 2-5). Yang teaches that the 5’ adaptor was then ligated by T4 RNA Ligase 1, and rRNA or other uninterested, abundant RNA could be easily removed by RNase H method; DNase I treatment could also prevent the possible contamination of cell-free DNA; and RNA with 3’ polyadenylation and 5’ adaptor was reverse transcribed by oligo(dT) with 3’ adaptor and amplified by PCR (Fig. 1a) (interpreted as tailing; adaptor ligation; removal of rRNA; Rnase H digestion; and DNase digestion,, claims 1 and 5) (pg.4, first full paragraph, lines 7-13). Figure 1a is shown below:
PNG
media_image1.png
272
364
media_image1.png
Greyscale
PNG
media_image2.png
370
402
media_image2.png
Greyscale
(interpreted as adding a tail, T4 PNK treatment, ligating adaptor, removing rRNA, primer annealing/adding DNA; reverse transcription; PCR; and removing DNA hybrids, claim 1) (pg.19; Figure 1a). Yang teaches the depletion of uninformative abundant RNA (e.g., rRNA) can increase mapping rate and maximize the coverage of transcripts (interpreted as removing rRNA, claim 1) (pg. 6, last partial paragraph). Yang teaches that the 5’ adaptor was then ligated by T4 RNA Ligase 1, and rRNA or other uninterested, abundant RNA could be easily removed by RNase H method; DNase I treatment could also prevent the possible contamination of cell-free DNA; and RNA with 3’ polyadenylation and 5’ adaptor was reverse transcribed by oligo(dT) with 3’ adaptor and amplified by PCR (Fig. 1a) (interpreted as tailing; adaptor ligation; removal of rRNA; Rnase H digestion; and DNase digestion, claims 1 and 5) (pg.4, first full paragraph, lines 7-13).
Regarding claim 19, Yang teaches that the processing pipeline of sequencing data is shown in Figure 1b (interpreted as sequencing, claim 19) (pg. 4, first full paragraph, lines 14-15; and Figure 1b).
Regarding claims 21 and 22, Yang teaches that rRNA can be removed efficiently by target depletion (TD), especially in PNKT condition, otherwise, the rRNA ratio would be extremely high; and Y RNA and Vault RNA can also be removed by TD, wherein SMARTer Seq removed rRNA through CRISPER (interpreted as the mixture comprises DNA probes that are reverse complementary to Y RNA (pg. 7, first partial paragraph).
Yang meets all the limitations of the claims and, therefore, anticipates the claimed invention.
Response to Arguments
Applicant’s remarks filed October 30, 2025 have been fully considered but they are not persuasive. Applicants essentially assert that: (a) the priority date of the present application is before the publication date of Yang. As such, Yang is not prior art to the instant invention (Applicant Remarks, pg. 14, 35 USC 102).
Regarding (a), the English Translation provided by Applicant is not a certified English Translation. Moreover, the instant as-filed Specification and original claims do not teach that the DNA probe mixture “comprises” DNA probes that are reverse complementary to rRNAs, such that the priority date of the instant invention is March 5, 2021, the filing date of US Patent Application 17/274,009. Thus, the claim remain rejected.
Claim Rejections - 35 USC § 103
The rejection of claims 1, 19, 21 and 22 is maintained under 35 U.S.C. 103 as being unpatentable over Allen et al. (hereinafter “Allen”) (US Patent No. 10711271, issued July 14, 2020; effective filing date November 20, 2017) in view of Huang et al. (hereinafter “Huang”) (Current Protocols in Molecular Biology, 2013, Supplement 102(4), 1-14) as evidenced by Wang et al. (hereinafter “Wang”) (Nucleic Acids Research, 2002, 30(4), 1073-1080).
Regarding claims 1 (in part), 19, 21 and 22, Allen teaches a method for making a cDNA library comprising reverse transcribing mRNA to produce DNA:mRNA hybrids, treating the DNA:mRNA hybrids with RNAseH to produce mRNA fragments, and reverse transcribing the mRNA fragments (interpreted as producing a cDNA library; producing RNA fragments; DNA probe/RNA hybrids; and treating with RNAseH, claims 1 and 5) (Abstract). Allen teaches that the cDNAs that are sequenced can be a pool of nucleic acids extracted from a plurality of sources, such as a pool of nucleic acids from a plurality of organisms (interpreted as extracting; and sequencing the cDNA library, claim 1 and 19) (col 11, lines 23-25). Allen teaches that an RNA sample can contain a total RNA sample including mRNA molecules, which are typically at least 100 nt in length (e.g., 200 nt to 10 kb in length), wherein an RNA sample can contain a variety of small non-coding regulatory RNAs that can be generically referred herein to as "small RNAs", e.g., short interfering RNAs, microRNAs (miRNAs), tiny non-coding RNAs, piwi-interacting small RNAs (piRNAs), snoRNAs and small modulatory RNAs, wherein small RNAs are typically below 100 nt in length and have a median length in the range of 18 nt to 40 nt; as well as, containing rRNA molecules, tRNA molecules, pre-miRNA molecules, snRNAs and long noncoding RNA molecules such as large intergenic RNA (lincRNA) molecules (interpreted as a mixture of RNA molecules, claim 1) (col 2, lines 42-55; and col 7, lines 1-5). Allen teaches that Figure 1 illustrates that some embodiments of the method can comprise reverse transcribing RNA sample 2 that comprises mRNA 4 to produce first strand cDNA product 6 that comprises DNA:mRNA hybrids 8 that comprise mRNA 4 and cDNA copy of the mRNA 10, wherein the term “cDNA copy” refers to a DNA molecule that has the reverse complement of an RNA molecule (interpreted as DNA probe mixture that are reverse complementary to mRNAs; and DNA probe-RNA hybrids, claim 1) (col 6, lines 56-63). Allen teaches in Figure 1 that the reverse transcription can be primed using an oligo(dT) primer (e.g., an anchored oligo(dT) primer), wherein the initial reverse transcription step can be done using one more sequence-specific primers such as primers that hybridize to unique sequences in the mRNA and/or short RNAs (interpreted as ligating DNA probes, claim 1) (col 6, lines 63-67; and col 7, line 1). Allen teaches that the method can comprise treated the first strand cDNA product 6 with RNAseH to produce digested sample 12 that comprises fragments of the mRNA 14 (e.g., fragments 14a, 14b, 14c, 14d and 14e) (interpreted as RNAse digestion, claim 5) (col 7, lines 18-21). Allen teaches that all of the fragments should have a 5' phosphate and a 3' hydroxyl and, as such, can be processed in the same way, wherein the 5' end fragment 16 can be treated enzymatically to contain a 5' phosphate, if necessary (interpreted as enzymatic treatment of fragments for 3’ hydroxyl and 5’ phosphate group, claim 1) (col 7, lines 33-36). Allen teaches that the fragments can be reverse transcribed by ligating a 5’ adaptor to the fragments, and tailing the 3’ end of the fragments using polyA polymerase, and reverse transcribing the fragments using an oligo(dT) primer, wherein the ligating and tailing steps can be done in any order (interpreted as adding a polyA tail; ligating an adaptor; producing DNA probe-RNA hybrids; ligating and tailing in any order; and reverse transcription, claim 1, steps (ii)-(v)) (col 8, lines 22-30). Allen teaches that the cDNA molecules made in the initial step can be degraded using DNAse treatment, then discarded (e.g., purified away from the cDNA in the library) and/or diluted out (interpreted as removing DNA by DNAse digestion, claim 5) (col 8, lines 55-57). Allen teaches that the amplification product can be subjected to a size selection step to remove unincorporated primers and/or unwanted species such as rRNA fragments or snoRNAs prior to analysis (interpreted as removing rRNA; and interpreted to encompass removing Y RNA, claims 1 and 22) (col 10, lines 44-47). Allen teaches that Figure 3 illustrates a method of making a cDNA library, wherein digested sample 12 contains mRNA fragments 30 and small RNAs 32 including 5’ adaptor ligation and adding a tail to the 3’ end of fragment (col 9, lines 43-48; and Figure 3). Figures 1 and 3 are shown below:
PNG
media_image3.png
778
470
media_image3.png
Greyscale
PNG
media_image4.png
696
510
media_image4.png
Greyscale
Figure 1 Figure 3
Allen teaches that the cDNA library can be amplified using one or more primers that hybridize to the added sequences (or their complements), the primers used can have sequences that are compatible with the sequencing platform being used (e.g., P5 and P7 sequences, which sequences are compatible with Illumina's sequencing platform) and the amplification products will have those sequences at their ends (e.g., P5 sequence at one and the P7 sequence at the other, if the Illumina sequencing platform is being used) (interpreted as PCR amplification and sequencing; and probes comprising reverse complement to Y RNA, claims 1, 19 and 21) (col 8, lines 48-58). Allen teaches the term "depleted", in the context of a total cellular RNA sample that has been depleted for tRNA, rRNA, or another type of RNA, is total cellular RNA sample from which tRNA, rRNA, or another type of RNA has been subtracted, i.e., removed (interpreted as encompassing removing rRNA and Y RNA, claim 22) (col 4, lines 15-19). Allen teaches that the term “cDNA copy” refers to a DNA molecule that has the reverse complement of an RNA molecule (interpreted as encompassing a reverse complement of Y RNA, claim 21) (col 6, lines 4-5). Allen teaches that the term “sequence-specific primer” refers to a primer that hybridizes to a unique sequence in mRNA or a target RNA (interpreted as hybridizing DNA probe to RNA, claim 1) (col 5, lines 65-67).
Allen does not specifically exemplify the enzyme T4 PNK (claim 1, in part).
Regarding claim 1 (in part), Huang teaches facilitating experimental analysis by in vitro synthesizing RNAs including RNAs radiolabeled with 32P (pg. 1, second full paragraph). Huang teaches the synthesis and labeling of RNA in vitro, wherein to end-label an in vitro-transcribed RNA at its 5’ end, dephosphorylated RNA is then re-phosphorylated in a forward reaction catalyzed by T4 poly-nucleotide kinase (PNK); and the RNA substrate can be prepared either from in vitro transcription or in vivo purification (pg. 4, last full paragraph), wherein it is known that T4 polynucleotide kinase (T4 PNK) is a bifunctional 5’-kinase/3’-phosphatase that aids in the repair of broken termini in RNA by converting 3’-PO4/5’-OH ends into 3’-OH/5’PO4 ends, which are then sealed by RNA ligase as evidenced by Wang (Abstract, lines 1-4).
It is prima facie obvious to combine prior art elements according to known methods to yield predictable results; the court held that, "…a conclusion that a 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 would have yielded nothing more than predictable results to one of ordinary skill in the art. KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 82 USPQ2d 1385, 1395 (2007); Sakraida v. AG Pro, Inc., 425 U.S. 273, 282, 189 USPQ 449, 453 (1976); Anderson’s-Black Rock, Inc. v. Pavement Salvage Co., 396 U.S. 57, 62-63, 163 USPQ 673, 675 (1969); Great Atlantic & P. Tea Co. v. Supermarket Equipment Corp., 340 U.S. 147, 152, 87 USPQ 303, 306 (1950)”. Therefore, in view of the benefits of treating RNAs with enzymes including T4 PNK as exemplified by Huang, it would have been prima facie obvious before the effective filing date of the claimed invention to modify the method of producing a cDNA library from a sample comprising total RNA including enzymatically synthesizing fragments comprising a 5’ phosphate and a 3’ hydroxy as disclosed by Allen to include treating RNA with appropriate enzymes for end-repair such as including treatment with T4 PNK as taught by Huang with a reasonable expectation of success in reverse transcribing RNA fragments to produce cDNA libraries; in producing cDNA libraries from total RNA samples via a single workflow; and/or in synthesizing libraries of radiolabeled cDNA for use in experimental analyses
Thus, in view of the foregoing, the claimed invention, as a whole, would have been obvious to one of ordinary skill in the art at the time the invention was made. Therefore, the claims are properly rejected under 35 USC §103(a) as obvious over the art.
Response to Arguments
Applicant’s remarks filed October 30, 2025 have been fully considered but they are not persuasive. Applicants essentially assert that: (a) Allen teaches producing DNA:mRNA hybrids and not DNA:rRNA hybrids, where rRNA/Y RNA is the unwanted RNA that needs to be removed, and mRNA is the target RNA to be library-prepared (Applicant Remarks, pg. 15, first through fourth full paragraphs); (b) Allen requires an initial step of producing DNA:mRNA hybrids followed by RNaseH digestions and other subsequent operations such as 3’ tailing, while the method of the present application requires 3’ tailing as a preceding steps, and the subsequent operations includes the formation of the DNA:RNA hybrids using DNA probes (Applicant Remarks, pg. 15, last full paragraph); (c) the DNA probe hybridizes with rRNA to form a DNA probe-rRNA hybrid, while Allen is silent on features regarding DNA probes (Applicant Remarks, pg. 16, first through third full paragraphs); (d) Allen teaches the RNAse digestion acts on mRNA and not on rRNA that is unwanted RNA to be removed (Applicant Remarks, pg. 16, fourth full paragraph); (e) the DNA probe as recited in the claimed method hybridize to the unwanted sequences (e.g., Y RNA) that need to be removed from the cDNA library. Secondly, the primers taught by Allen serve as the starting points for the extension reaction to initiate the amplification reaction; while the DNA probes as recited in the claimed method hybridize to the unwanted sequences (Applicant Remarks, pg. 18, second full paragraph); (f) cDNA copy disclosed by Allen are different and cannot be interpreted as the DNA probes recited in the claimed method (Applicant Remarks, pg. 19, fifth full paragraph); (g) Allen use RNAseH to prepare the target RNA for cDNA library, which is entirely different from the claimed method of the present application that utilizes RNAseH to remove unwanted RNA from cDNA library (Applicant Remarks, pg. 19, last full paragraph); (h) claim 1 differs from Allen in that claim 1 has a step of adding a 3’ tail to extracted RNA using T4PNK, and (2) removes rRNA after the step of adding the 5’ adaptor (Applicant Remarks, pg. 20 through pg. 21); and (i) the inventors unexpectedly found unexpected benefits by adopting the step of removing rRNA after adding a 5’ end adaptor (Applicant Remarks, pg. 22).
Regarding (a), (d) and (e), although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26USPQ2d 1057 (Fed. Cir. 1993). Moreover, it is noted that none of the references has to teach each and every claim limitation. If they did, this would have been anticipation and not an obviousness-type rejection. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). As noted in MPEP 2112.01(I),
where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). "When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).
MPEP 2123(I) states:
“The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain.” In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)) (underline added).
A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. Merck & Co. v.Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989). See also Upsher-Smith Labs. v. Pamlab, LLC, 412 F.3d 1319, 1323, 75 USPQ2d 1213, 1215 (Fed. Cir. 2005) (reference disclosing optional inclusion of a particular component teaches compositions that both do and do not contain that component); Celeritas Technologies Ltd. v. Rockwell International Corp., 150 F.3d 1354, 1361, 47 USPQ2d 1516, 1522-23 (Fed. Cir. 1998) (The court held that the prior art anticipated the claims even though it taught away from the claimed invention. “The fact that a modem with a single carrier data signal is shown to be less than optimal does not vitiate the fact that it is disclosed.”) (underline added).
Applicant’s assertion that Allen teaches producing DNA:mRNA hybrids and not DNA:rRNA hybrids, where rRNA/Y RNA is the unwanted RNA that needs to be removed, and mRNA is the target RNA to be library-prepared, is not found persuasive. As an initial matter, instant claim 1 does not recite terms such as, an “initial step”, unwanted RNA such as rRNA/Y RNA, and/or RNA that needs to be removed. The Examiner contends that the combined references of Allen and Huang teach all of the limitations of the claims. For example -
Allen teaches:
The RNA sample can contain total cellular RNA, total RNA that has been depleted for one or more types of RNA (e.g., rRNA and/or tRNA), or mRNA and small RNA) (interpreted as encompassing removing rRNA and Y RNA, claims 1 and 22) (col 7, lines 1-5).
The term "depleted", in the context of a total cellular RNA sample is one that has been depleted for tRNA, rRNA, or another type of RNA, or a total cellular RNA sample from which tRNA, rRNA, or another type of RNA has been subtracted, i.e., removed (interpreted as encompassing removing rRNA and Y RNA, claims 1 and 22) (col 4, lines 15-19).
Relative levels of an mRNA and/or small RNA in two or more different small RNA samples can be obtained using the above methods, and compared (interpreted as encompassing removing rRNA and Y RNA, claims 1 and 22) (col 12, lines 12-14).
Although Allen tends to focus on a method of producing DNA/mRNA hybrids for depletion from total cellular RNA, these hybrids are merely examples of the types of hybrids that can be produced. As indicated supra, the same methods can be used for the production of different DNA/RNA hybrids and the removal of other types of RNA including rRNA and Y RNA. Moreover, consistent with MPEP 2123(I), the teachings of Allen would have suggested to one of ordinary skill in the art that the method of removing mRNA from total cellular RNA can be used to remove other small RNAs from total cellular RNA (e.g., rRNA); as well as, the production and/or use of DNA/rRNA hybrids. The combined references teach all of the limitations of the claims. Thus, the claims remain rejected.
Regarding (b), please see the discussion supra regarding the Examiner’s response to Applicant’s arguments. Applicant’s assertion that Allen requires an initial step of producing DNA:mRNA hybrids followed by RNaseH digestions and other subsequent operations such as 3’ tailing, while the method of the present application requires 3’ tailing as a preceding steps, and the subsequent operations includes the formation of the DNA:RNA hybrids using DNA probes, is not found persuasive. As an initial matter, instant claim 1 does not recite that the steps of tailing and ligating are carried out in any particular order. Additionally, Allen teaches nucleic acid extraction, performing fragmentation, modifying the RNA fragments; ligating adaptors; tailing the 3’ ends; removing unwanted species of RNA; and performing reverse transcription and PCR amplification, wherein the ligating and tailing steps can be carried out in any order (col 8, lines 28-29). Thus, the claims remain rejected.
Regarding (c), please see the discussion supra regarding the Examiner’s response to Applicant’s arguments. Applicant’s assertion that the DNA probe hybridizes with rRNA to form a DNA probe-rRNA hybrid, while Allen is silent on features regarding DNA probes, is not found persuasive.
Allen teaches:
The RNA sample can contain total cellular RNA, total RNA that has been depleted for one or more types of RNA (e.g., rRNA and/or tRNA), or mRNA and small RNA) (interpreted as encompassing removing rRNA and Y RNA, claims 1 and 22) (col 7, lines 1-5).
Relative levels of an mRNA and/or small RNA in two or more different small RNA samples can be obtained using the above methods, and compared (interpreted as encompassing removing rRNA and Y RNA, claims 1 and 22) (col 12, lines 12-14).
The term “sequence-specific primer” refers to a primer that hybridizes to a unique sequence in mRNA or a target RNA (interpreted as hybridizing DNA probe to rRNA, claim 1) (col 5, lines 65-67).
The initial reverse transcription step can be done using one or more sequence-specific primers (e.g., primers that hybridize to unique sequences in the mRNA and/or short RNAs) (interpreted as DNA probe hybridizing to mRNA) (col 6, lines 63-67).
The combined references of Allen and Huang teach all of the limitations of the claims including hybridizing a DNA probe with RNA including small RNAs such as rRNA. Thus, the claims remain rejected.
Regarding (f), please see the discussion supra regarding the Examiner’s response to Applicant’s arguments. Applicant’s assertion that the cDNA copy disclosed by Allen are different and cannot be interpreted as the DNA probes recited in the claimed method, is not found persuasive. Applicant has not provided any specific argument as to how the cDNA copy of Allen is different from the DNA probe of claim 1, and/or why the cDNA copy of Allen cannot be the DNA probe of claim 1. Allen teaches that the term “cDNA copy” refers to a DNA molecule that has the reverse complement of an RNA molecule, which is hybridized to mRNA (or rRNA as noted supra). Instant claim 1 recites DNA probes that are reverse complementary to rRNAs. Thus, Applicant’s argument is unclear. The claims remain rejected.
Regarding (g), please see the discussion supra regarding the Examiner’s response to Applicant’s arguments. Applicant’s assertion that Allen use RNAseH to prepare the target RNA for cDNA library, which is entirely different from the claimed method of the present application that utilizes RNAseH to remove unwanted RNA from cDNA library, is not found persuasive. Please see the discussion supra regarding that although Allen provides methods regarding the removal of mRNA from total RNA, Allen teaches that the method can be used for the removal of other small RNA such as rRNA (e.g., a non-preferred embodiment). Moreover, the teachings of Allen would have suggested to one of ordinary skill in the art, how to remove other small RNAs including rRNA from total RNA using the same steps. Thus, the claims remain rejected.
Regarding (h), please see the discussion supra regarding the Examiner’s response to Applicant’s arguments. It is noted that instant claim 1 uses the term “comprising”, which is open-ended and does not exclude additional, unrecited elements or method steps. Applicant’s assertion that claim 1 differs from Allen in that claim 1 has a step of adding a 3’ tail to extracted RNA using T4PNK, where Allen never teaches adding a 3’ tail to extracted RNA, or (2) removes rRNA after the step of adding the 5’ adaptor, is not found persuasive. As previously noted, please note that Allen teaches that the steps of ligating and tailing can be carried out in any order. Regarding extracted RNA:
Allen teaches:
The cDNAs that are sequenced can be a pool of nucleic acids extracted from a plurality of sources, such as a pool of nucleic acids from a plurality of organisms (interpreted as extracting RNA).
The fragments can be reverse transcribed by ligating a 5’ adaptor to the fragments, and tailing the 3’ end of the fragments using polyA polymerase (interpreted as ligating and 3’ tailing, claim 1).
Treating DNA:mRNA hybrids with RNaseH to produce mRNA fragments, and reverse transcribing the mRNA fragments (interpreted as removing RNAs and reverse transcription).
Huang teaches:
Re-phosphorylation of RNA at the 5’ end using T4 PNK (interpreted as T4 PNK) (Figure 4.15.2).
Allen teaches all of the limitations of claim 1 including extracting, fragmenting, ligating adaptors, and 3’ tailing, and removing small RNA after tailing. Thus, the method of Allen will inherently provide the same unexpected benefits provided by claim 1. The claims remain rejected.
Regarding (i), please see the discussion supra regarding the Examiner’s response to Applicant’s arguments. As noted in MPEP 716.02(b)(I), the burden is on Applicant to establish that the results are unexpected and significant. Moreover, MPEP 2145 states (in part) that a showing of unexpected results must be based on evidence, not argument or speculation. In re Mayne, 104 F.3d 1339, 1343-44, 41 USPQ2d 1451, 1455-56 (Fed. Cir. 1997) (conclusory statements regarding unusually low immune response or unexpected biological activity that were unsupported by comparative data held insufficient to overcome prima facie case of obviousness). Additionally: MPEP 2145 also states:
Rebuttal evidence may also include evidence that the claimed invention yields unexpectedly improved properties or properties not present in the prior art. Rebuttal evidence may consist of a showing that the claimed compound possesses unexpected properties. Dillon, 919 F.2d at 692-93, 16 USPQ2d at 1901. A showing of unexpected results must be based on evidence, not argument or speculation. In re Mayne, 104 F.3d 1339, 1343-44, 41 USPQ2d 1451, 1455-56 (Fed. Cir. 1997) (underline and italics added).
Additionally, the evidence must be reasonably commensurate in scope with the claimed invention. See, e.g., In re Kulling, 897 F.2d 1147, 1149, 14 USPQ2d 1056, 1058 (Fed. Cir. 1990); In re Grasselli, 713 F.2d 731, 743, 218 USPQ 769, 777 (Fed. Cir. 1983) (underline and italics added).
in order for evidence of secondary considerations to be accorded substantial weight, there must be a nexus, i.e., a legally and factually sufficient connection or correspondence between the submitted evidence and the claimed invention. Fox Factory, Inc. v. SRAM, LLC, 944 F.3d 1366, 1373, 2019 USPQ2d 483355 (Fed. Cir. 2019), cert. denied, 141 S.Ct. 373 (2020). See MPEP § 716.01(b) (underline and italics added).
MPEP 2112.01(II) indicates:
"Products of identical chemical composition cannot have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id. (underline added).
Applicant’s assertion that the inventors unexpectedly found unexpected benefits by adopting the step of removing rRNA after adding a 5’ end adaptor, is not found persuasive. As an initial matter:
Applicant has not pointed to where the “unexpected or superior results” can be found in the as-filed Specification.
No evidence supporting the unexpected results has been provided by Applicant.
Applicant’s has not provided any evidence of improved properties that are reasonably commensurate in scope with the claimed invention.
There is no nexus or co-extensiveness between Applicant’s asserted improvements and the steps as recited in claim 1 including residual rRNA remaining after depletion, downstream library preparation steps, effects on library quality, amount of effective input material, the difference in sizes between target RNA and rRNA, etc.
Evidence has not been provided that the "superior results" asserted by Applicant were unknown in the prior art.
Allen teaches all of the limitations of claim 1 including extracting, fragmenting, ligating adaptors, and 3’ tailing, and removing small RNA after tailing. Thus, the method of Allen will inherently provide the same unexpected benefits provided by claim 1. The claims remain rejected.
New Objections/Rejections
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 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 may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, 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.
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.
(2) Claims 1, 19, 21 and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Shishkin et al. (hereinafter “Shishkin”) (US Patent No. 10612088, issued April 7, 2020; effective filing date March 14, 2014) in view of Krude et al. (hereinafter “Krude”) (Journal of Cell Science, 2009, 12216), 2836-2845) as evidenced by Kowalski et al. (hereinafter “Kowalski”) (The International Journal of Biochemistry & Cell Biology, 2015, 66, 20-29); and Kohn et al. (hereinafter “Kohn”) (Biomolecules, 2013, 3, 143-156). This is a new rejection necessitated by amendment of the claims in the response filed 10-30-2025.
Regarding claim 1, Shishkin teaches a method for parallel sequencing of target RNA from samples from multiple sources while maintaining source identification, where the method includes providing samples of RNA comprising target RNA from two or more sources (interpreted as encompassing total RNA); labeling, at the 3' end, the RNA from the two or more sources with a first nucleic acid adaptor that comprises a nucleic acid sequence that differentiates between the RNA from the two or more sources; reverse transcribing the two or more sources to create a single stranded DNA comprising the nucleic acid sequence that differentiates between the RNA from the two or more sources (interpreted as reverse transcription); amplifying including by PCR amplification of the single stranded DNA to create DNA amplification products that comprise the nucleic acid sequence that differentiates between the RNA from the two or more sources (interpreted as PCR amplification); sequencing the DNA amplification products thereby parallel sequencing target RNA from samples from multiple sources while maintaining source identification (interpreted as sequencing, claim 1(v) and 19) (Abstract; and Figure 1). Shishkin teaches that advantages of the disclosed method over current protocols includes, but is not limited to, a strand-specific sequencing of all classes of RNA from any species including eukaryotes and prokaryotes including total RNA, antibody-selected RNA, 5'-DGE and 3'-DGE selected fragments, polyA-selected RNA, cross-linked RNA fragments from human, bacteria, and fungi; the method allows for sequencing of dozens to several thousands of independent RNA samples simultaneously at very low cost and low time per sample compared to commercial kits (interpreted as encompassing RNA fragments; total RNA; 3’-polyA tailed RNA; and interpreting antibody-selected RNA as extracting total RNA, claim 1(i) and 1(iii)) (col 2, lines 12-22). Shishkin teaches that a biological sample can be a biological fluid obtained from, for example, blood, plasma, serum, urine, bile, ascites, saliva, cerebrospinal fluid, aqueous or vitreous humor, or any bodily secretion, a transudate, an exudate (for example, fluid obtained from an abscess or any other site of infection or inflammation), or fluid obtained from a joint; a sample obtained from any organ or tissue including a biopsy or autopsy specimen or medium conditioned by any cell, tissue or organ (interpreted and encompassing extracting RNA, claim 1(i)) (col 8, lines 27-40). Shishkin teaches using selected RNA or up to 250 ng of total RNA/sample, fragment and dephosphorylate RNA samples with FastAP and PNK (interpreted as fragmenting; and modifying RNA fragments to have a phosphate group at the 5’ end and a hydroxyl group at the 3’ end by treating with PNK, claim 1(ii)) (col 15, lines 12-14). Shishkin teaches binding an oligonucleotide such as a probe or primer to a target nucleic acid, such that the oligonucleotide is hybridized to its target nucleic acid (interpreted as a DNA probe mixture, claim 1) (col 3, lines 45-50). Shishkin teaches that the method has been used in testing hundreds of poly-A selected samples including 5’-DGE and 3’-DGE RNA samples, where PCR enrichment can be carried out on poly-A RNA (interpreting poly-A selected 3’-DGE as 3’ adenylation or tailing of a 3’-DGE adaptor, claim 1(iii)) (col 11, lines 14-16; and col 17, lines 30 and 49-52). Shishkin teaches that the single stranded RNA (such as the target RNA) can be labeled at the 5' end with a second nucleic acid adaptor that comprises a site for binding of a PCR primer (interpreted as ligating an adaptor to the 5’ end, claim 1(iii)) (col 12, lines 3-6). Shishkin teaches that a binding site is a region on a protein, DNA, or RNA to which other molecules stably bind; and capture moieties are molecules or other substances that when attached to a nucleic acid molecule, such as a DNA molecule, allow for the capture of the nucleic acid molecule through interactions of the capture moiety and something that the capture moiety binds to, such as a particular surface and/or molecule, such as a specific binding molecule that is capable of specifically binding to the capture moiety, wherein a capture moiety is a biotin, which can be captured by avidin and or streptavidin and/or the capture moiety is biotin attached to nucleic acid sequence that is used to remove non-target RNA from a sample, such as rRNA (interpreted as encompassing DNA probes that bind a reverse complementary sequence of rRNA; and forming DNA hybrids, claim 1) (col 3, lines 52-65). Shishkin teaches that the sequence 5’-ATCG-3’ is the reverse complement of 3’-TAGC-5’ (interpreted as a reverse complementary sequence of rRNA, claim 1) (col 4, lines 26-27). Shishkin teaches that rRNA depletion works by hybridizing RNA samples to probes antisense to the RNA to be depleted, where the antisense probes include a capture moiety that can be captured by a specific binding agent; and depleting the samples of non-target RNA comprises using one or more probes that specifically hybridize to the nontarget RNA, wherein the one or more probes comprise a label that facilitates removal of the probe from the sample and/or a plurality of probes, wherein probes in the plurality are selected to tile across the sequence of the non-target RNA (interpreted as removing rRNA; DNA probe mixture; and reverse complement, claim 1(iv)) col 12, lines 58-67; and col 13, line 1). Shishkin teaches in Figure 1, in the first step of the disclosed method, RNA is labeled (or barcoded) by attachment, such as ligation, of a 3' adaptor, which is typically coded to the source of the RNA, for example the specific sample; and/or one can perform oligo-based RNA depletion, such as depletion of rRNA, to remove RNA, which can interfere with the method or analysis (interpreted as 3’ adaptor ligation or barcoding) (col 9, lines 21-27; and Figure 1). Shishkin teaches in Example 2, Step A - an RNA depletion protocol including making anti-sense RNA probes using bio-UTP and bio-CTP, wherein the probe generation mix comprises DNA, ATP and UTP, which is incubated with Turbo-DNAse; and Step B - an oligo-based rRNA depletion hybridization using 10 x rRNA probes mix (interpreted as tailing; DNA probe mixture; rRNA depletion; and DNA digestion using DNase, claim 1) (col 18, lines 21-35). Shishkin teaches that the RNA can be degraded from the RNA/cDNA hybrid using NaOH, RNAseH or any other enzymatic or chemical method (interpreted as RNAseH digestion of RNA, claim 1) (col 10, lines 29-31).
Regarding claim 19, Shishkin teaches that Figure 1 is a schematic of an exemplary method of RNA sequencing, comprising: obtaining RNA samples, label target RNA with a 3’ identification tag, non-target depletion, reverse transcription/first strand cDNA synthesis, prepare ssDNA for enrichment, PCR enrichment, and sequencing (interpreted as sequencing the cDNA library, claim 19) (col 2, lines 31-32; and Figure 1).
Regarding claim 21, Shishkin teaches that the sample can be depleted of non-target RNA by using one or more probes that specifically hybridize to the non-target RNA, and wherein one or more probes comprise a label that facilitates removal of the probe from the sample (interpreted as including removal of Y RNA, claim 21) (col 10, lines 54-57). Shishkin teaches that rRNA depletion is very important for quality of sequencing data because rRNAs and regulatory RNAs are responsible for 95% to 98% of sequencing reads, such that any RNA that does not need to be sequenced can be depleted including ribosomal RNAs, tRNAs, regulatory RNAs and introns (interpreting regulatory RNAs and “any RNA that does not need to be sequenced” to encompass Y RNA, claims 21 and 22) (col 12, lines 52-57).
Regarding claim 22, Shishkin teaches that the RNA can be degraded from the RNA/cDNA hybrid using NaOH, RNAseH or any other enzymatic or chemical method (interpreted as RNAseH digestion of RNA, claim 22) (col 10, lines 29-31).
Shishkin does not specifically teach the term Y RNA (instant claim 21, in part).
Regarding claim 21 (in part), Krude teaches that Y RNAs were originally discovered in the early 1980s as an RNA component of Ro ribonucleoprotein particles, detected by sera from patients suffering from systemic lupus erythematosus (pg. 836, col 2, first full paragraph). Krude teaches that in humans, four Y RNAs are expressed including hY1, hY3, hY4 and hY5, and they are present in the soluble cell extracts used in cell-free DNA-replication systems (interpreted as extracting RNA) (pg. 2836, col 2, last full paragraph, lines 1-3). Krude teaches that antisense DNA oligonucleotide treatment depletes the amount of hY3 RNA in human cytosolic extracts by more than 99% (interpreted as Y RNA, claim 21) (pg. 2837, Figure 1), where it is known that small RNA fragments derived from Y RNAs become enriched in apoptotic cell; and these Y-RNA fragments are of clinical interest as potential biomarkers of disease as evidenced by Kowalski (pg. 21, col 2, last partial paragraph; and pg. 22, col 1, first partial paragraph); and it was known that RNA sequencing approaches frequently reported fragments comprising parts of Y RNAs as evidenced by Kohn (pg. 145, last full paragraph). Krude teaches that continuous ribonucleolytic degradation as used in the studies would deplete the targeted Y RNA pools in cell nuclei and cytoplasm, thus inhibiting initiation of DNA replication (pg. 2843, col 1, first partial paragraph).
It is prima facie obvious to combine prior art elements according to known methods to yield predictable results; the court held that, "…a conclusion that a 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 would have yielded nothing more than predictable results to one of ordinary skill in the art. KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 82 USPQ2d 1385, 1395 (2007); Sakraida v. AG Pro, Inc., 425 U.S. 273, 282, 189 USPQ 449, 453 (1976); Anderson’s-Black Rock, Inc. v. Pavement Salvage Co., 396 U.S. 57, 62-63, 163 USPQ 673, 675 (1969); Great Atlantic & P. Tea Co. v. Supermarket Equipment Corp., 340 U.S. 147, 152, 87 USPQ 303, 306 (1950)”. Therefore, in view of the benefits of identifying and detecting Y RNAs as exemplified by Krude, it would have been prima facie obvious before the effective filing date of the claimed invention to modify the method for sequencing preparation of all classes of RNA including mRNA, rRNA, tRNA, regulatory RNAs, etc. from samples from multiple sources; as well as, depleting samples of non-target RNA as disclosed by Shishkin to include the non-coding Y RNAs and/or the method of depleting Y RNA from samples as taught by Krude with a reasonable expectation of success in producing and/or enriching an RNA-seq library; in simultaneously sequencing several thousand independent RNA samples for target RNA from any species, while maintaining source identification; and/or in removing non-coding RNAs such as rRNA and/or Y RNA that can interfere with downstream analysis and/or sequencing.
Thus, in view of the foregoing, the claimed invention, as a whole, would have been obvious to one of ordinary skill in the art at the time the invention was made. Therefore, the claims are properly rejected under 35 USC §103(a) as obvious over the art.
Conclusion
Claims 1, 19, 21 and 22 are rejected.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMY M BUNKER whose telephone number is (313) 446-4833. The examiner can normally be reached on Monday-Friday (6am-2:30pm).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Heather Calamita can be reached on (571) 272-2876. The fax phone number for the organization where this application or proceeding is assigned is (571) 273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/AMY M BUNKER/Primary Examiner, Art Unit 1684