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 .
Status of the Application
Claims 1-32 are pending and under examination
The following Office Action is in response to Applicant's communication dated 05/03/2024.
Priority
Applicant's claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or
under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with
one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. §
112(a) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original non provisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 62/673,023, filed May 17 2018, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. Independent Claims 1, 4, and 5, as well as dependent Claims 2, 3, 6-32 (which include the limitation of "a linear amplification mediator" as present in the independent claims) which are not literally or descriptively supported by the earlier US provisional application as filed.
A review of application 62/673,023 shows that while it describes use of in vitro transcription (IVT) to generate "linear amplified single-stranded RNA molecules downstream of the T7 promoter" (page 9, lines 4-5), this disclosure fails to provide sufficient support for the full range of "linear amplification mediator" to constitute an adequate written description of the pending claims containing these limitations. (See also "linear amplification via transposon insertion ("LIANTI")" on page 41, first ¶; "linear amplification via T7-based transcription provides a potential solution Chenet al. developed Linear Amplification via Transposon Insertion ("LIANTI")" on page 43, last¶; and "linear amplification by in vitro transcription" (italics in original) on page 81, bottom, for additional examples of the insufficient description.
The limited disclosure of linear amplification via transposon mediated insertion of T7 promoters followed by use of T7 RNA polymerase to generate transcripts in a linear fashion does not adequately support the much broader genus of "linear amplification mediator", which includes other, distinct components for other methods of linear amplification (like those included on page 43, , ¶00123 of the instant application).
In light of the above, the effective filing date for Claims 1-32 is March 21, 2019, the filing date of provisional application 62/821,864, to which the instant application claims benefit of priority.
Drawings
The drawings are objected to because the specification refers to Fig. 1C; however, Fig. 1C is not included in the drawing file. Corrected drawing sheets in compliance with 37 CFR 1.121(d) 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. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. 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 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.
Claim(s) 21, 22, and 31 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 21 and 22 recite “the first index sequence added to DNA”. However, claim 19, from which claims 21 and 22 depend, recites only “adding a first index sequence to RNA nucleic acids” and does not recite adding first index to DNA. Although claim 18 alternative recites “adding a first index to DNA nucleic acids present in the isolated nuclei or cells, a first index to RNA nucleic acids present in the isolated nuclei or cells, or a combination thereof.”, claim 19 does not clearly require selection of combination alternative. Hence, it is unclear what previously recited DNA index sequence is being referred to in claims 21 and 22, and whether both claims require both DNA and RNA index sequences.
Claim 31 recites “each compartment of the second plurality of compartments”. However, claim 1, from which claims 31 depend, recites only recites a “ first plurality of compartments” and does not introduce a second plurality of compartments. The second compartments limitation is recited in claim 24, from which claim 31 does not depend.
For purposes of examination only, and to facilitate a complete analysis of the claim, the Examiner interprets claim 31 to depend on claim 24 instead of claim 1, which is consistent with workflow shown in Fig 3A of Applicant’s specification and consistent with antecedent basis. This interpretation is adopted solely for examination and does not resolve the lack of clarity in the claim language.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 3-6, 8-21, 23-24, and 29-32 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Adey et al. (US 2018/0023119 Al, published 1/25/2018, disclosed in IDS).
In the interested of clarity of the record, Claim 1 as presented is interpreted as having the 5 steps of "providing", "introducing", "amplifying", "processing", and "combining". The 5 steps may be "conducted in any feasible order" as stated in Applicant’s specification [¶0048], of the instant specification, which is supported by Claim 3, where the step of "processing" occurs before "amplifying" (and without limitation on whether "amplifying" may occur after "combining"). Claim 1 is additionally interpreted as encompassing the combination of steps, such as the combination of the "providing" and "processing" steps (with a permitted reordering of the steps per ¶0048) and/or the "introducing" and "amplifying" steps, based on the admission that "as appropriate, any combination of two or more steps may be conducted simultaneously" ¶0048. A combination of the "providing" and "processing" steps is further consistent with the specification ¶0107, which states "[i]n one embodiment, addition of an index (corresponding to "processing" in Claim 1) is achieved during the processing of nucleic acids into nucleic acid fragments (corresponding to "providing" in Claim 1)."
Regarding claim 1, Adey discloses method comprising: providing a plurality of isolated nuclei or cells in a first plurality of compartments, wherein each compartment comprises a subset of isolated nuclei or cells, and wherein nuclei or cells comprise nucleic acid fragments; (e.g. providing isolated nuclei from a plurality of cells; distributing subsets of the nuclei into a first plurality of compartments; fragmenting nucleic acids in the subsets of nucleosome-depleted nuclei into a plurality of nucleic acid fragments [¶0007])
processing each subset of nuclei or cells to generate indexed nuclei or cells, wherein the processing comprises adding to nucleic acid fragments present in the isolated nuclei or cells a first compartment specific index sequence to result in indexed nucleic acids present in isolated nuclei or cells, wherein the processing comprises ligation, primer extension, hybridization, amplification, or transposition; (e.g. contacting each subset with a transposome complex, where the transposome complex in each compartment includes a transposase and a first index sequence that is different from first index sequences in the other compartments [¶0007])
combining the indexed nuclei or cells to generate pooled indexed nuclei or cells, thereby producing a sequencing library from the plurality of nuclei or cells. (e.g. combining the indexed nuclei to generate pooled indexed nuclei [¶0007])
introducing a linear amplification mediator to the cells or nuclei; amplifying the nucleic acid fragments by linear amplification; (e.g. "index fragments by PCR" [Figure 1, step 17] where amplification includes linear replication of a nucleic acid molecule. Amplification conditions include a catalyst for amplification or for nucleic acid synthesis: polymerase, primers, nucleic acid to be amplified; and nucleotides [¶0071-0072]).
Regarding claim 3, Adey discloses the processing occurs before the amplifying as explained above.
Regarding claims 6 and 8, Adey discloses linear amplification mediator comprises adding to nucleic acid fragments present in the isolated nuclei or cells the linear amplification mediator; wherein linear amplification mediator comprises linear amplification primer; (e.g. both linear and exponential replication of nucleic acids, then mention amplification conditions include a catalyst for amplification or for nucleic acid synthesis: polymerase, primers, nucleic acid to be amplified; and nucleotides [¶0072]).
Regarding claim 9, Adey discloses exposing the plurality of isolated nuclei or cells of each compartment to a predetermined condition (e.g. subjecting the isolated nuclei to a chemical treatment to generate nucleosome-depleted nuclei while maintaining integrity of the isolated nuclei; and distributing subsets of the pooled indexed nuclei into a second plurality of compartments for second index sequence incorporation [¶0007])
Regarding claim 10, Adey discloses isolating nuclei from the plurality of cells after the exposing. (e.g. isolate single nuclei after treatment with transposase [¶0051])
Regarding claim 12, Adey discloses subjecting the isolated nuclei to conditions to generate nucleosome-depleted nuclei while maintaining integrity of the isolated nuclei. (e.g. subjecting the isolated nuclei to a chemical treatment to generate nucleosome-depleted nuclei while maintaining integrity of the isolated nuclei [¶0007])
Regarding claims 13, 18, and 20, Adey discloses contacting each subset with a transposome complex, wherein the transposome complex in each compartment comprises the first index sequence that is different from first index sequences in the other compartments; and fragmenting nucleic acids in the subsets into a plurality of nucleic acids and incorporating the first index sequences into at least one strand of the nucleic acids to generate the indexed nuclei or cells comprising the indexed nucleic acids. (e.g. contacting each subset with a transposome complex, where the transposome complex in each compartment includes a transposase and a first index sequence that is different from first index sequences in the other compartments; fragmenting nucleic acids in the subsets of nucleosome-depleted nuclei into a plurality of nucleic acid fragments and incorporating the first index sequences into at least one strand of the nucleic acid fragments to generate indexed nuclei that include indexed nucleic acid fragments [¶0007])
Regarding claims 14 and 15, Adey discloses contacting each subset with reverse transcriptase and a target specific primer that anneals to a specific RNA molecules in the isolated nuclei, wherein the primer in each compartment comprises the first index sequence that is different from first index sequences in the other compartments to generate the indexed nuclei or cells comprising the indexed nucleic acids. (e.g. Primer are any nucleic acid that can hybridize to a target sequence of interest. The term can encompass cDNA, that is complementary or copy DNA produced from an RNA template, for example by the action of reverse transcriptase. The primer may comprise tag or index sequence [¶0067-0068]. Index sequence varies between compartments [¶0119]).
Regarding claims 16 and 17, Adey discloses the processing to add the first compartment specific index sequence comprises a twostep process of adding a nucleotide sequence comprising a universal sequence to the nucleic acid fragments and then adding the first compartment specific index sequence to the nucleic acid fragments, wherein the adding comprises a transposome complex that comprises the universal sequence. (e.g. In one embodiment, each of the transposome complexes includes a transposon, and each of the transposons includes a transferred strand. The transferred strand includes the first index sequence and a first universal sequence. The incorporation of the second index sequence into the indexed nucleic acid fragments includes contacting the indexed nucleic acid fragments in each compartment with a first universal primer and a second universal primer, each including an index sequence and each including a sequence identical to or complementary to a portion of the first universal sequence, and performing an exponential amplification reaction. [0013-0014])
Regarding claims 19 and 21, Adey discloses the adding a first index sequence to RNA nucleic acids comprises: contacting each subset with a reverse transcriptase and a primer that anneals to RNA molecules in the isolated nuclei or cells, wherein the primer in each compartment comprises the first compartment specific index sequence to generate the indexed nuclei or cells comprising the indexed nucleic acids. (e.g. Primer are any nucleic acid that can hybridize to a target sequence of interest. The term can encompass cDNA, that is complementary or copy DNA produced from an RNA template, for example by the action of reverse transcriptase. The primer may comprise tag or index sequence [¶0067-0068]. Index sequence varies between compartments [¶0119]. The primer used by reverse transcriptase is DNA by nature, and can anneal to complementary DNA sequences within the nuclei to add the same first compartment specific index sequence to a DNA of interest molecule.).
Regarding claim 23, Adey discloses an exponential amplification of the nucleic acid fragments, wherein the exponential amplification comprises a target specific primer that anneals to a specific nucleotide sequence. (e.g. amplification can be exponential [¶0072]. This process for amplifying the polynucleotide of interest consists of introducing a large excess of two oligonucleotide primers to the DNA mixture containing the desired polynucleotide of interest, followed by a series of thermal cycling in the presence of a DNA polymerase. The two primers are complementary to their respective strands of the double stranded polynucleotide of interest. [¶0074])
Regarding claim 24, Adey discloses distributing subsets of the pooled indexed nuclei or cells into a second plurality of compartments; and introducing a second compartment specific index sequence to indexed nucleic acids to generate dual-indexed nuclei or cells comprising dual-indexed nucleic acids, wherein the introducing comprises ligation, primer extension, amplification, or transposition. (e.g. distributing subsets of the pooled indexed nuclei into a second plurality of compartments; incorporating into the indexed nucleic acid fragments in each compartment a second index sequence to generate dual-index fragments [¶0007], wherein the introducing comprises primer extension [¶0014])
Regarding claim 29, Adey discloses the compartment comprises a well or a droplet [¶0060].
Regarding claims 30 and 31, Adey discloses each compartment of the first plurality of compartments comprises from 50 to 100,000,000 nuclei or cells. (e.g. method provided herein includes distributing subsets of the nucleosome-depleted nuclei into a first plurality of compartments, wherein the number of nuclei present in a subset can be 1,000 to 10,000, 10,000 to 100,000, or 100,000 to 1,000,000 [¶0105]).
Regarding claim 32, Adey discloses providing a surface comprising a plurality of amplification sites, wherein the amplification sites comprise at least two populations of attached single stranded capture oligonucleotides having a free 3′ end, and contacting the surface comprising amplification sites with the indexed fragments under conditions suitable to produce a plurality of amplification sites that each comprise a clonal population of amplicons from an individual fragment comprising a plurality of indexes. (e.g. the method can include providing a surface that includes a plurality of amplification sites, where the amplification sites include at least two populations of attached single stranded capture oligonucleotides having a free 3′ end, and contacting the surface that includes amplification sites with the dual-index fragments under conditions suitable to produce a plurality of amplification sites that each include a clonal population of amplicons from an individual dual-index fragment. [¶0016)]
In the interested of clarity of the record, Claim 4 as presented is interpreted as having the 6 steps of "providing", "introducing", “distributing”, "amplifying", "processing", and "combining". The 6 steps may be "conducted in any feasible order" as stated in Applicant’s specification [¶0048], of the instant specification, where the step of "processing" occurs before "amplifying", and wherein the step of "introducing" occurs after both "distributing" and "processing". In addition, claim 4 is interpreted as encompassing the combination of steps, such as the combination of the "providing" and "processing" steps (with a permitted reordering of the steps per ¶0048) and/or the "introducing" and "amplifying" steps, based on the admission that "as appropriate, any combination of two or more steps may be conducted simultaneously" ¶0048. A combination of the "providing" and "processing" steps is further consistent with the specification ¶0107, which states "[i]n one embodiment, addition of an index (corresponding to "processing" in Claim 4) is achieved during the processing of nucleic acids into nucleic acid fragments (corresponding to "providing" in Claim 4)."
Regarding claim 4, , Adey discloses method for preparing a sequencing library comprising: providing a plurality of isolated nuclei or cells, wherein nuclei or cells comprise nucleic acid fragments; distributing the isolated nuclei or cells into a first plurality of compartments, wherein each compartment comprises a subset of isolated nuclei or cells; (e.g. providing isolated nuclei from a plurality of cells; distributing subsets of the nuclei into a first plurality of compartments; fragmenting nucleic acids in the subsets of nucleosome-depleted nuclei into a plurality of nucleic acid fragments and incorporating the first index sequences into at least one strand of the nucleic acid fragments [¶0007])
processing each subset of isolated nuclei or cells to generate indexed nuclei or cells, wherein the processing comprises adding to nucleic acid fragments present in the isolated nuclei or cells a first compartment specific index sequence to result in indexed nucleic acids present in isolated nuclei or cells, wherein the processing comprises ligation, primer extension, amplification, or transposition; (e.g. contacting each subset with a transposome complex, where the transposome complex in each compartment includes a transposase and a first index sequence that is different from first index sequences in the other compartments [¶0007])
combining the indexed nuclei or cells to generate pooled indexed nuclei or cells, thereby producing a sequencing library from the plurality of nuclei or cells. (e.g. combining the indexed nuclei to generate pooled indexed nuclei [¶0007])
introducing a linear amplification mediator to the isolated nuclei or cells; amplifying the nucleic acid fragments by linear amplification; (e.g. "index fragments by PCR" [Figure 1, step 17] where amplification includes linear replication of a nucleic acid molecule. Amplification conditions include a catalyst for amplification or for nucleic acid synthesis: polymerase, primers, nucleic acid to be amplified; and nucleotides [¶0071-0072]).
Regarding claim 11, , Adey discloses exposing the plurality of isolated nuclei or cells to a predetermined condition. (e.g. subjecting the isolated nuclei to a chemical treatment to generate nucleosome-depleted nuclei while maintaining integrity of the isolated nuclei; and distributing subsets of the pooled indexed nuclei into a second plurality of compartments for second index sequence incorporation [¶0007]).
In the interested of clarity of the record, Claim 5 as presented is interpreted as having the 5 steps of "providing", "processing", "introducing", "amplifying", and "combining". and the claim is interpreted as encompassing the combination of steps, such as the combination of the "providing" and "processing" steps and/or the "introducing" and "amplifying" steps, based on the admission that "as appropriate, any combination of two or more steps may be conducted simultaneously" ¶0048. A combination of the "providing" and "processing" steps is further consistent with the specification ¶0107, which states "[i]n one embodiment, addition of an index (corresponding to "processing" in Claim 5) is achieved during the processing of nucleic acids into nucleic acid fragments (corresponding to "providing" in Claim 5)."
Regarding claim 5, , Adey discloses method for preparing a sequencing library comprising:
providing a plurality of isolated nuclei or cells in a first plurality of compartments, wherein each compartment comprises a subset of isolated nuclei or cells, and wherein nuclei or cells comprise nucleic acid fragments; (e.g. providing isolated nuclei from a plurality of cells; distributing subsets of the nuclei into a first plurality of compartments; fragmenting nucleic acids in the subsets of nucleosome-depleted nuclei into a plurality of nucleic acid fragments [¶0007])
processing each subset of nuclei or cells to generate indexed nuclei or cells, wherein the processing comprises adding to nucleic acid fragments present in the isolated nuclei or cells (i) a first compartment specific index sequence to result in indexed nucleic acids present in isolated nuclei or cells and (ii) a nucleotide sequence recognized by a linear amplification mediator, wherein the processing comprises ligation, primer extension, hybridization, amplification, or transposition; (e.g. contacting each subset with a transposome complex, where the transposome complex in each compartment includes a transposase and a first index sequence that is different from first index sequences in the other compartments; fragmenting nucleic acids in the subsets of nucleosome-depleted nuclei into a plurality of nucleic acid fragments and incorporating the first index sequences into at least one strand of the nucleic acid fragments to generate indexed nuclei that include indexed nucleic acid fragments [¶0007]. Each of the transposome complexes comprises a transferred strand, which may further comprise universal sequence [0013].)
combining the indexed nuclei or cells to generate pooled indexed nuclei or cells, thereby producing a sequencing library from the plurality of nuclei or cells. (e.g. combining the indexed nuclei to generate pooled indexed nuclei [¶0007])
introducing a linear amplification mediator to the cells or nuclei; amplifying the nucleic acid fragments by linear amplification; (e.g. "index fragments by PCR" [Figure 1, step 17] where amplification includes linear replication of a nucleic acid molecule. Amplification conditions include a catalyst for amplification or for nucleic acid synthesis: polymerase, primers, nucleic acid to be amplified; and nucleotides [¶0071-0072]).
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.
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.
Adey et al.
Claims 22 are rejected under 35 U.S.C. 103 as being unpatentable over Adey et al. (US 2018/0023119Al, published 1/25/2018, disclosed in IDS)
Regarding claim 22, Adey does not explicitly disclose the first index sequence added to DNA nucleic acids and the first index sequence added to RNA nucleic acids in each compartment are not identical. Adey discloses addition of a first index sequence to the cDNA as explained above for Claim 19, which may occur prior to the addition of a first index sequence by use of a transposase complex (per Applicant’s specification ¶0048 steps may be "conducted in any feasible order"). One of ordinary skill in the art would have understood that different index sequences may be used by transposase complex to identify sequences from RNA versus those from DNA. Additionally, Adey discloses secondary amplification need not be identical to the first amplification (e.g. different target-specific primers) [¶0073]. A skilled artisan would have understood that second amplification may be utilized for DNA fragment amplification. As of the application’ s effective filing date, it would have been prima facie obvious to a person of ordinary skill in the art to use different index sequences to differentiate DNA and RNA genetic information origin.
Adey et al. and Hashimshony et al.
Claims 1, 2, 6-9, 12, 13, 16-20, 23, 24 and 29-32 are rejected under 35 U.S.C. 103 as being unpatentable over Adey et al. (US 2018/0023119Al, published 1/25/2018, disclosed in IDS) in view of Hashimshony et al. (Cell Rep. 2012;2(3):666-673, Disclosed in IDS).
In the interested of clarity of the record, Claim 1 as presented is interpreted as having the 5 steps of "providing", "introducing", "amplifying", "processing", and "combining". While the 5 steps may be "conducted in any feasible order" as stated in Applicant’s specification [¶0048], Claim 1 is interpreted as encompassing the 5 steps in the order presented as addressed hereafter. This interpretation is consistent with Claim 2, which requires that the step of "amplifying" occur before the step of "processing".
Regarding claim 1, 2, and 6-8, Adey discloses method comprising: providing a plurality of isolated nuclei or cells in a first plurality of compartments, wherein each compartment comprises a subset of isolated nuclei or cells, and wherein nuclei or cells comprise nucleic acid fragments; (e.g. providing isolated nuclei from a plurality of cells; distributing subsets of the nuclei into a first plurality of compartments; fragmenting nucleic acids in the subsets of nucleosome-depleted nuclei into a plurality of nucleic acid fragments [¶0007])
processing each subset of nuclei or cells to generate indexed nuclei or cells, wherein the processing comprises adding to nucleic acid fragments present in the isolated nuclei or cells a first compartment specific index sequence to result in indexed nucleic acids present in isolated nuclei or cells, wherein the processing comprises ligation, primer extension, hybridization, amplification, or transposition; (e.g. contacting each subset with a transposome complex, where the transposome complex in each compartment includes a transposase and a first index sequence that is different from first index sequences in the other compartments [¶0007])
combining the indexed nuclei or cells to generate pooled indexed nuclei or cells, thereby producing a sequencing library from the plurality of nuclei or cells. (e.g. combining the indexed nuclei to generate pooled indexed nuclei [¶0007])
Additionally, Adey et al. further teach their methods with use of targets obtained from a primary RNA sample by reverse transcription into cDNA [¶0064].
Adey does not expressly teach the amplifying of fragments, and thus nuclei, prior to the step of "processing". And Adey does not teach the amplification comprises nucleic acid fragments with T7 promoter and linear amplification mediator include T7 RNA polymerase.
Hashimshony discloses a method that linearly amplifies mRNA in isolated cells with the use of in vitro transcription by addition of a linear amplification primer containing a T7 promoter and the use of T7 RNA polymerase [Abstract, page 667, Figure 1A].
As of the application’ s effective filing date, it would have been prima facie obvious to a person of ordinary skill in the art to modify the methods of Adey et al. to treat their isolated nuclei using the reverse transcription and linear amplification (in vitro transcription) followed by conversion to double stranded DNA, as taught by Hashimshony, that is then processed with transposase complex mediated addition of an index sequence and combination into pooled nuclei, with the reasonable expectation of successfully improving the methods by being able to target mRNA sequences and enrich them prior to addition of index sequences and subsequent sequence analysis. Additional motivation for the modification is provided by recognition that linear amplification can provide higher fidelity than exponential amplification. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (MPEP § 2143).
Regarding claim 9, Hashimshony discloses exposing the plurality of isolated nuclei or cells of each compartment to a predetermined condition. (e.g. single cells are added to tubes, each with a uniquely bar-coded primer for reverse transcription. [Fig 1A])
Regarding claim 12, Adey discloses subjecting the isolated nuclei to conditions to generate nucleosome-depleted nuclei while maintaining integrity of the isolated nuclei. (e.g. subjecting the isolated nuclei to a chemical treatment to generate nucleosome-depleted nuclei while maintaining integrity of the isolated nuclei [¶0007]).
Regarding claims 13, 18 and 20, Adey discloses contacting each subset with a transposome complex, wherein the transposome complex in each compartment comprises the first index sequence that is different from first index sequences in the other compartments; and fragmenting nucleic acids in the subsets into a plurality of nucleic acids and incorporating the first index sequences into at least one strand of the nucleic acids to generate the indexed nuclei or cells comprising the indexed nucleic acids.
Regarding claims 19, Hashimshony discloses adding a index sequence to RNA nucleic acids comprises: contacting each subset with a reverse transcriptase and a primer that anneals to RNA molecules in the isolated nuclei or cells, wherein the primer in each compartment comprises the first compartment specific index sequence to generate the indexed nuclei or cells comprising the indexed nucleic acids. (e.g. single-cell reverse-transcription reaction using a primer designed with an anchored polyT, a unique barcode, the 5′ Illumina sequencing adaptor, and a T7 promoter [Fig. 1A])
Regarding claims 16 and 17, Adey discloses the processing to add the first compartment specific index sequence comprises a twostep process of adding a nucleotide sequence comprising a universal sequence to the nucleic acid fragments and then adding the first compartment specific index sequence to the nucleic acid fragments, wherein the adding comprises a transposome complex that comprises the universal sequence. (e.g. In one embodiment, each of the transposome complexes includes a transposon, and each of the transposons includes a transferred strand. The transferred strand includes the first index sequence and a first universal sequence. The incorporation of the second index sequence into the indexed nucleic acid fragments includes contacting the indexed nucleic acid fragments in each compartment with a first universal primer and a second universal primer, each including an index sequence and each including a sequence identical to or complementary to a portion of the first universal sequence, and performing an exponential amplification reaction. [0013-0014])
Regarding claim 23, Adey discloses an exponential amplification of the nucleic acid fragments, wherein the exponential amplification comprises a target specific primer that anneals to a specific nucleotide sequence. (e.g. amplification can be exponential [¶0072]. This process for amplifying the polynucleotide of interest consists of introducing a large excess of two oligonucleotide primers to the DNA mixture containing the desired polynucleotide of interest, followed by a series of thermal cycling in the presence of a DNA polymerase. The two primers are complementary to their respective strands of the double stranded polynucleotide of interest. [¶0074])
Regarding claim 24, Adey discloses distributing subsets of the pooled indexed nuclei or cells into a second plurality of compartments; and introducing a second compartment specific index sequence to indexed nucleic acids to generate dual-indexed nuclei or cells comprising dual-indexed nucleic acids, wherein the introducing comprises ligation, primer extension, amplification, or transposition. (e.g. distributing subsets of the pooled indexed nuclei into a second plurality of compartments; incorporating into the indexed nucleic acid fragments in each compartment a second index sequence to generate dual-index fragments [¶0007], wherein the introducing comprises primer extension [¶0014])
Regarding claim 29, Adey discloses the compartment comprises a well or a droplet [¶0060].
Regarding claims 30 and 31, Adey discloses each compartment of the first plurality of compartments comprises from 50 to 100,000,000 nuclei or cells. (e.g. method provided herein includes distributing subsets of the nucleosome-depleted nuclei into a first plurality of compartments, wherein the number of nuclei present in a subset can be 1,000 to 10,000, 10,000 to 100,000, or 100,000 to 1,000,000 [¶0105]).
Regarding claim 32, Adey discloses providing a surface comprising a plurality of amplification sites, wherein the amplification sites comprise at least two populations of attached single stranded capture oligonucleotides having a free 3′ end, and contacting the surface comprising amplification sites with the indexed fragments under conditions suitable to produce a plurality of amplification sites that each comprise a clonal population of amplicons from an individual fragment comprising a plurality of indexes. (e.g. the method can include providing a surface that includes a plurality of amplification sites, where the amplification sites include at least two populations of attached single stranded capture oligonucleotides having a free 3′ end, and contacting the surface that includes amplification sites with the dual-index fragments under conditions suitable to produce a plurality of amplification sites that each include a clonal population of amplicons from an individual dual-index fragment. [¶0016)]
Adey et al., Hashimshony et al., and Gunderson et al.
Claims 25 is rejected under 35 U.S.C. 103 as being unpatentable over Adey et al. (US 2018/0023119Al, published 1/25/2018, disclosed in IDS) in view of Hashimshony et al. (Cell Rep. 2012;2(3):666-673, Disclosed in IDS) and Gunderson et al. (US 20180273933 Al, published September 27th 2018, disclosed in IDS)
Regarding claim 25, Adey and Hashimshony do not teach addition of a third index to dual indexed nuclei.
Gunderson discloses a schematic of a four tier combinatoric indexing of DNA in of single cell to attach compartment-specific indexes via repeated rounds of ligation, polymerase extension, tagmentation. [¶0004 and Fig. 1]
As of the application’ s effective filing date, it would have been prima facie obvious to a person of ordinary skill in the art to modify Adey’s method in view of Hashimshony et al. to further incorporate a third or additional index, in a manner as taught by Gunderson, such as by use of a third plurality of compartments after the second plurality taught by Adey et al., with the reasonable expectation of successfully improving the methods by being able to better ensure a unique identifier (in the form of three index sequences via combinatorial indexing) to aid subsequent sequence analysis. Additionally. Gunderson mentions that such indexing enables haplotype information to be obtained at higher concentrations of nucleic acid compared to the mere dilution of a nucleic acid in a single compartment to an amount equivalent to a haplotype of the nucleic acid [¶0019].
Adey et al., Hashimshony et al., and Gravina et al.
Claims 26 is rejected under 35 U.S.C. 103 as being unpatentable over Adey et al. (US 2018/0023119Al, published 1/25/2018, disclosed in IDS) in view of Hashimshony et al. (Cell Rep. 2012;2(3):666-673, Disclosed in IDS) and Gravina et al. (Nucleic Acids Res. 2015;43(14), disclosed in IDS)
Regarding claim 26, Adey and Hashimshony do not teach treating the indexed nuclei or cells for methylation analysis to generate nucleic acid fragments suitable for methylation analysis.
Gravina discloses treatment of single cells, and the nuclei therein, to cause bisulfite conversion for sequencing based analysis of DNA methylation patterns [Abstract and page 2].
As of the application’ s effective filing date, it would have been prima facie obvious to a person of ordinary skill in the art to modify the methods of Adey in view of Hashimshony to further incorporate a Gravina’s treatment with the reasonable expectation of successfully improving the methods by broadening them to include sequencing based analysis of DNA methylation patterns [Gravina’s Abstract]. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (MPEP § 2143)
Adey et al., Hashimshony et al., and Ramani et al.
Claims 27 is rejected under 35 U.S.C. 103 as being unpatentable over Adey et al. (US 2018/0023119Al, published 1/25/2018, disclosed in IDS) in view of Ramani et al. (Cell Rep. 2012;2(3):666-673, Disclosed in IDS) and Ramani et al. (Nucleic Acids Res. 2015;43(14), Disclosed in IDS)
Regarding claim 27, Adey and Hashimshony do not teach subjecting the indexed nuclei or cells to proximity ligation to generate nucleic acid fragments for analysis of chromatin conformation.
Ramani discloses single-cell combinatorial indexed Hi-C (sciHi-C), which applies the concept of combinatorial cellular indexing to chromosome conformation capture. The method comprises the steps of nucleus fixation and in situ digestion, first-round barcoding via bridge adapters, proximity ligation, and second-round indexing during library preparation [Fig 1A].
As of the application’ s effective filing date, it would have been prima facie obvious to a person of ordinary skill in the art to modify the methods of Adey in view of Hashimshony to further incorporate proximity ligation to measure local protein-protein, RNA-RNA, and DNA-DNA interactions, allowing one is able to query relative contact probabilities genome-wide [page 2]. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (MPEP § 2143).
Adey et al., Hashimshony et al., and Drmanac et al.
Claims 28 is rejected under 35 U.S.C. 103 as being unpatentable over Adey et al. (US 2018/0023119Al, published 1/25/2018, disclosed in IDS) in view of Ramani et al. (Cell Rep. 2012;2(3):666-673, Disclosed in IDS) and Drmanac et al. (Science 327,78-81(2010), Disclosed in IDS)
Regarding claim 28, Adey and Hashimshony do not disclose amplifying the nucleic acid fragments of the sequencing library to produce DNA nanoballs.
Drmana discloses a genome sequencing platform that achieves efficient imaging and low reagent consumption with combinatorial probe anchor ligation chemistry to independently assay each base from patterned nanoarrays of self-assembling DNA nanoballs [Abstract].
As of the application’ s effective filing date, it would have been prima facie obvious to a person of ordinary skill in the art to modify the methods of Adey in view of Hashimshony to further incorporate rolling-circle replication, producing DNA nanoballs, because this amplification method is disclosed to increase DNA read length, produce higher DNA content per array and image information density relative to random genomic DNA arrays [Drmanac, Page 78]. Additionally, the method of amplification is high accuracy and affordable [Drmanac, Abstract].
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.
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U.S. 11,981,891 B2
Claim 1, 3-7, 9, 11-12, 14-15, 18-32 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5-16, and 20 of U.S. Patent No. 11981891 B2 (the '891 patent). Although the claims at issue are not identical, they are not patentably distinct from each other because the rejected claims of the present invention would be anticipated and/or rendered obvious by the subject matter in the claims of the reference patent.
Claim 1 as presented is interpreted as having the 5 steps of "providing", "introducing", "amplifying", "processing", and "combining". The 5 steps may be "conducted in any feasible order" as stated in Applicant’s specification [¶0048].
Regarding present claim(s) 1 and 3, the claim of the '891 patent discloses method for preparing a sequencing library comprising nucleic acids from a plurality of single nuclei or cells, the method comprising: providing a plurality of isolated nuclei or cells in a first plurality of compartments, wherein each compartment comprises a subset of isolated nuclei or cells, and wherein nuclei or cells comprise nucleic acid fragments; introducing a linear amplification mediator to the cells or nuclei; amplifying the nucleic acid fragments by linear amplification; processing each subset of nuclei or cells to generate indexed nuclei or cells, wherein the processing comprises adding to nucleic acid fragments present in the isolated nuclei or cells a first compartment specific index sequence to result in indexed nucleic acids present in isolated nuclei or cells, wherein the processing comprises ligation, primer extension, hybridization, amplification, or transposition; combining the indexed nuclei or cells to generate pooled indexed nuclei or cells, thereby producing a sequencing library from the plurality of nuclei or cells. (e.g. as per claim(s) 1, 2 of the '891 patent)
Claim 4 as presented is interpreted as having the 6 steps of "providing", "introducing", “distributing”, "amplifying", "processing", and "combining". The 6 steps may be "conducted in any feasible order" as stated in Applicant’s specification [¶0048]
Regarding present claim(s) 4, the claim of the '891 patent discloses method for preparing a sequencing library comprising nucleic acids from a plurality of single nuclei or cells, the method comprising: providing a plurality of isolated nuclei or cells, wherein nuclei or cells comprise nucleic acid fragments; introducing a linear amplification mediator to the isolated nuclei or cells; distributing the isolated nuclei or cells into a first plurality of compartments, wherein each compartment comprises a subset of isolated nuclei or cells; amplifying the nucleic acid fragments by linear amplification; processing each subset of isolated nuclei or cells to generate indexed nuclei or cells, wherein the processing comprises adding to nucleic acid fragments present in the isolated nuclei or cells a first compartment specific index sequence to result in indexed nucleic acids present in isolated nuclei or cells, wherein the processing comprises ligation, primer extension, amplification, or transposition; combining the indexed nuclei to generate pooled indexed nuclei or cells, thereby producing a sequencing library from the plurality of nuclei or cells. (e.g. as per claim(s) 1 of the '891 patent)
Claim 5 as presented is interpreted as having the 5 steps of "providing", "processing", "introducing", "amplifying", and "combining". The 5 steps may be "conducted in any feasible order" as stated in Applicant’s specification [¶0048]
Regarding present claim(s) 5, the claim of the '891 patent discloses method for preparing a sequencing library comprising nucleic acids from a plurality of single nuclei or cells, the method comprising: providing a plurality of isolated nuclei or cells in a first plurality of compartments, wherein each compartment comprises a subset of isolated nuclei or cells, and wherein nuclei or cells comprise nucleic acid fragments; processing each subset of nuclei or cells to generate indexed nuclei or cells, wherein the processing comprises adding to nucleic acid fragments present in the isolated nuclei or cells (i) a first compartment specific index sequence to result in indexed nucleic acids present in isolated nuclei or cells and (ii) a nucleotide sequence recognized by a linear amplification mediator, wherein the processing comprises ligation, primer extension, hybridization, amplification, or transposition; introducing a linear amplification mediator to the cells or nuclei; amplifying the nucleic acid fragments by linear amplification; combining the indexed nuclei or cells to generate pooled indexed nuclei or cells, thereby producing a sequencing library from the plurality of nuclei or cells. (e.g. as per claim(s) 1 of the '891 patent)
Regarding present claim(s) 6, the claim of the '891 patent discloses the linear amplification mediator comprises a phage RNA polymerase or a linear amplification primer. (e.g. as per claim(s) 2 and 20 of the '891 patent)
Regarding present claim(s) 7, the claim of the '891 patent discloses the nucleic acid fragments comprise a T7 promoter and the phage RNA polymerase comprises a T7 RNA polymerase (e.g. as per claim(s) 3 of the '891 patent)
Regarding present claim(s) 9, the claim of the '891 patent discloses introducing the linear amplification mediator comprises adding to nucleic acid fragments present in the isolated nuclei or cells the linear amplification mediator. (e.g. as per claim(s) 5 of the '891 patent)
Regarding present claim(s) 11, the claim of the '891 patent discloses exposing the plurality of isolated nuclei or cells to a predetermined condition. (e.g. as per claim(s) 5 of the '891 patent)
Regarding present claim(s) 12, the claim of the '891 patent discloses subjecting the isolated nuclei to conditions to generate nucleosome-depleted nuclei while maintaining integrity of the isolated nuclei. (e.g. as per claim(s) 6 of the '891 patent)
Regarding present claim(s) 14, the claim of the '891 patent discloses the processing comprises: contacting each subset with reverse transcriptase and a primer that anneals to RNA molecules in the isolated nuclei, wherein the primer in each compartment comprises the first index sequence that is different from first index sequences in the other compartments to generate the indexed nuclei or cells comprising the indexed nucleic acids. (e.g. as per claim(s) 1 and 7 of the '891 patent)
Regarding present claim(s) 15, the claim of the '891 patent discloses the contacting further comprises a target specific primer that anneals to a specific nucleotide sequence. (e.g. as per claim(s) 8 of the '891 patent)
Regarding present claim(s) 18, the claim of the '891 patent discloses the processing comprises adding a first index to DNA nucleic acids present in the isolated nuclei or cells, a first index to RNA nucleic acids present in the isolated nuclei or cells, or a combination thereof. (e.g. as per claim(s) 1 of the '891 patent)
Regarding present claim(s) 19, the claim of the '891 patent discloses the adding a first index sequence to RNA nucleic acids comprises: contacting each subset with a reverse transcriptase and a primer that anneals to RNA molecules in the isolated nuclei or cells, wherein the primer in each compartment comprises the first compartment specific index sequence to generate the indexed nuclei or cells comprising the indexed nucleic acids. (e.g. as per claim(s) 1 of the '891 patent)
Regarding present claim(s) 20, the claim of the '891 patent discloses the adding a first index sequence to DNA nucleic acids comprises: contacting each subset with a transposome complex, wherein the transposome complex in each compartment comprises the first compartment specific index sequence; and fragmenting nucleic acids in the subsets into a plurality of nucleic acids and incorporating the first compartment specific index sequences into at least one strand of the nucleic acids to generate the indexed nuclei or cells comprising the indexed nucleic acids. (e.g. as per claim(s) 1 of the '891 patent)
Regarding present claim(s) 21-22, the claim of the '891 patent discloses the first index sequence added to DNA nucleic acids and the first index sequence added to RNA nucleic acids in each compartment are identical or not identical. (e.g. as per claim(s) 1 of the '891 patent)
Regarding present claim(s) 23, the claim of the '891 patent discloses an exponential amplification of the nucleic acid fragments, wherein the exponential amplification comprises a target specific primer that anneals to a specific nucleotide sequence. (e.g. as per claim(s) 9 of the '891 patent)
Regarding present claim(s) 24, the claim of the '891 patent discloses after the combining: distributing subsets of the pooled indexed nuclei or cells into a second plurality of compartments; and introducing a second compartment specific index sequence to indexed nucleic acids to generate dual-indexed nuclei or cells comprising dual-indexed nucleic acids, wherein the introducing comprises ligation, primer extension, amplification, or transposition. (e.g. as per claim(s) 1 of the '891 patent)
Regarding present claim(s) 25, the claim of the '891 patent discloses combining the dual-indexed nuclei to generate pooled dual-indexed nuclei or cells, distributing subsets of the pooled dual-indexed nuclei or cells into a third plurality of compartments; and introducing a third compartment specific index sequence to indexed nucleic acids to generate triple-indexed nuclei or cells comprising triple-indexed nucleic acids, wherein the introducing comprises ligation, primer extension, amplification, or transposition. (e.g. as per claim(s) 1 of the '891 patent)
Regarding present claim(s) 26, the claim of the '891 patent discloses treating the indexed nuclei or cells for methylation analysis to generate nucleic acid fragments suitable for methylation analysis. (e.g. as per claim(s) 10 of the '891 patent)
Regarding present claim(s) 27, the claim of the '891 patent discloses subjecting the indexed nuclei or cells to proximity ligation to generate nucleic acid fragments suitable for analysis of chromatin conformation. (e.g. as per claim(s) 11 of the '891 patent)
Regarding present claim(s) 28, the claim of the '891 patent discloses amplifying the nucleic acid fragments of the sequencing library to produce DNA nanoballs. (e.g. as per claim(s) 12 of the '891 patent)
Regarding present claim(s) 29, the claim of the '891 patent discloses the compartment comprises a well or a droplet. (e.g. as per claim(s) 13 of the '891 patent)
Regarding present claim(s) 30, the claim of the '891 patent discloses each compartment of the first plurality of compartments comprises from 50 to 100,000,000 nuclei or cells. (e.g. as per claim(s) 14 of the '891 patent)
Regarding present claim(s) 31, the claim of the '891 patent discloses each compartment of the second plurality of compartments comprises from 50 to 100,000,000 nuclei or cells. (e.g. as per claim(s) 15 of the '891 patent)
Regarding present claim(s) 32, the claim of the '891 patent discloses providing a surface comprising a plurality of amplification sites, wherein the amplification sites comprise at least two populations of attached single stranded capture oligonucleotides having a free 3′ end, and contacting the surface comprising amplification sites with the indexed fragments under conditions suitable to produce a plurality of amplification sites that each comprise a clonal population of amplicons from an individual fragment comprising a plurality of indexes. (e.g. as per claim(s) 16 of the '891 patent)
Conclusion
No claims are allowed
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Khai Quynh Tien Pham whose telephone number is (571)272-6998. The examiner can normally be reached M-T, 9-4 ET.
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/KHAI QUYNH TIEN PHAM/ Examiner, Art Unit 1684
/JEREMY C FLINDERS/ Primary Examiner, Art Unit 1684
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