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 .
This action is in response to the papers filed on April 29, 2025.
Currently, claims 1-5 are pending.
Claims 2-5 were withdrawn as directed to a non-elected invention.
Claim 1 is under examination.
Any objections and rejections not reiterated below are hereby withdrawn.
The rejection under U.S.C. 112(b) has been withdrawn in view of the claim amendments filed on April 29, 2025.
Election/Restrictions
Applicant's election with traverse of “Group I, claim 1” and “a first and second set of primers designed to amplify human nucleic acids” in the reply filed on December 10, 2024 is acknowledged. The traversal is on the grounds that the prior art does not teach the second set of claimed forward and reverse primers. This argument has been thoroughly reviewed. Upon reconsideration, the inventions lack unity as evidenced by Dash, P. et al., “Single-Cell Analysis of T-Cell Receptor ab Repertoire.” In: Shaw A. (eds) Immunosenescence. Methods in Molecular Biology, vol 1343. Humana Press, New York, NY (2015) in view of US2015/0337396 A1 (Davis) and Illumina Document # 1000000002694 v01 (February 2016).
Briefly, Dash teaches nested PCR primers for analyzing single T cells that are identical to the target annealing primers of the claimed invention with the exception that the second set (the internal primers) do not additionally comprise adapter and barcode sequences. However, Davis teaches analyzing single T cells comprising nested amplification of nucleic acids encoding TCR α and β (i.e. the same targets as the claimed invention) (Davis, Figure 1A) Davis teaches a first and second set of primers for nested PCR amplification of nucleic acids encoding TCRs, where the internal (second set) of primers comprise adapter and barcode sequences for Illumina sequencing (Davis, Figure 1A, 4A, and 4B) with total primer lengths exceeding 50 nucleotides (Davis, figure 12, for example, SEQ ID 90). Davis teaches that a pair of adapter sequences can be added at the 5’ and 3’ ends of a DNA template to allow amplification or sequencing of multiple DNA templates simultaneously by the same set of primers. (Davis, 0118)
Illumina teaches commercially available adapters and indices that are identical to the sequences appended to the primers taught by Dash in the claimed invention.
The requirement is still deemed proper and is therefore made FINAL.
Claims 2-5 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on December 10, 2024.
Applicant is reminded, the examiner has required restriction between product or apparatus claims and process claims. Where applicant elects claims directed to the product/apparatus, and all product/apparatus claims are subsequently found allowable, withdrawn process claims that include all the limitations of the allowable product/apparatus claims should be considered for rejoinder. All claims directed to a nonelected process invention must include all the limitations of an allowable product/apparatus claim for that process invention to be rejoined.
In the event of rejoinder, the requirement for restriction between the product/apparatus claims and the rejoined process claims will be withdrawn, and the rejoined process claims will be fully examined for patentability in accordance with 37 CFR 1.104. Thus, to be allowable, the rejoined claims must meet all criteria for patentability including the requirements of 35 U.S.C. 101, 102, 103 and 112. Until all claims to the elected product/apparatus are found allowable, an otherwise proper restriction requirement between product/apparatus claims and process claims may be maintained. Withdrawn process claims that are not commensurate in scope with an allowable product/apparatus claim will not be rejoined. See MPEP § 821.04. Additionally, in order for rejoinder to occur, applicant is advised that the process claims should be amended during prosecution to require the limitations of the product/apparatus claims. Failure to do so may result in no rejoinder. Further, note that the prohibition against double patenting rejections of 35 U.S.C. 121 does not apply where the restriction requirement is withdrawn by the examiner before the patent issues. See MPEP § 804.01.
Priority
This application is a 371 of PCT/US2020/040218, filed June 30, 2020 and claims the benefit of U.S. Provisional application number 62/869204, filed July 1, 2019.
Claim Rejections – Improper Markush Grouping
Claim 1 is/remains rejected under the judicially approved “improper Markush grouping” doctrine. ((See Federal Register, Vol. 76, No. 27, Wednesday, February 9, 2011, page 7166). This rejection is appropriate when the claim contains an improper grouping of alternatively useable species. See In re Harnisch,631 F.2d 716, 719-20 (CCPA 1980). A Markush claim contains an “improper Markush grouping” if:
(1) the species of the Markush group do not share a “single structural similarity,” or (2) the species do not share a common use. Members of a Markush group share a “single structural similarity” when they belong to the same recognized physical or chemical class or to the same art-recognized class. Members of a Markush group share a common use when they are disclosed in the specification or known in the art to be functionally equivalent. See MPEP § 2117.
Here each species is considered to be: (a) the first and second set of primers designed to amplify human nucleic acids, and (b) the first and second set of primers designed to amplify mouse nucleic acids. The primer sets for the human and the mouse are different species.
The primers for amplifying human and the primers for amplifying the mouse TCR nucleic acids do not share a single structural similarity, as each primer set is specific to a different organism (human vs. mouse). The primer sets recited in the instant claims do not share a single structural similarity since each consists of different nucleotide sequences with specificity for nucleic acids encoded by different organisms. The only structural similarity present is that all of the primers are nucleic acid molecules. The fact that the primers comprise nucleotides per se does not support a conclusion that they have a common single structural similarity because the structure of comprising a nucleotide alone is not essential to the common activity of specifically priming nucleic acid synthesis of a specific TCR sequence.
MPEP 2117 (II)(A) provides the following guidance as to what constitutes a physical, chemical, or art recognized class:
A recognized physical class, a recognized chemical class, or an art-recognized class is a class wherein “there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention. In other words, each member could be substituted one for the other, with the expectation that the same intended result would be achieved”
The recited genes do not belong to a recognized chemical class because there is no expectation from the knowledge in the art that the primers will behave in the same manner and can be substituted for one another with the same intended result achieved. In other words, there is no expectation from the knowledge in the art that each of the recited primers would function in the same way; it is only in the context of this specification that it was disclosed that all members of this group may behave in the same way in the context of the claimed invention.
MPEP 2117 (II) further states the following:
Where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the compounds do not appear to be members of a recognized physical or chemical class or members of an art-recognized class, the members are considered to share a "single structural similarity" and common use when the alternatively usable compounds share a substantial structural feature that is essential to a common use. Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984).
The recited alternative species do not share a substantial common structure just because they all have a sugar phosphate backbone. The sugar phosphate backbone of a nucleic acid chain is not considered to be a substantial common structural feature to the group of primers being claimed because it is shared by ALL nucleic acids. Further, the fact that the primers all have a sugar phosphate backbone does not support a conclusion that they have a common single structural similarity because the structure of comprising a sugar phosphate backbone alone is not essential to the asserted common use of being priming synthesis of specific TCR-encoding sequences.
Following this analysis, the claims are rejected as containing an improper Markush grouping.
Response to arguments
The response argues that the grouping of primers recited by claim 1 constitute a proper Markush grouping on the grounds that they belong to the single structural class of “nucleic acid primers that bind to a gene encoding a T cell receptor” and have a common use of “amplification of portions of the T cell receptor… genes”.
This argument has been thoroughly reviewed and is not found to be persuasive for the reasons which follow: The primers recited by Claim 1 do not have a common scientific use. The primers recited in Claim 1, part (a) and (b) share the structural and functional property of being primers that bind to a group of genes encoding human T cell receptors and may be used together for the common use of amplification of portions of the T cell receptor genes in single human T cells. In contrast, the primers recited in Claim 1, part (c) and (d) share the structural and functional property of being primers that bind to a group of genes encoding mouse T cell receptors and may be used together for the common use of amplification of portions of the T cell receptor genes in single mouse T cells. The response references Ex parte Narva Appeal No. 2018-004371 (P.T.A.B. 2016) wherein a group of nucleic acid molecules, usable together as a broadly acting insecticide for coleopteran pests because they share the common use of silencing expression of ROP proteins were ruled as a proper Markush grouping. In Narva, applicants successfully argues that the claimed sequences shared a common use such that the sequences can be substituted for the other, with the expectation that the same intended result would be achieved.
In the instant case, the ordinary artisan would not expect that the primers for human and mouse TCR genes would be interchangeable alternative (e.g. the human primers would not be usable to amplify the mouse and other mammals’ genes) because they likely contain significant sequence divergence that would reduce their affinity for their homologous target sequences. Furthermore, the ordinary artisan would likely not use the sets of primers in combination when analyzing a single human (or mouse) T cell because the homologous primer sequences, while likely not sufficiently similar to the target sequence in the other species, would likely interfere with amplification by (i) directly competing for annealing at or near the target gene, or (ii) producing off-target amplification products by annealing to unintended sequences in the genome for which they have not been optimized.
Therefore, claim 1 remains rejected as containing an improper Markush grouping.
Claim Rejections - 35 USC § 103
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.
Claim 1 remain/is rejected under 35 U.S.C. 103 as being unpatentable over Dash, P. et al. “Single-Cell Analysis of T-Cell Receptor ab Repertoire.” In: Shaw A. (eds) Immunosenescence. Methods in Molecular Biology, vol 1343. Humana Press, New York, NY (2015) in view of US 2015/0337369 A1 (Davis) and Illumina Document # 1000000002694 v01 (February 2016).
Dash teaches a first and second set of forward and reverse primers for analyzing a single T cell. (Dash, figure 1) The “External primer sequence (EXT)” column in Dash table 1 corresponds to the external primer sequences in Table 1 in the instant specification. All of the claimed “first set” primers (SEQ ID NO: 1-71) are taught by Dash. Dash also teaches an “Internal primer sequence (INT)” that are the target binding regions of SEQ ID NO: 72-176.
Dash does not teach the second set primers comprise Illumina adapter and barcoding sequences. The claimed primers of SEQ ID NO: 72-176 comprise the target binding region of Dash and additionally comprise “Lower case letters, adapter sequences (ILLUMINA®)” and “Bold and underlined sequences, barcode sequences (ILLUMINA®)”. (Specification, page 41, table 3 footnotes and page 43, table 4 footnotes)
However, Davis teaches analyzing single T cells comprising nested amplification of nucleic acids encoding TCR α and β (the same targets as the claimed invention). (Davis, Figure 1A) Davis teaches the second set (internal) primers comprise Illumina adapters and barcode sequences. (Davis, Figure 4A and 4B). Finally, Davis teaches that a pair of adapter sequences can be added at the 5’ and 3’ ends of a DNA template to allow amplification or sequencing of multiple DNA templates simultaneously by the same set of primers. (Davis, 0118) Davis teaches internal primers comprising “Universal Adapters” and Illumina barcodes. “FIG. 4A shows 5′ primers (SEQ ID NO:263), containing a consensus sequence having an Illumina™ Paired-End Primer site, a common sequence, and variable barcodes that specify plate number and row of a multi-well plate. FIG. 4B shows a 3′ primer (SEQ ID NO:264), containing a consensus sequence having an Illumina™ Paired-End Primer site and a TCR alpha chain constant region, and variable barcodes that specify column of a multi-well plate” (Davis, 0032)
Illumina Document #1000000002694 v01 (February 2016) teaches “Nextera Transpose Adapters”, and Illumina index sequences, namely “RNA PCR” indices. These Nextera Transpose adapters are 100% identical to the adapters appended to SEQ ID NO: 72-176 of the instant application. The RNA PCR indices are also 100% identical to the barcodes of SEQ ID NO: 112-129 and 159-176. The “forward” and “reverse” adapter sequences included in the Internal primers of the SEQ ID NO: 72-176 (see lowercase sequence in primers listed in tables 3 and 4) are identical to the commercially available adapters in the “Illumina Nextera Library Prep Kits” (Illumina, page 12, lines 5-8). Similarly, the 6-base index sequences claimed as a constituent of the internal reverse primers (see bold, underlined sequences in primers listed in tables 3 and 4) are identical to the commercially “RNA PCR Index Primers” taught by Illumina (Illumina, page 22-25).
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention for one of ordinary skill in the art to modify the internal primers taught by Dash for amplifying TCR with adapters and barcodes, as taught by Davis because Davis teaches including adapters and barcodes allows for sequencing of multiple DNA templates simultaneously by the same set of primers. (Davis 0118) The ordinary artisan would have been reasonably confident that modifying the primers taught by Dash with a suitable combination of Illumina adaptors and barcodes as taught by Davis would have dramatically increased the throughput and reduced the cost of analysis of nucleic acid sequences encoding TCRs in single T cells taught by Dash and Davis relative to the “Big Dye terminator” (single-template Sanger sequencing) technique employed by Dash. The ordinary artisan would have been motivated to have selected known adapters sequences and known barcode sequences to modify the internal primers of Dash. Illumina teaches the “Nextera Transpose Adapters” and the 6-base pair barcodes used. It would have been obvious to one of ordinary skill in the art to replace the adapters and barcodes used in Davis with alternative commercially available adapters and barcodes known in the art. One of ordinary skill in the art would have recognized this simple substitution of one set of known adapters for another set of known adapters was a routine substitution, and the results were reasonably predictable. Specifically, a person of ordinary skill in the art would have recognized that the adapter and barcoding sequences taught by Illumina (i.e. the “Illumina Nextera” adapters and the “RNA PCR Index” barcode sequences appended to the TCR-specific sequences taught by Dash in the claimed invention) would have been interchangeable with the “Universal adapter” and variable barcodes taught by Davis for the purpose of constructing properly barcoded and indexed amplicons (i.e. a sequencing library) and would have been predictable.
Response to arguments
The response argues that Dash does not teach each and every primer set forth in claim 1. In particular, the response asserts that Dash does not describe at least SEQ ID NOs: 7, 50, 52-54, OR 73-78, 85, 87, 89, 91, 93-96, 98, 99,01, 102, 105-107, 109, 112-129, 135, 139-142, 148, or 149. However, on further examination, Applicant’s assertion is unpersuasive. It’s apparent that at least some of these sequences (SEQ ID NO:7 and SEQ ID NO: 50) would certainly have been obvious to one of ordinary skill in the art given the teachings of Dash.
To demonstrate obviousness of primer selection recited in claim 1, for example, SEQ ID NO: 50 (“huTRBV7-4_9ext_new” is identical to the primer “TRBV7-4,7-6,7-7,7-8,7-9” taught by Dash with the sole exception that SEQ ID NO: 50 comprises one additional nucleotide at the 5’ end.
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Similarly, SEQ ID NO: 7, “huTRAV7ext” and “TRAV7” external primer sequence taught by Dash, anneal to target sequence separated on TRAV7 by only 27 nucleotides.
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Absent unexpected results, it is the position of the examiner that such minor modifications to the primer set taught by Dash, and now claimed by Applicant, constitute obvious variants of the primers previously disclosed by Dash and does not constitute an inventive step over the prior art.
The response further argues that Davis and Illumina do not teach labeling the primers with a single unique barcode name for each plate so that multiple plates can be pooled for sequence analysis. This argument has been reviewed and is not persuasive. Illumina teaches a variety of commercially available adapters and barcodes, and methods of barcoding with varying degrees of complexity up to and including so called “unique molecular indexes” such that each library molecule has a unique barcode, have been well-known in the art.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim 1 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 and 10-13 of copending Application No. 18/721,777 (herein referred to as ‘777). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of ‘777 render obvious the instant claim 1.
The claims of ‘777 are directed to a kit (claims 1-5) and method (claims 10-13) for analyzing a T cell receptor of a single T cell (i.e. analyzing a single T cell) comprising:
a first set of primers comprising a first set of forward primers comprising the nucleotide sequences of SEQ ID NOs 1-40 and 42-70 (identical to instant sequences) (‘777, claim 3), a first set of reverse primers comprising SEQ ID NO 41 and 71 (‘777, claim 4); and
a second set of primers comprising a second set of forward primers comprising the nucleotide sequences of SEQ ID NOs 72-111 and 130-158 (‘777, claim 5), and a second set of reverse primers comprising adapter sequences and unique barcodes. (‘777, claim 6-7)
It would have been obvious for one of ordinary skill in the art to combine the sets of primers taught by the claims of ‘777 because they are all preferred embodiments of ‘777.
The claimed methods of ‘777 (‘777, claims 10-13) recite using the primers from the kit to analyze a single T cell. Therefore, the ‘777 method claims encompass a use of primers that are identical to the primers of the claimed invention and thus render obvious the primers of the claimed invention. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to arguments
The applicant requests that this rejection be held in abeyance until allowable subject matter is found in the pending application. This requires has been noted and is denied. See M.P.E.P. 804(l)(b)(1) and 37 C.F.R. 1.111(b), which allows that some objections may be held in abeyance but includes no provision for holding rejections in abeyance. Thus, for the reasons above and those already of record, the rejection is maintained.
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. 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.
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/Z.M.T./Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682