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 .
Election/Restrictions
Applicant’s election without traverse of Group I, claims 81-99, in the reply filed on 12/31/2025 is acknowledged.
Applicant further elected as the de-crosslinking agent species: 2-amino-5-methylbenzoic acid recited in claim 81, part (b)(i) to fulfill the election of species. This election is made without traverse.
Claims 98 and 99 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claim 100 is cancelled.
Claims 81-99 are pending and claims 81-97 are under examination on the merits.
Priority
This application 18/018,101 filed on 01/26/2023 is a 371 national phase of PCT/US2020/066681 filed on 12/22/2020, and claims the benefit of provisional U.S. Patent Application No. 63/059,535, filed on 07/31/2020.
The priority date of claim 81 and its dependent claims 82-99 is determined to be 07/31/2020, the filing date of provisional U.S. Patent Application No. 63/059,535.
Specification
The disclosure is objected to because of the following informalities:” ArcticZyme proteinse” of p. 45, line 30 is assumed to be a typographical error intended to be “ArcticZyme proteinase”. Appropriate correction is required.
The use of terms which are trade names or marks used in commerce (including Qiagen™ and Invitrogen™ among others), has been noted in this application. The term should be accompanied by the generic terminology; furthermore, the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM, or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 81-97 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 81 recites the limitation "at least one of the de-crosslinking agent" in lines 6-7. There is insufficient antecedent basis for this limitation in the claim. No de-crosslinking agent(s) is/are recited earlier in the claim.
Claims 82-97 are similarly indefinite because they directly or indirectly depend from claim 81.
Claim 95 recites the limitation “wherein deparaffinizing the FFPE tissue section comprises, contacting the FFPE tissue section with xylene, absolute ethanol, about 96% ethanol, and about 70% ethanol”. This limitation is unclear because as written it requires deparaffinizing by contacting the tissue section with all of the recited elements simultaneously. For purposes of examination, the limitation is interpreted to intend a series of deparaffinizing steps with each of the recited elements in order.
Claim 96 recites the limitation "50 mM compound (1)" in line 7. There is insufficient antecedent basis for this limitation in the claim. Claims which claim 96 depend from do not recite a “compound (1)”. For purposes of examination “(compound (1)” is interpreted as the elected species 2-amino-5-methylbenzoic acid represented in the Table on page 27 of the specification with the numeral (1).
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.
Claims 81-97 are rejected under 35 U.S.C. 103 as being unpatentable over Frisen et al. (US20140066318, on IDS dated 06/08/2023) in view of Kool et al. (US20170283860, on IDS dated 06/08/2023).
Regarding claim 81, Frisen teaches a method for determining the location of nucleic acids in a tissue sample, the method comprising: providing an array comprising multiple species of capture probes (i.e., a plurality), wherein each species of capture probe comprises i) a positional domain, and (ii) a capture domain; and contacting said array with a tissue sample and allowing nucleic acid of the tissue sample to hybridize to the capture domain in said capture probes (abstract). Frisen teaches the positional domain corresponds to the position of the capture probe on the array (abstract) and contains a unique barcode sequence (para 100, claim 6), which reads on a spatial barcode.
Frisen teaches the tissue sample may be fixed (paras 127, 495) and permeabilized by placing the sample in SSC and microwaving (para 502), which reads on de-crosslinking a fixed biological sample.
Frisen teaches generating cDNA that incorporates sequence from the positional tags and template RNA and further sequencing the cDNA to determine a transcriptome with exact positional information (paras 21, 177, 183).
Frisen does not teach the de-crosslinking agent comprises 2-amino-5-methylbenzoic acid.
Kool teaches methods for reducing the number of aldehyde fixation related adducts and/or crosslinks in a sample such as a formalin fixed paraffin embedded (FFPE) tissue sample using an adduct reversal agent (Abstract). Kool teaches the adduct reversal agent includes an aromatic ring and at least one of: an amine group and a proton-donating group (Abstract, Fig. 19). Kool states that existing methods for removal of formaldehyde adducts can cause extensive degradation and loss of nucleic acids, particularly RNA and further that water-soluble bifunctional catalysts speed the reversal of formaldehyde adducts, enhance the removal and uncrosslinking of adducts, are compatible with common RNA extraction protocols and substantially enhance the quantities of amplifiable RNA recovered (para 105).
Kool teaches screening catalysts (p. 10-13, Table 1) including compound 2:
2 - aminobenzoic acid,
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84
98
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(p. 11, Table 1).
Kool does not explicitly teach 2-amino-5-methylbenzoic acid
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210
272
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.
However, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine and modify the teachings of Frisen and Kool to arrive at the instantly claimed invention. The modification would have entailed using the teachings of Kool to select a decrosslinking agent for de-crosslinking the fixed sample of Frisen. The modification would further have entailed substituting a methyl group in place of the H at position 5 of 2 - aminobenzoic acid. Substitution of methyl for hydrogen is considered routine substitution of obvious variants and a matter of judicious selection and routine optimization, and not considered a patentable modification in the absence of proof of unexpected results. Kool teaches screening of catalysts with similar structures (see Table 1 and para 105). One would have been motivated by the desire to optimize nucleic acid analyte recovery using agents selected from water-soluble bifunctional catalysts as taught by Kool. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Regarding claim 82, Frisen teaches placing the tissue sections (biological sample) on the array (para 21, Fig. 16).
Regarding claim 83, Frisen teaches an array comprising a substrate (abstract) and placing the tissue sections (biological sample) on the array (para 21, Fig. 16), which reads on the limitation wherein the fixed biological sample is disposed on a substrate.
Regarding claim 84, Frisen teaches placing the tissue sections (biological sample) on the array orienting the sample in relation to features on the array (para 143).
Regarding claim 85, Frisen teaches the nucleic acid molecule (analyte) is RNA (para 3).
Regarding claim 86, Frisen teaches the nucleic acid molecule (analyte) is mRNA (para 3).
Regarding claim 87, Frisen teaches the nucleic acid molecule (analyte) is DNA (para 3).
Regarding claim 88, Frisen teaches the method further comprises extending an end of the capture probe using the captured RNA as a template to generate a first strand cDNA (para 63). Frisen further teaches a first strand cDNA molecule is an extended capture probe (para 171).
Regarding claim 89, Frisen teaches second strand synthesis following extending the capture probe (para 63) and further teaches extending capture probes to produce extended DNA molecules that are tagged and generating a complementary strand (paras 293-294)
Regarding claim 90, Frisen teaches capture probes further comprise a universal domain (para 88), which may comprise a cleavage domain (para 102, claim 5 and Fig. 22).
Regarding claim 91, Frisen teaches the biological sample is formalin-fixed (paras 365, 495), which reads on a formaldehyde-fixed biological sample.
Regarding claim 92, Frisen teaches the biological sample is a fixed tissue section (para 129, claims 26-27, 41).
Regarding claim 93, Frisen teaches the tissue section may be formalin-fixed and paraffin-embedded (FFPE) (paras 129, 383).
Regarding claim 94, Frisen teaches the FFPE sample is deparaffinized (paras 130 and 368-369).
Regarding claim 95, Frisen teaches deparaffinization comprising incubating the sample in an appropriate solvent e.g. xylene, followed by an ethanol rinse, e.g. 99.5% ethanol, 96% ethanol, and 70% ethanol (para 130).
Regarding claim 96, Frisen does not teach any of the limitations required by the claim.
Kool teaches contacting the sample with adduct reversal agents (decrosslinking agents) or catalysts, in Tris buffer (paras 13, 16,21, 22, 27), at concentrations including 50mM (para 84), at temperatures ranging from 15° C. to 70° C (para 70), and for times such as 1 hour (para 69), which reads on part (iii) the FFPE sample is contacted with 50 mM compound (1) in Tris or TE buffer for 1 hour at 70 °C.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine and modify the teachings of Frisen and Kool to arrive at the instantly claimed invention. The modification would have entailed contacting the fixed sample of Frisen using the teachings of Kool to select conditions for the decrosslinking agent. Determining an appropriate concentration, temperature, and time is deemed merely a matter of judicious selection and routine optimization which is well within the purview of the skilled artisan. One of ordinary skill in the art would have been motivated to try different concentrations, temperatures, and times in order optimize conditions of the decrosslinking reaction in different samples and optimize nucleic acid analyte recovery. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Regarding claim 97, Frisen does not teach any of the conditions required by the claim.
Kool teaches adduct reversal agents (decrosslinking agents) at concentration ranges including 10 mM to 500mM.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine and modify the teachings of Frisen and Kool to arrive at the instantly claimed invention. The modification would have entailed contacting the fixed sample of Frisen using the teachings of Kool to select conditions for the decrosslinking agent. Determining an appropriate concentration is deemed merely a matter of judicious selection and routine optimization which is well within the purview of the skilled artisan. One of ordinary skill in the art would have been motivated to try different concentrations in order optimize conditions of the decrosslinking reaction in different samples and optimize nucleic acid analyte recovery. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior 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.
(I). Claim 81 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 7 of copending Application No. 17/889,025 in view of Frisen et al. (US20140066318, on IDS dated 06/08/2023) in view of Kool et al. (US20170283860, on IDS dated 06/08/2023).
Although the claims at issue are not identical, they are not patentably distinct from each other because the copending claims substantially anticipate the identified claims of this application.
Regarding instant claim 81, copending claim 1 is directed to a method of determining the presence of a target nucleic acid in a fixed biological tissue section that requires: contacting the fixed biological tissue section with a de-crosslinking agent wherein at least one of the de-crosslinking agent is selected from the group consisting of: 2-amino-5-methylbenzoic acid; contacting the de-crosslinked biological tissue section with a plurality of probes, wherein a probe of the plurality hybridizes to a target nucleic acid sequence in the de-crosslinked biological tissue section and wherein the probe further comprises a barcode that identifies the target nucleic acid; and determining the presence of the target nucleic acid in the de-crosslinked biological tissue section, wherein said determining comprises determining (I) a sequence corresponding to the target nucleic acid or a complement thereof and (II) a sequence corresponding to the barcode of the probe or a complement thereof, and using the determined sequences of (I) and (II) to identify the presence of the target nucleic acid in the fixed biological tissue section. Copending claim 7 requires wherein the de-crosslinking agent is 2-amino-5-methylbenzoic acid or a pharmaceutically acceptable salt thereof.
Regarding limitations of instant claim 81 not required by copending claims, the teachings of Frisen and Kool as they relate to these claims are given previously in this office action and are fully incorporated here.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
(II). Claim 81 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2 and 3 of copending Application No. 18/828,673 in view of Frisen et al. (US20140066318, on IDS dated 06/08/2023) in view of Kool et al. (US20170283860, on IDS dated 06/08/2023).
Although the claims at issue are not identical, they are not patentably distinct from each other because the copending claims substantially anticipate the identified claims of this application.
Regarding instant claim 81, copending claim 2 requires providing a plurality of fixed cells; un-fixing the fixed cell with an un-fixing agent; generating the plurality of barcoded nucleic acid molecules wherein a barcoded nucleic acid molecule comprises (i) a sequence corresponding to an un-crosslinked nucleic acid molecule or a complement thereof, and (ii) a barcode sequence; wherein the un-fixing agent comprises a compound selected from the group consisting of: 2-amino-5-methylbenzoic acid. Copending claim 3 requires the un-fixing agent comprises 2-amino-5-methylbenzoic acid.
Regarding limitations of instant claim 81 not required by copending claims, the teachings of Frisen and Kool as they relate to these claims are given previously in this office action and are fully incorporated here.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
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/JESSICA GRAY/Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682
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