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 .
Claims 56-77 are pending and are being examined on the merits.
Preliminary Amendment
The Preliminary Amendment filed July 15, 2025 is acknowledged.
Information Disclosure Statement
The Information Disclosure Statements submitted October 22, 2024, May 9, 2025, July 16, 2025 and August 6, 2026 have each been considered.
Specification
The disclosure is objected to because of the following informalities:
The “Cross-Reference to Related Applications” paragraph should be updated to reflect
that the parent application, US Serial No. 17/933,058, has issued into US Patent No. 12,006,532.
Appropriate correction is required.
Claim Objections
Claims 62-63 and 71 are objected to because of the following informalities:
Claim 62 depends from claim 56, which recites steps (a) through (f). Claim 62 then
recites “further comprising (f)”. Since claim 56 already recites a step (f), claim 62 should be corrected to recite “further comprising (g)”. Corresponding corrections should be made to claims 63 and 71.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 56-77 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.
Indefiniteness rejections
Claim 56 steps (d) and (e) recite that the SMI is “at least partially maintained” in the first and second nucleic acid products, and then in step (f) recites “sequencing the [first and second] nucleic acid product[s] to obtain sequence reads each comprising a maintained SMI sequence …”. The meaning of “partially maintained” and “maintained” are unclear. First, the term “partially” is a relative term which renders the claim indefinite. The term “partially” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Specifically, it is not clear what the minimum level of maintenance is required for an SMI to be “partially” maintained. Second, it is not clear if the step (f) reference to sequencing nucleic acid products comprising “a maintained SMI” is intended to exclude nucleic acid products that are partially, but not fully maintained. Stated differently, the limitation “at least partially maintained” comprises embodiments where the SMI is fully maintained and embodiments where the SMI is only partially maintained. Is the step (f) reference to “a maintained SMI” excluding the only partially maintained embodiments? Since the ordinary artisan would not be able to determine the metes and bounds of the claim, it is indefinite.
Claims 57-77 depend directly or indirectly from claim 56 and consequently incorporate
the indefiniteness issues of claim 56.
Claim 57 recites the limitation “an SMI element”, the meaning of which is unclear. Specifically, the term “element” does not have a fixed meaning in the art of nucleic acid assays. Further, the specification describes the location of SMI elements as being comprised within an SMI, and which can be, e.g., adjacent to one another or spatially distinct, or which can comprise exogenous or endogenous components (para. 85). However, the specification does not define or describe the structure or function of an “element”, particularly as to how to distinguish an “SMI element” from an “SMI”. For example, the specification at para. 85 recites that the SMI is “any material… that is capable of distinguishing an individual molecule in a large heterogeneous population of molecules”, but then para. 120 recites that “[i]n some embodiments, … an element … renders the amplification products … substantially distinguishable”. Thus, if both the SMI and the SMI element render an individual molecule distinguishable from other molecules, what is the difference between an SMI and an SMI element, both of which are recited in claim 57. Since the ordinary artisan would not be able to determine the metes and bounds of the claim, it is indefinite. Claim 65 additionally recites an “SMI” and an “SMI element” and is rejected with corresponding reasoning.
Claims 58-61 and 64 depend from claim 57 and consequently incorporate the indefiniteness issues of claim 57.
Claims 66-67 depend from claim 65 and consequently incorporate the indefiniteness issues of claim 65.
The term “substantially non-complementary” in claim 77 is a relative term which renders the claim indefinite. The term “substantially” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The specification (para. 86) does recite embodiments of “substantially non-complementary” sequences, including, e.g., “a segment of a substantially non-complementary sequence within an adapter sequence can be provided by an adapter molecule comprising a Y-shape”. However, claim 76, from which claim 77 depends, already recites that the adapter is Y-shaped. Thus, it is not clear what the “substantially non-complementary” in claim 77 is referring to that is additional to the Y-shaped adapter in claim 76.
Lack of antecedent basis rejections
Claim 73 recites the limitation "the first set" and “the second set” of sequence reads in steps (i) and (ii), respectively. There is insufficient antecedent basis for these limitations in the claim. Claims 63, from which claim 73 depends, also recites a “set” of sequence reads. However, it is not clear what the relationship is between the claim 63 “set” and the claim 73 “[first/second] set”. Do the claim 73 sets refer back to the claims 63 “set” or are the claim 73 sets different sets?
Claim 74 depends from claim 73 and consequently incorporates the lack of antecedent
basis issues of claim 74.
Claim 75 recites the limitations “the set obtained from the first nucleic acid product” in ll. 2-3, and “the set obtained from the second nucleic acid product” in l. 3. There is insufficient antecedent basis for these limitations in the claim. Claim 63, from which claim 75 indirectly depends, recites generating a set of sequence reads, but does not recite sets of sequence reads corresponding to the first or second nucleic acid products, per se.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 56-77 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-11 and 18 of U.S. Patent No. 12,006,532 (hereinafter, the ’532 patent).
Although the claims at issue are not identical, they are not patentably distinct from each other because claim 1 of the ‘532 patent teaches or suggests the limitations of instant claims 56 and 62-63. That is, claim 1 of the ‘532 patent teaches amplifying adapter-ligated double-stranded nucleic acid constructs, where the construct comprises an SMI, separating the amplicons into first and second samples where each sample comprises amplicons from both strands, amplifying amplicons from only one strand in each sample, sequencing the amplicons, and matching the top and bottom strands using the SMI sequence. However, claim 1 of the ‘532 patent teaches these limitations in different embodiments as compared to instant claims 56 and 62-63.
Regarding instant claims 57-61 and 64-67, the meaning of these claims is unclear, as noted above. Nevertheless, claim 1 of the ‘532 patent teaches an SMI component that renders the amplification products substantially distinguishable.
Further, claims 4, 5, 6, 7, 8, 9, 10, 11 and 18 of the ‘532 patent teach or suggest all of the limitations of instant claims 68, 69, 70, 71, 72, 73, 74, 75 and 76/77, respectively.
Modifying the ‘532 patent limitations to arrive at the instantly claimed embodiments would have been prima facie obvious to the ordinary artisan as they would have been motivated to do so to optimize the assay as desired through routine experimentation. The ordinary artisan would have had an expectation of success as creating adapter-ligated nucleic acid constructs is well-known in the art.
Claims 56-75 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 10-12, 16-20 and 22 of U.S. Patent No. 11,479,807 (hereinafter, the ‘807 patent) in view of Iafrate1 (US Patent App. Pub. No. 2013/0303461).
Although the claims at issue are not identical, they are not patentably distinct from each other because claim 1 of the ‘807 patent teaches or suggests most of the limitations of instant claims 56 and 62-63. That is, claim 1 of the ‘807 patent teaches amplifying adapter-ligated double-stranded nucleic acid constructs, where the construct comprises an SMI, separating the amplicons into first and second samples where each sample comprises amplicons from both strands, amplifying amplicons from only one strand in each sample, sequencing the amplicons, and matching the top and bottom strands using the SMI sequence.
Claim 1 of the ‘807 patent does not teach that the end portions of the adapter molecules are at least partially double-stranded. However, Iafrate teaches this limitation (Fig. 1; para. 8).
Regarding instant claims 57-61 and 64-67, the meaning of these claims is unclear, as noted above. Nevertheless, claim 1 of the ‘807 patent teaches an SMI component that renders the amplification products substantially distinguishable.
Further, claims 12, 10, 11, 16-19, 20 and 22 of the ‘807 patent teach or suggest all of the limitations of instant claims 68, 69, 70, 71/72/73, 74 and 75 respectively.
Modifying the ‘807 patent to incorporate the partially double-stranded adapters of Iafrate would have been prima facie obvious to the ordinary artisan, as claim 1 teaches generating strand-specific amplicons relating to a double-stranded molecule, while at the same time incorporating an SMI into each strand of the amplicons. The ordinary artisan would have been motivated to incorporate the Iafrate adapters, as doing so would provide additional information that would be useful for matching sequencing data derived from each strand (e.g., the non-complementary portion of the amplicon would identify which strand of the double-stranded molecule the amplicon corresponded to), and hence additional complexity in the method. The ordinary artisan would have had an expectation of success as creating adapter-ligated nucleic acid constructs is well-known in the art (e.g., in next generation sequencing; Iafrate, para. 232), and because Iafrate teaches that the adapters can be ligated to a variety of double-stranded molecules (paras. 10, 15-16).
Prior Art and Patent Eligibility
Claims 56-77 are free of the art.
The closest prior art is Schmitt2 (US Patent App. Pub. No. 2015/0044687), Shin3 (US Patent App. Pub. No. 2016/0362751) and Iafrate4 (US Patent App. Pub. No. 2013/0303461). Schmitt is generally directed to methods for duplex consensus sequencing. Schmitt teaches providing double-stranded nucleic acid molecules with ligated adapters, where the adapters comprise single molecule identifier (SMI) sequences, amplifying and sequencing each strand of a double-stranded nucleic acid molecule, and comparing the sequences of each of the two strands from the same double-stranded molecule to generate a consensus sequence (Fig. 1; paras. 9, 22-23, 31, 89, 114). Shin is directed to high resolution STR analysis, and teaches strand-specific amplification of double-stranded nucleic acid molecules (Fig. 1; para. 81). Iafrate is directed to methods of enriching target sequences prior to sequencing, and teaches amplification using a primer pair comprising an adapter primer and a target-specific primer (paras. 7, 13).
However, none of Schmitt, Shin and Iafrate, whether considered alone or in combination, teach or suggest, at least the combination of amplifying adapter-ligated double-stranded nucleic acid constructs, where the construct comprises an SMI, separating the amplicons into first and second samples where each sample comprises amplicons from both strands, amplifying amplicons of only one strand in each sample, resulting in amplicons from both strands each with at least a partially maintained SMI, and then sequencing and matching the top and bottom strands using the at least partially maintained SMI sequence, as recited in independent claim 56. Since these limitations are novel and non-obvious, they are also not routine and conventional. Thus, while some of the instant claims recite abstract ideas/mental steps (e.g., claim 62: confirming sequence reads; claim 71: comparing sequence reads), the claims are nevertheless patent eligible, at least, in view of these additional limitations that are not routine or conventional.
Conclusion
Claims 56-77 are being examined and are rejected. Claims 62-63 and 71 are objected to. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CAROLYN GREENE whose telephone number is (571)272-3240. The examiner can normally be reached M-Th 7:30-5:30 EST.
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/CAROLYN L GREENE/Examiner, Art Unit 1681
1 Iafrate was cited in the Information Disclosure Statement submitted October 22, 2024.
2 Schmitt was cited in the Information Disclosure Statement submitted October 22, 2024.
3 Shin was cited in the Information Disclosure Statement submitted October 22, 2024.
4 Iafrate was cited in the Information Disclosure Statement submitted October 22, 2024.
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