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
Claim(s) 17-25 is/are pending and are under examination.
Claim(s) 1-6 and 11-16 is/are withdrawn.
Claim(s) 7-10 are canceled
Applicant's election with traverse of Group II, claims 17-25, in the reply filed on 03/30/2026 is acknowledged. The traversal is on the ground(s) that 1) WO '666 allegedly does not teach or suggest a cyclization adapter and 2) it would not be a serious burden to search and examine the claims of Groups I and II. This is not found persuasive because 1) WO '666 teaches adaptor mediate circularization of dsDNA using compatible T/A sticky ends ligation [Fig. 5]. Thus, the shared feature is not a special technical feature over the prior art. 2) the no search burden argument is not found persuasive because search burden is not an issue herein, since the instant case is a 371 national stage entry of a PCT case, and search burden is only applicable in restriction practice for applications which enter under, for example, 35 U.S.C. 111. See also, MPEP §801, which explicitly states that, “applications entering the National Stage under 35 U.S.C. 371 as a Designated or Elected Office in the U.S. Patent and Trademark Office is covered in Chapter 1800.” Wherein Chapter 1800, and specifically, 1893.03 (d), clearly states that, “Examiners are reminded that unity of invention (not [US] restriction practice pursuant to 37 CFR 1.141 -1.146)) practice is applicable …in national stage applications submitted under 35 U.S.C. 371.” (Emphasis added). Therefore, an argument for rejoining groups on an alleged lack of undue search burden is not persuasive.
The requirement is still deemed proper and is therefore made FINAL.
Drawings
The drawings are objected to because:
Specific deficiency - Sequences appearing in the drawings for Figs. 1 & 2 are not identified by sequence identifiers in accordance with 37 CFR 1.831(c). Sequence identifiers for sequences (i.e., “SEQ ID NO:X” or the like) must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Amended drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers (i.e., “SEQ ID NO:X” or the like) into the Brief Description of the Drawings, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Claim Interpretation
The claims listed below recite intended use, purpose, or result language. Such language must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. Furthermore, as per MPEP § 2115, “[i]nclusion of material or article worked upon by a structure being claimed does not impart patentability to the claims.” In re Young, 75 F.2d 996, 25 USPQ 69 (CCPA 1935) (as restated in In re Otto, 312 F.2d 937, 136 USPQ 458, 459 (CCPA 1963)), and that the manner or method in which a machine is to be utilized is not germane to the issue of patentability of the machine itself. See also MPEP § 2111.02, citing In re Sinex, 309 F.2d 488, 492, 135 USPQ 302, 305 (CCPA 1962) (statement of intended use in an apparatus claim did not distinguish over the prior art apparatus), and MPEP § 2112.01 citing In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990) stating that “discovery of an unobvious property and use does not overcome the statutory restraint of section 102 when the claimed composition is known”.
In claim 17, “for constructing cyclized library “ and “fragment to be cyclized” is/are intended use language and does not structurally limit the claimed adapter. Hence the claim is interpreted base on the adapter’s recited structural features, not function/purpose of the adapter.
In claim 19, “for distinguishing samples between the two mis-match regions” is/are intended use language and does not structurally limit the claimed adapter. Hence the claim is interpreted base on the adapter’s recited structural features, not function/purpose of the adapter.
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.
Claim(s) 17-18 and 20-21 is/are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Yan et al. (CN112226821A, disclosed in IDS).
Regarding claim 17, Yan discloses a cyclization adapter for constructing cyclized library, the cyclization adapter is formed by incompletely complementary double strands and has a 3' overhang at both ends, and the 3' overhang of the cyclization adapter is complementary with the 3' overhang of the fragment to be cyclized. (e.g. the reference discloses gDNA fragments are A-tailed, then adapters’ (T) overhang at the 3' end hybridizes with the A-overhang of the DNA fragment to form a ring, generating a double strand DNA constructs. [Fig. 2 and “Summary of the invention” section])
Regarding claim 18, Yan further discloses the incompletely complementary double strands comprise a nick in one strand or a mis-matching region between the double strands (e.g. nicked region is highlighted in box below [Fig. 2])
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Regarding claim 20 and 21, Yan further discloses the cyclization adapter of claim 17, the cyclization adapter comprises cyclization adapter (a) as follows: the cyclization adapter (a) comprises a long strand and two short strands complementary with both ends of the long strand, wherein the long strand comprises phosphoric acid modification at the 5' end , the 5' end of short strand complementary with the 3' end of the long strand comprises phosphoric acid modification, and the complementary double-stranded adapter comprises a T-sticky end at the 3' end and a single stranded non-complementary region of 8-12nt. [Fig. 2 below show the disclosed features and the single stranded non-complementary region is 10 nt long [“DNA fragment 1” sequence listing])
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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.
Yan et al. and Ach et al.
Claim(s) 19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Yan et al. (CN112226821A, disclosed in IDS) in view of Ach et al. (US20170283864A1)
Regarding claim 19, Yan does not disclose two mis- matching regions between the double strands and include a barcode sequence for distinguishing samples between the two mis-matching regions.
Ach discloses a DNA structure comprising internal double-stranded region and two single-stranded regions on both ends in which the opposing sequences are not complementary (i.e. two mismatch regions). Additionally, the barcode locates in between the non-complementary region as claimed.
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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 Yan’s adapter with an additional non-complimentary region because such design was known adapter design feature for providing exposed single strand portions that carry functional sequencing elements, such as primer binding, sample identifier, adapter, while maintaining internal double stranded portions suitable for hybridization/ligation. The modification would have been predictably producing an adapter having two mismatching regions with Yan’s barcode in between.
Yan et al. and Wang et al.
Claim(s) 22 is/are rejected under 35 U.S.C. 103 as being unpatentable over Yan et al. (CN112226821A, disclosed in IDS) in view of Wang et al. (CN111910258A, EFD: August 19th 2020).
Regarding claim 22, Yan further discloses in the long strand sequence “AGTCGGAGGCCAAGCGGTCTTAGGAAGACAANNNNNNNNNNCAACTCCTTGGCTCACAGAACGACATGGCTACGATCCGACTT” is a MGI sequencing backbone. Although Yan does not explicitly call the “NNNNNNNNNN” region a barcode/index, Wang provides this information . Wang discloses MGI sequencing adapter constructs use variable sequence as a library tag sequence for splitting sequencing data. Wang further discloses MGI sequence containing “NNNNNNNNNNCAACTCCTTGGCTCACAGAACGACATGGCTACGA” and identify the “NNNNNNNNNN” region (i.e. feature at positions (21) to (30) of SEQ ID 771) as library tag sequence (i.e. index/barcode). Accordingly, Yan places the 10-nt variable region at the same MGI adapter position before “CAACTCCTTGGCTC…” adapter. 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 “NNNNNNNNNN” sequence region as unique library tag sequence (i.e. barcode/index) for distinguishing samples, as taught by Wang, since both references directed to building MGI sequencing ready libraries using the same sequence adapter downstream from degenerate tag sequence.
Yan et al. and Johnson et al.
Claim(s) 23-25 is/are rejected under 35 U.S.C. 103 as being unpatentable over Yan et al. (CN112226821A, disclosed in IDS) in view of Johnson et al. (WO2019068797A1, EFD: October 10th 2018)
Regarding claim 23, Yan discloses cyclization adapters used in an MGI double strand cyclization library workflow, including barcode, phosphoric acid modification at the 5' end, and 3’-T-sticky end that hybridize with A-tailed DNA fragments. However, Yan adaptor system comprises 3 different sequences instead of 2 as claimed.
Johnson discloses circularization of nucleic acid insert using double strand adapter/backbone segment having functional sequence, such as primer site and barcode. As shown in Fig. 4 and 9, the adapter/backbone insert comprise terminal overhangs. Under broadest reasonable interpretation, Johnson’s connector construct is considered partially complementary strands because the strands are complementary in the double strand portion, while include non-complementary sticky 3’ ends. Thus, Johnson teaches to use connector segment comprising two partially complementary strands, wherein two ends of the two strands are paired to form a double stranded structure to circularized double strand DNA molecules.
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 Yan’s MGI three sequences adaptor system to Johnson’s two sequence double strand adaptor configuration. Both references directed to the same general purpose, which is constructing circularized double stranded nucleic acid construct for sequencing library preparation. Yan teaches that double stranded DNA fragments can be circularized in an MGI sequencing workflow using adaptor mediated sticky end ligation, including a 5’ phosphoric acid modification and a 3’ T-sticky end that hybridize with A-tailed DNA fragments. Johnson further teaches that it was known in the art to use separate double strand connector that comprise functional sequences to circularize double strand DNA molecules. A person of ordinary skill in the art would have been motivated to substitute Johnson’s adaptor architecture to replace Yan’s more complex three sequences adaptor system, while retaining Yan’s known 5’ phosphoric acid modification and a 3’ T-sticky end that hybridize with A-tailed DNA fragments, with reasonable expectation of success because both rely on complementary terminal interactions followed by enzymatic ligation to produce double strand DNA constructs.
Regarding claim 24, Johnson further discloses the backbone may contain useful elements such as barcodes [page 14, lines 20-21], Barcodes can be 1- 20 nucleotides long [page 14, lines 9-10]. 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 routine optimize double-stranded barcode sequence to be 8-12nt. See MPEP § 2144.05 (I) “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists”; MPEP § 2144.05 (II) A "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.”
Regarding claim 25, Johnson further discloses the backbone may contain useful elements such as barcodes [page 14, lines 20-21], Barcodes can be 1- 20 nucleotides long [page 14, lines 9-10]. 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 routine optimize double-stranded barcode sequence to be 10 nt. See MPEP § 2144.05 (I) “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists”; MPEP § 2144.05 (II) A "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.”
Allowable Subject Matter
Claim 19 is currently rejected under 35 USC § 112(d) and objected to as being dependent upon a rejected base claim, but may contain allowable subject matter. As set forth in the claim interpretation above, claim 19 is interpreted as requiring cyclization adapter of claim 17 to further comprise incompletely complementary double strands with two mismatching regions and a barcode sequence for distinguishing samples between the two mis-matching regions, as illustrated in applicant’s figure 2 (A and D).
The closest prior art reference to claim 19 is Yan et al. (CN112226821A, disclosed in IDS). Yan teaches the cyclization adapter that comprises a long strand and two short strands complementary with both ends of the long strand, but Yan does not teach or suggest the arrangement required by claim 19. The additional references of record also fail to teach or suggest modifying Yan to arrive at the claimed configuration, namely double strand connector comprising two mismatching regions and a barcode sequence between the two mis-matching regions.
Another close reference considered is Jiang et al (US10954559B2), which discloses the use of adaptor that comprise incompletely complementary double strands with one mismatching region in sequencing library preparation. Jiang uses these adapters as terminal sequencing adapters ligated to the ends of linear double strand DNA fragments. The adapters enable selective amplification of the target DNA and facilitating single-strand circularization. On the other hand, claim 19 is interpreted as requiring cyclization connector that bridges the ends of double stand DNA fragments to form a circularized double strand molecule, with two mismatching regions and a barcode on the same connector duplex. Thus, comparing to the interpreted invention in claim 19, Jiang’s adaptor differs in both structure and function. The additional references of record also fail to teach or suggest modifying Jiang to arrive at the claimed configuration.
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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