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 1-77 have been canceled. Claims 78-97 are pending. In view of the restriction set forth in the previous Office Action, applicants’ election of claims 78-93 will be examined and claims 94-97 have been withdrawn from further consideration as drawn to a non-elected invention without traverse.
This application is a CON of PCT PCT/US2022/033468, filed 06/14/2022 and claims provisional status to PRO 63/210,527 filed on 06/15/2021. The filing date, or 371(c) date of the instant application is 12/14/2023. 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 nonprovisional 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, PRO No. 63/210527, 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. Claim 81 is not expressly supported by the provisional application because the claim recites “less than 2,500 nucleic acid molecules per square micron,” but the provisional disclosure only appears to describe square-micron density at a different value, namely “less than about 20,000 nucleic acid molecules per square micron,” while the specific value of 2,500 is disclosed in connection with “per cubic micron” language rather than per square micron. Accordingly, the provisional does not clearly disclose the exact combination of 2,500 and square micron required by claim. Accordingly, priority is assigned for the instant application to 06/14/2022.
This application should be reviewed for errors. At page 37, in [0115], line 5, the sentences “In some embodiments, not more than is less than.” is noted. It is not clear what this sentence is intended to convey. Correction is required. Note that new matter must be avoided.
Prior art
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 78-87 are rejected under 35 U.S.C. 103 as being unpatentable over US/2002/0137074 in view of Brenner et al. and US/2009/0118128.
US/2002/0137074 discloses methods and substrates for increasing hybridization selectivity by controlling the density of immobilized nucleic acids on a substrate. See, for example, paragraphs 0032-0035, 0047-0053, 0056-0064, 0076-0083, and 0089-0090, which define low, medium, medium-high, and high immobilization density and explain that selectivity is affected by packing density and interfacial chemistry. The reference also discloses substrates having immobilized nucleic acids alone or in combination with other oligomers, as well as density-dependent selectivity effects.
Brenner et al. further teach bead-based nucleic acid capture and clonal amplification on microbeads, including in vitro cloning of DNA templates on microbeads and formation of loaded microbead libraries suitable for high-throughput sequencing, as shown in the discussion of microbead libraries and flow-cell array processing, especially pages 630-634, Figure 3, Figure 4, and the experimental protocol for “Construction of oligonucleotide tag and anti-tag libraries, in vitro cloning, and formation of microbead libraries.”
US2009/0118128 further teaches support-bound nucleic acid molecules in duplex or partially duplex form, attached at the 5’ end to a solid support and later linearized or denatured to generate single-stranded sequencing templates. See paragraphs 0015-0027, 0038-0045, 0126-0154, and 0189-0194.
It would have been obvious to a person of ordinary skill in the art at the time the invention was made to combine these teachings to arrive at the claimed method of controlling density of nucleic acid molecules coupled to a solid support. US/2002/0137074 provides the motivation to control immobilization density because density affects hybridization selectivity and surface behavior, while Brenner et al. teach practical bead-based nucleic acid capture and amplification systems that depend on surface loading, and US/2009/0118128 teaches that nucleic acids on supports may be provided in duplex or partially duplex configurations and then converted into useful templates. In view of these teachings, using a bulky second strand or a partially duplex construct to reduce the effective number or density of nucleic acids coupled to a support would have been a predictable and routine variation. Claims 79-81 merely recite numerical or definitional limits on the density relationship and therefore amount to selection of a result-effective variable, namely occupancy or packing density. Claims 82-87 likewise recite features that would have been obvious in light of the cited art: hybridization between complementary strands is expressly taught by US/2009/0118128; non-nucleic-acid coupling moieties and covalent attachment are conventional support-functionalization approaches taught by US/2002/0137074 and US/2009/0118128; click chemistry is an obvious choice for covalent coupling chemistry in view of the known nucleic-acid conjugation art; the azide/DBCO pair is a routine species within that class of coupling reactions; and non-covalent nucleic-acid coupling through hybridization is a well-known alternative mode of attachment in immobilized nucleic-acid systems as reflected in US/2002/0137074.
Under the Graham v. John Deere framework, the scope and content of the prior art are substantial: the art teaches density-controlled nucleic acid immobilization on substrates, bead-based nucleic acid capture and clonal amplification, and support-bound duplex nucleic acids with predetermined linearization or denaturation steps. The differences between the prior art and the claims are limited to the particular use of a bulky duplex/hairpin-like construct for density reduction and the recitation of numerical thresholds or specific coupling chemistries. The level of ordinary skill in the art would have included knowledge of oligonucleotide synthesis, support chemistry, hybridization thermodynamics, and bead-based sequencing or amplification platforms. No objective evidence of nonobviousness is apparent from the record provided. Accordingly, claims 78-87 would have been obvious in view of the cited combination.
Claims 88-93 are rejected under 35 U.S.C. § 103 as being unpatentable over US/2009/0118128 in view of US/2002/0137074 and Brenner et al. (2000).
US/2009/0118128 expressly teaches cleavage-enabled nucleic acid structures attached to a solid support, including embodiments in which a strand includes a cleavable site, an abasic site, a ribonucleotide, a methylated nucleotide, a photocleavable element, or a peptide linker. See paragraphs 0018-0025, 0052-0065, 0072-0086, 0143-0150, and 0154-0158. The reference also teaches spacer nucleotides, including polyT spacers, and discusses predetermined cleavage positions relative to support attachment and sequencing-template regions. US/2002/0137074 provides the additional teaching that nucleic-acid immobilization density may be controlled by altering surface chemistry and the spatial organization of immobilized oligomers, and Brenner et al. supplies the bead-based capture/amplification platform context in which such density control would be useful.
It would have been obvious to a person of ordinary skill in the art at the time the invention was made to modify the support-bound nucleic acid constructs of US/2009/0118128 by incorporating a removable unhybridized region or loop with a cleavable or excisable base, because the reference already teaches removable portions of nucleic acids and multiple cleavage strategies. Re-claim 88 unhybridized region between first and second regions of a third strand is merely a hairpin or loop variant of the known support-bound duplex/template systems. Claim 89 step of cleaving or excising the base to produce separate strands is directly consistent with the cleavage and denaturation steps taught in US/2009/0118128. Claim 90 merely enumerates specific cleavable or excisable bases and corresponding enzymes or treatments, all of which are taught or suggested by that reference’s disclosure of uracil, ribonucleotides, photolysis, methylated nucleotides, and cleavage chemistries. Claims 91 and 93 merely place the cleavable moieties at specified positions adjacent to the ends of the hybridized regions, which is a straightforward design choice once the goal is to remove an unwanted spacer or loop. Re-claim 92, polyT stretch is expressly suggested by the spacer-nucleotide disclosures of US/2009/0118128, including the teaching that 1 to 20 spacer nucleotides may be used and that polyT spacers are preferred. In combination with US/2002/0137074, the claimed removable-bulk hairpin embodiments would have been an obvious way to control surface crowding while maintaining a useful support-bound nucleic acid substrate.
Under the Graham factors, the prior art is highly relevant and closely aligned with the claimed subject matter. The scope and content of US/2009/0118128 include support-bound nucleic acids with cleavage-enabled modifications and predetermined linearization. The differences between that art and the claims are limited to the specific hairpin-loop architecture and exact placement of the cleavable elements. The level of ordinary skill in the art would have encompassed standard nucleic-acid chemistry and surface functionalization. No persuasive objective indicia of nonobviousness are apparent from the record. Therefore, claims 88-93 would have been obvious over the cited combination.
For the reasons stated above, claims 78-87 are rejected under 35 U.S.C. § 103 as obvious over 20020137074 in view of Brenner et al. (2000) and 20090118128 A1, and claims 88-93 are rejected under 35 U.S.C. § 103 as obvious over 20090118128 A1 in view of 20020137074 and Brenner et al. (2000).
Conclusion
No claim is allowed.
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GARY BENZION, Ph.D.
Supervisory Patent Examiner
Art Unit 1681
/GARY BENZION/ Supervisory Patent Examiner, Art Unit 1681
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