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 .
Priority
The application claims domestic benefit to provisional patent 62/804,587 filed on Feb. 12, 2019. All claims are examined using the earlier filing date.
Claim Status
Claims 1-5,10-18, and 25 are pending in the application and under examination. Claims 6-9 and 19 have been cancelled. Claims 1 and 13 have been amended. Claim 1 is the only independent claim.
Response to Arguments
Rejections Withdrawn
The rejection of claim 13 under 35 USC 112(a) is withdrawn following the applicant’s amendments.
The rejection of claim 19 under 35 USC 112(d) is withdrawn following the applicant’s amendments.
The rejection of claims 1-19 and 25 under 35 USC 102(a)(1)/102(a)(2) is withdrawn following the applicant’s amendments.
New Rejections
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-5,10-18, and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Carpenter et al. (US 2018/0298421 A1, of record) in view of O’Geen et al. (PLoS ONE, 2018) and Wei et al. (Genes and Diseases, 2016).
In regards to claim 1, Carpenter teaches methods (Figs. 1-3, Figs. 7-11) of depleting a first nucleic acid from a sample comprising: (a) providing a sample comprising the first nucleic acid and a second nucleic acid (i.e. providing a sample comprising nucleic acids from a first genome and nucleic acids from a second genome, (see [0012]) (b) capping 5' and 3' ends of the first nucleic acid and the second nucleic acid (i.e. by adapter ligation (see ¶0010-¶0011); (c) contacting the sample to an endonuclease to form at least one cleaved first nucleic acid, wherein the endonuclease cleaves the first nucleic acid but does not cleave the second nucleic acid (see Figs. 1-3, Figs. 7-11); and (d) contacting the sample to an exonuclease (see ¶0010- ¶0011) and throughout); and wherein the first nucleic acid comprises an Alu element (see ¶0010, ¶0014, ¶0016, ¶0098, ¶0100). While Carpenter does not explicitly teach using Argonaute as the endonuclease. The art at the time recognized both CRISPR/Cas systems and Argonaute proteins as programmable, guide-directed nucleases capable of sequence-specific cleavage (seen O’Geen, and Wei Abstracts and throughout). These reference explicitly describe Argonaute systems as alternatives or competitors to CRISPR/Cas (see O’Geen pg. 1 ¶2 and throughout; Wei Title, pg. 169, ¶2 and throughout), differing primarily in predictable design parameters such as guide chemistry and targeting constraints rather than in fundamental mode of action. Accordingly it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to substitute Argonaute in place of CRISPR/Cas system using the methods taught by Carpenter. One of ordinary skill in the art would have been motivated to substitute an Argonaute endonuclease for a CRISPR/Cas endonuclease based on known advantages, such as no PAM restrictions for Argonaute endonuclease activity allowing it to target any location in the DNA, using DNA guides instead of RNA guides provide more thermostability, and unlike CRISPR/Cas systems, Argonaute is highly efficient in editing any sequence including G/C-rich regions (see Wei pg.2 ¶2 for list of advantages of Ago over CRISPR/Cas). Given the established guide-directed cleavage activity of Argonaute systems and their explicit comparison to CRISPR/Cas platforms in the art, a person of ordinary skill in the art would have reasonably expected that substitution of an Argonaute endonuclease for a CRISPR/Cas endonuclease would successfully achieve sequence-specific nucleic acid cleavage in an otherwise known workflow.
In regards to claim 2, Carpenter teaches capping the 5’ and/or 3’ ends of the first and second nucleic acids to make them resistant to exonuclease degradation (Figs. 1-3, Figs. 7-11, ¶0183 – ¶0185 and throughout).
In regards to claim 3 and 4, Carpenter teaches attaching adapters to each end of the first and second nucleic acids (Figs. 1-3, Figs. 7-12, ¶0183 – ¶0185 and throughout). Carpenter further demonstrates using either a hairpin adapter (¶0121-¶0122) or a linear adapter (Figs. 1-3, Figs. 7, 9-11, ¶0118-¶0121 and throughout).
In regards to claim 5, Carpenter teaches the use of adapters with methylated purines or pyrimidines, acylated purines or pyrimidines, alkylated ribose or other heterocycles (¶0044), locked nucleic acids, zip nucleic acids, RNAs, affinity reactive molecules, azides, alkynes, phosphorthioate modifications (¶0206), or phosphorylation (¶0241) in the adapter sequences.
In regards to claim 10, the CRISPR-Cas system utilized by Carpenter relies upon a guide RNA to provide sequence specificity to the endonuclease. One of ordinary skill in the art would realize that this may be adjusted to target any sequence, making it specific for that sequence, and may make the Cas protein an Alu specific restriction enzyme (Title and throughout). Furthermore, SEQ ID NO 4 discloses a CRISPR-Cas guide RNA that would cleave at the same target as another Alu specific restriction enzyme AluI (between the G and C of 5’-AGCT -3’), implying that the first nucleic acid being targeted by this guide would have at least one sequence that maps to the restriction enzyme.
In regards to claims 11 and 12, Carpenter teaches that the nucleic acid may be capped at only one end and cleaved (¶0011-¶0013, ¶0018, ¶0056, and throughout).
In regards to claim 13, Carpenter teaches purifying the products after endonuclease digestion (Fig. 2, Figs. 8 -10, ¶0191-¶0192, ¶0197, and throughout).
In regards to claim 14, Carpenter teaches that the nucleic acids in the sample may consist of any form of RNA, DNA or a combination of the two (¶0043 - ¶0045).
In regards to claims 15 - 18, Carpenter teaches both amplifying and sequencing the nucleic acids (Figs. 1-3, Fig. 10, ¶0080, ¶0115, ¶0163, and throughout). Carpenter teaches using 2nd generation sequencing and nanopore sequencing methods (¶0067, and throughout).
In regards to claim 25, Carpenter teaches the second nucleic acid comprises a microbiome nucleic acid, an oncogenic nucleic acid, a symbiont nucleic acid, a single copy region of a haploid genome, a nucleic acid from a pathogen, or a nucleic acid from a tumor (Figs. 1 – 2, Fig. 8 – 11., ¶0010, ¶0021, ¶0068 - ¶0073, ¶0105, and throughout).
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 1-3 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 4 of copending Application No. 18/041,041. Although the claims at issue are not identical, they are not patentably distinct from each other because each dependent claim of these applications requires a starting material of a plurality of nucleic acid molecules, consisting of a first and second nucleic acid. The first and second nucleic acids are modified at the 5’ and 3’ ends and then contacted with an endonuclease that cleaves the first nucleic acid. The sample is subsequently contacted with an exonuclease, which digest the previously cleaved first nucleic acid, while leaving the second nucleic acid intact. While claim 4 of the ‘041 application does not specify a species of endonuclease, they do describe the genus of endonuclease to be utilized, which includes Argonaute (see ‘041, ¶0046). Selection of the species Argonaute form among the disclosed genus of endonucleases represents an obvious variation that does not render the instant claims patentably distinct from the claims of the ‘041 application. While the preamble of claim 1 in the current application describes a method of depleting a first nucleic acid in a sample and doesn’t specify that they are preparing a library, the abstract of the application states the goal of the method is to prepare a database of nucleic acids in which the first nucleic acid has been removed, which a person having ordinary skill in the art would recognize as synonymous with preparing a library. Copending application ‘041 further adds a step for size exclusion, which is an obvious variant of the current application and is taught as a preferred embodiment of the invention (‘102; ¶0125 - ¶0144). While not explicitly stated in the claim 4 of copending application, the nucleic acid containing an Alu repeat as required by the current application is an obvious variant, as they make up are over 10 % of the human genome (reviewed by Deininger; “Alu elements: know the SINEs, Genome Biology 12, Article 236, 2011). Furthermore, claims 15 and 24 of the copending application would imply that targeting nucleic acids possessing Alu elements is the preferred embodiment of the copending application as well. One of ordinary skill in the art would be likely to target this abundant region of the genome when aiming to deplete human nucleic acids from a sample, and would be motivated to do so as these short-interspersed elements are primate specific (Deininger; Abstract), making it more them more likely to succeed at deplete only human nucleic acids from the sample.
Instant claims 4 and 5 were not amended and therefore the rejections cited in the previous office action still apply in light of the arguments stated above regarding the amendments to claim 1.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Matthew H Raymonda whose telephone number is (703)756-5807. The examiner can normally be reached Monday - Friday 10:00 am - 4:00 pm.
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/MATTHEW HAROLD RAYMONDA/Examiner, Art Unit 1684 /AARON A PRIEST/Primary Examiner, Art Unit 1681