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 .
DETAILED ACTION
Election/Restrictions
Claim 37 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the telephone conversation on 7/10/2025. The reply filed on 12/17/2025 also did not include any traversal.
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 1, 3-9, 12, 15, 17-21, 24-27 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 1 recites steps of contacting and ligating. While the contacting step requires that the RNA sample contain at least one component of a translational machinery, there is nothing in the contacting and ligating steps that suggests that the oligonucleotide conjugated entities bind to the component of a translational machinery. Applicant has added “thereby forming a complex” to claim 1 (amendment, 12/17/2025), but the claim still does not specify that the complex includes a component of translational entities, nor does the claim state that the oligonucleotide conjugated entities are specific for or target the translational machinery. Therefore, it is unclear how the contacting and ligating are sufficient to allow for the final step of identifying any RNA in the RNA sample associated with the translational machinery “based on” the chimeric RNA since there is nothing in the claim to link the ligation to form chimeric RNA to the translational machinery.
Claim 1 is further indefinite because it now recites “ligating any RNA targets from the complex” but it fails to state what the RNA targets are ligated to, and thus leaves the claims ambiguous and indefinite. All claims depend from claim 1 and fail to remedy this issue, so all claims are indefinite for at least his reason.
Claim Rejections - 35 USC § 103
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.
Claim(s) 1, 3, 4-7, 9, 12, 15, 17, 18, 19, 20, 24, 25, 26, and 27 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lewis (US 2015/0011398) in view of Yeo et al. (US 2023/0135002).
Lewis teaches a method for identifying RNAs bound by RNA binding proteins comprising:
contacting an RNA sample with a multiplexed mixture of oligonucleotide conjugated entities, thereby forming a complex;
ligating any RNA targets from the complex by proximity-based ligation to form one or more chimeric RNA molecules; and
identifying any RNA in the RNA sample associated with the RNA binding protein based on the one or more ligated chimeric RNA molecules. See Lewis, Example 3, ¶55, and Figure 8.
In Example 3, Lewis teaches selecting “antibodies” for “a set” of RNA binding proteins (¶55), and that teach antibody is conjugated with its specific signature oligonucleotide such as a barcode of other identifying sequence. Thus, regarding claim 1, Lewis teaches contacting an RNA sample with a multiplexed mixture of oligonucleotide conjugated entities.
Lewis teaches that the oligonucleotide conjugated entities comprise barcode sequences capable of identifying the one or more chimeric RNA molecules (¶54-55).
Lewis teaches that the method can be carried out with as few as two or as many as 50,000 different proteins (¶37), and that the antibodies each have a unique oligo (¶54, 55).
Lewis teaches isolating the ligated RNA (¶55).
Lewis teaches the sample is UV cross-linked (¶55).
Lewis teaches amplifying the chimeric RNA molecules to produce an amplified product (¶52).
Lewis teaches identifying a chimeric RNA molecule of interest by sequencing the one or more chimeric molecules (¶55). Lewis teaches identifying the sequence of the chimeric oligonucleotides and using this to identify the RNA binding protein via the signature oligo, which identifies the antibody, which identifies the protein and the RNA sequence where it binds (¶55).
Lewis teaches wherein the one or more oligonucleotide conjugated entities comprises an oligo-barcoded sequence (¶54, 55).
Regarding claim 18, the claim only appears to require the recited RNA binding proteins are present in the sample, there is no action required such as binding the RNA binding proteins. As these are ubiquitously expressed binding proteins, it would have been inherent that they were present in the HEK293 cells taught by Lewis.
Lewis does not teach identifying any RNA in the RNA sample associated with translational machinery. Lewis does not teach fragmenting RNA.
Yeo teaches a method wherein a biological sample is crosslinked and the sample is then lysed and RNA in the biological sample is fragmented with RNASE and a ribosomal subunit (example: RPS3 or RPS2) is immunoprecipitated using an antibody which pulls down the ribosomal subunit and the crosslinked RNA. The RNA is ligated to DNA adapters and sequenced. See Figure 1, ¶18. Yeo that quantification of ribosome-associated RNA is highly similar to profiling of RNAs associated with other RNA binding proteins (¶33). Yeo teaches that carrying out the method with RNA binding proteins that are part of the ribosomal subunit (¶12).
It would have been prima facie obvious to have modified the method taught by Lewis so as to have used an antibody or antibodies that bind to ribosomal RNA binding proteins, such as RPS2 or RPS3 in order to enable the application of the method taught by Lewis to the profiling of RNAs associated with ribosomes (¶33), since Yeo teaches that the quantification of ribosome-associated RNA is highly similar to profiling of RNAs associated with other RNA binding proteins, and Lewis teaches carrying out the method with a set of antibodies specific for RNA binding proteins (¶55).
Further, it would have been prima facie obvious to have included a step of fragmenting the crosslinked RNA with RNASE as taught by Yeo as yeo teaches that the RNA fragmentation step is performed to enable improved depletion of ribosomal RNAs (¶38).
Claim(s) 8 and 21 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lewis (US 2015/0011398) in view of Yeo et al. (US 2023/0135002) as applied to claims 1, 3, 4-7, 9, 12, 15, 17, 19, 20, 24, 25, 26, and 27 above, and further in view of Wu et al. (NATURE COMMUNICATIONS | (2019) 10:3854; 10 pages).
The teachings of Lewis in view of Yeo et al. are given previously in this Office action and are fully incorporated here.
The combined references do not teach a method wherein the barcode contains a randomized sequence capable of determining if a molecule is unique or a PCR duplicate.
The combined references do not teach the means of attachment of the antibody to the oligonucleotide.
Wu et al. teach conjugating antibodies with DNA oligonucleotides comprising a random 8 nucleotide molecular identifier to distinguish individual protein molecules after PCR amplification (p. 2, Col. 2). Wu et al. additionally teach oligonucleotide conjugation to antibodies using a thiol reactive probe (p. 8, Col. 2).
It would have been obvious to have modified the method taught by Lewis in view of Yeo so as to have added a UMI to the anti-body specific oligos for the expected benefit of adding a way to distinguish individual protein molecules after PCR.
It would also have been obvious to have conjugated the oligonucleotide taught by Lewis to the antibodies using a thiol reactive probe technique in order to provide the predictable result of conjugating the antibodies and the oligos. Although Lewis clearly teaches conjugating the oligos to the antibodies, they do not provide any specific techniques. One skilled in the art would have been motivated to use the technique disclosed by Wu in order to achieve the desired effect of providing antibodies conjugated to oligonucleotides.
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, 3-9, 12, 15, 17-21, 24-27 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 11795500 in view of Yeo et al.
The copending claims teach a very similar method to the claimed method, except that they do not teach that the RNA binding protein is part of the translational machinery.
The teachings of Yeo are given previously in this office action and are fully incorporated here.
It would have been prima facie obvious to have modified the method taught by the issued claims so as to have used antibodies that bind to ribosomal RNA binding proteins, such as RPS2 and RPS3 in order to enable the application of the method taught by Lewis to the profiling of RNAs associated with ribosomes (¶33), since Yeo teaches that the quantification of ribosome-associated RNA is highly similar to profiling of RNAs associated with other RNA binding proteins, and the Lewis teachs carrying out the method with a set of antibodies specific for RNA binding proteins (¶55).
Further, it would have been prima facie obvious to have included a step of fragmenting the crosslinked RNA with RNASE as taught by Yeo as yeo teaches that the RNA fragmentation step is performed to enable improved depletion of ribosomal RNAs (¶38).
Claims 1, 3-9, 12, 15, 17-21, 24-27 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-20 of U.S. Patent No. 12460257 in view of Yeo et al.
The copending claims teach a very similar method to the claimed method, except that they do not teach that the RNA binding protein is part of the translational machinery.
The teachings of Yeo are given previously in this office action and are fully incorporated here.
It would have been prima facie obvious to have modified the method taught by the issued claims so as to have used an antibody or antibodies that bind to ribosomal RNA binding proteins, such as RPS2 or RPS3 in order to enable the application of the method taught by Lewis to the profiling of RNAs associated with ribosomes (¶33), since Yeo teaches that the quantification of ribosome-associated RNA is highly similar to profiling of RNAs associated with other RNA binding proteins, and the issued claims teach carrying out the method with a set of antibodies specific for RNA binding proteins (¶55).
Further, it would have been prima facie obvious to have included a step of fragmenting the crosslinked RNA with RNASE as taught by Yeo as yeo teaches that the RNA fragmentation step is performed to enable improved depletion of ribosomal RNAs (¶38).
Response to Remarks
On page 7 of the response applicant points out that Lewis does not teach profiling multiple ribosomal proteins. This is a piecemeal analysis; the rejection itself addresses that Lewis fails to teach antibodies that bind “translational machinery.”
Applicant points out that Yeo does not teach a multiplex method. This is also a piecemeal analysis, since Lewis very clearly teaches employing multiple antibodies that bind RNA binding proteins.
Applicant argues that the references teach fundamentally different concepts; however, Lewis teaches a RBP profiling approach to determine RNA molecules that are bound by RNA binding proteins, and Yeo also teaches attempts to analyze RNA that are bound by RNA binding proteins, specifically RNA binding proteins that function in translational processes. The two references are closely related.
Applicant argues that the examiner’s rational is unsupported by any teaching of suggestion in either reference1. However, Yeo teaches that the quantification of ribosome-associated RNA is highly similar to profiling of RNAs associated with other RNA binding proteins, and the Lewis specifically carrying out the method with a set of antibodies specific for RNA binding proteins (¶55). Lewis teaches a general method which employs antibodies specific for RNA binding proteins, and Yeo provides specific targets of interest. As to applicant’s argument that no motivation is provided MPEP 2144 teaches “When considering obviousness, Office personnel are cautioned against treating any line of reasoning as a per se rule.” Here the rejection has explained why one would have been motivated to apply the method of Lewis to ribosomal protein binding: that is to analyze the RNA bound by ribosomal machinery, as taught by Yao.
Applicant further argues that combining the methods would fundamentally change the principle of operation of Yeo’s single-plex assay. However, there is no evidence that employing the antibodies of Yeo in the multiplex assay of Lewis would have resulted in less or inferior information about the RNA bound by the subject proteins. Studying that RNA is the goal of both methods.
Accordingly, the rejections are maintained.
Applicant requested the rejections under double patenting be held in abeyance. Rejections are not held in abeyance. The rejection is maintained.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Nostrand et al. (Nature Methods VOL.13 NO.6 | JUNE 2016 pages 508-514, plus online methods) teach an immunoprecipitation-based method for capturing RNA bound by RNA binding proteins and sequencing the bound RNA. The method is designed to identify RNA bound by RNA binding proteins. The reference teaches conducting the eCLIP experiment with 73 different RBPs, and provide data related to RBFOX2, throughout.
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 Juliet Switzer whose telephone number is (571)272-0753. The examiner can normally be reached Monday to Thursday, 8:00 AM-3:30 PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Winston Shen can be reached at (571)-272-3157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Juliet Switzer
Primary Examiner
Art Unit 1682
/JULIET C SWITZER/Primary Examiner, Art Unit 1682
1 The portion of MPEP 2144 which was quoted by Applicant could not be identified, particularly the part that reads “without also providing evidence of the motivating force which would impel one skilled in the art to do what the patent applicant has done.”