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 .
Response to Arguments
The Amendment filed 12/04/2025 in which claims 3, 15, 17, and 36 were amended has been entered.
Claim 15 has an improper status identifier. Applicant is reminded that after each claim number, the status identifier of the claim must be presented in a parenthetical expression, and the text of each claim under examination as well as all withdrawn claims (each with markings if any, to show current changes) must be presented. Claim 15 was amended in the Response filed on 12/05/2025, but is still identified as “Original”. See MPEP 714(II)(C).
Claims 1-7, 15-17, and 36 are under examination on the merits.
Nucleotide and/or Amino Acid Sequence Disclosures
(Previous objection, withdrawn) REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Drawings
(Previous objection, withdrawn) The drawings are objected to because Figure 8B contains sequences without corresponding SEQ ID NOs.
(New objection, necessitated in view of the amendment) The drawings are objected to because Figure 8 is not of sufficient quality. The labels for both the X and Y axis of Figure 8B are illegible. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Rejections - 35 USC § 112(b)
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.
(Previous objection, withdrawn) Claims 15 and 36 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 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.
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.
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.
(Previous objection, maintained) Claims 1-7, 15-17, and 36 are rejected under 35 U.S.C. 103 as being unpatentable over Larman and Credle (US20180208967A1- included on IDS) in view of Kearney et al (WO1990012116- included on IDS).
Claim 1 is drawn to a method for forming a target RNA proxy in a sample comprising use of a target capture probe, a 3’ acceptor probe, and a 5’ phosphorylated donor probe wherein the target capture probes are immobilized on a solid support and the acceptor probes and donor probes are ligated to form the target RNA proxy. Claim 15 is drawn to a method identical to claim 1 except wherein the sample is obtained from a patient suspected of being infected with a pathogen.
Regarding claims 1 and 15, Larman and Credle teach a method of forming an RNA proxy in a sample comprising applying one or more multi-partite probes comprising a 3’ acceptor probe, a 5’ phosphorylated probe (paragraphs 0004-0005), and a capture probe (paragraph 0091). Larman and Credle teach that the method comprises the steps of hybridizing the probes to the sample, washing away excess probes, and ligating the annealed probes (paragraph 0070). Regarding claim 15, Larman and Credle also teach that the sample can be obtained from a subject suspected of being infected with a pathogen (Larman and Credle claim 30). Larman and Credle do not teach that the capture probes are immobilized on a solid support.
However, Kearney et al teaches a method for determining the presence of a target nucleic acid in a sample comprising use of capture probes that hybridize to the target nucleic acid and wherein the capture probes are immobilized on a solid support to enable separation of the capture probe – target nucleic acid hybrids (Kearney et al claim 27).
It would have been prima facie obvious to a person with ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Larman and Credle and Kearney et al to arrive at a method for forming a target RNA proxy in a sample comprising use of a target capture probe, a 3’ acceptor probe, and a 5’ phosphorylated donor probe wherein the target capture probes are immobilized on a solid support and the acceptor probes and donor probes are ligated to form the target RNA proxy. One would have been motivated to do so for the advantage of specifically detecting target RNAs and enabling efficient separation of the capture probe - target RNA hybrid from the rest of the sample through use of the solid support as taught by Kearney et al. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Regarding claims 2 and 16, Larman and Credle teach that the 3’ acceptor probe and 5’ phosphorylated probe comprise primer binding sites for amplifying the target nucleic acid proxy (Larman and Credle claim 4).
Regarding claims 3 and 17, Larman and Credle teach detecting the target nucleic acid proxy by sequencing (paragraph 0009).
Regarding claim 4, Larman and Credle teach quantification of the nucleic acid proxy ligation products (i.e., target RNA) by qPCR (paragraph 0105).
Regarding claims 5 and 6, Larman and Credle teach that ligation with Rnl2 requires a 3’-dirbonucleotide probe (i.e., two 3’ terminal ribonucleotides) (paragraph 0093).
Regarding claim 7, Larman and Credle teach that the target nucleic acid is viral, bacterial, or fungal (i.e., derived from a pathogen) (paragraph 0015).
Regarding claim 36, Larman and Credle teach labeled probes (paragraph 0137) and that the label is biotin (paragraph 0032).
Thus, the inventions of claims 1-7, 15-17, and 36 as a whole were prima facie obvious to one of ordinary skill in the art before the effective filing date of the invention, especially in the absence of evidence to the contrary.
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.
(Previous objection, maintained) Claims 1-7, 15-17, and 36 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-4, 33, 46-47, and 54 of copending Application No. 18209992 in view of Larman and Credle and Kearney et al. Although the claims at issue are not identical, they are not patentably distinct from each other because:
Instant claims 1 and 15 are drawn to methods for forming a target RNA proxy in a sample comprising use of a target capture probe, a 3’ acceptor probe, and a 5’ phosphorylated donor probe wherein the target capture probes are immobilized on a solid support and the acceptor probes and donor probes are ligated to form the target RNA proxy. Instant claim 15 expands on this method wherein the sample is derived from a patient suspected of being infected with a pathogen.
Copending application ‘992 claims 1 and 33 are drawn to methods comprising applying one or more multi-partite probes to a sample comprising at least two sub-probes, annealing the probes to a target nucleic acid within the sample, and ligating the sub-probes to generate a detectable proxy nucleic acid. Copending application ‘992 claim 54 is drawn to the method of claim 33 wherein one of the sub-probes is 3’ diribonucleotide terminated and another sub-probe contains a 5’ phosphorylated end.
As discussed above, Kearney et al teaches capture probes immobilized on a solid support. The obviousness rationale of this combination is discussed above. Kearney et al also teaches that nucleic acid hybridization methods are used for pathogen detection (paragraph 3).
Regarding the dependent claims:
Instant claims 2, 5-6, and 16 and copending application ‘992 claims 4 and 54 are drawn to probes comprising a 3’ diribonucleotide, a 5’ phosphorylation, and primer annealing sites.
Instant claims 3, 4, 17, and 36 and copending application ‘992 claims 46-47 are drawn to detection and quantification of the nucleic acid proxy. Copending application ‘992 claims 46-47 are not drawn to sequencing-based detection, quantification, or a probe labeled with biotin. However, as discussed above, Larman and Credle teach sequencing based detection (paragraph 0009) and quantification (paragraph 0105) of the RNA proxy and biotin-labeled probes (paragraphs 0032 and 0137).
Instant claim 7 and copending application ‘992 claim 3 is drawn to the target nucleic acid. Copending application ‘992 claim 3 is not drawn to the target nucleic acid being pathogen-associated RNA. However, as discussed above, Larman and Credle teach that the target nucleic acid is viral, bacterial, or fungal (i.e., derived from a pathogen) (paragraph 0015).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant's arguments filed 12/04/2025 have been fully considered but they are not persuasive.
Applicant contends on page 9 of the Remarks: The nucleotide and/or amino acid sequence disclosures have been amended.
In response: The objection has been withdrawn.
Applicant contends on page 10 of the Remarks: Figure 8B has been corrected to include sequences with corresponding SEQ ID NOs
In response: While the Figure 8B has been corrected to have sequences corresponding SEQ ID NOs, Figure 8b is illegible. Appropriate corrections is required.
Applicant contends on page 10 of the Remarks: Claim 15 was amended to replace “5.” With “5””. Claim 36 was amended to longer be indefinite.
In response: The 35 U.S.C. § 112(b) rejection to claims 15 and 36 has been withdrawn.
Applicant contends on page 10 of the Remarks:
The capture probe mentioned in Larman and Credle is within the amplifiable RNA proxy sequence, not a distinct oligonucleotide
Kearney teaches “a certain capture of RNA for the purpose of generating a protected, RNAse A resistant sequence” while the application “discloses capture of target RNA for for purposes that include: (i) so that excess (unbound) ligation probes can be washed away to not add spurious background proxy signals, and (ii) to immobilize the target RNA and hybridized ligation.” And that “one of skill would have combined Larman and Credle with Kearney et al., the end result would not capture a target by use of a target capture probe. Instead of the target RNA, it would capture the amplifiable proxy, which would not improve specificity as described by the Applicant.”
Kearney teaches a first probe specific for the target nucleic acid, hybridizing the first probe to the target nucleic acid to form a hybrid, which is then immobilized on a solid support. Once the hybrids are released, these are then contacted with a second probe which is labeled and capable of binding to the target nucleic acid. The contacting step requires the reagent exemplified in claim 1 of Kearney and that Larman and Credle are concerned with analysis of RNA from fixed tissue specimens and that the use of a capture is not required for Larman and Credle. And “one of skill in the art would not have any motivation to add a capture probe as this would require that RNA to be extracted first from a fixed tissue sample resulting in further damage to the RNA”
In response: The 35 U.S.C. § 103(b) rejection is maintained.
Applicant argues that the capture probe mentioned in Larman and Credle is within the amplifiable RNA proxy sequence, not a distinct oligonucleotide.
Larman and Credle teach: “The detectable amplification molecule may include a capture probe sequence that is a nucleic acid sequence capable of hybridizing with the nucleic acid binding probe sequence for the bipartite probe” (¶0091). Larman and Credle do not limit the capture probe to a distinct oligonucleotide nor just within an amplifiable RNA proxy sequence. Furthermore, the instant claims do not limit the capture probe to a distinct oligonucleotide. Therefore, the arguments are not commensurate with the broad scope of the claims and do not overcome the rejection.
Kearney teaches “a certain capture of RNA for the purpose of generating a protected, RNAse A resistant sequence” while the application “discloses capture of target RNA for purposes that include: (i) so that excess (unbound) ligation probes can be washed away to not add spurious background proxy signals, and (ii) to immobilize the target RNA and hybridized ligation.” And that “one of skill would have combined Larman and Credle with Kearney et al., the end result would not capture a target by use of a target capture probe. Instead of the target RNA, it would capture the amplifiable proxy, which would not improve specificity as described by the Applicant.”
A target RNA according to the application can include capture of RNA for the purpose of generating a protected RNAse A resistant sequence. Kearney is not limited to just a purpose of generating RNAse A resistant sequences. The method and products described in Kearney can be used to target a multitude of different RNAs and for different purposes (Table 9) target RNA. Furthermore, the instant claims do not limit targeting RNA to exclude RNA capture for the purpose of generating a protected, RNAse A resistant sequence.
Kearney teaches a first probe specific for the target nucleic acid, hybridizing the first probe to the target nucleic acid to form a hybrid, which is then immobilized on a solid support. Once the hybrids are released, these are then contacted with a second probe which is labeled and capable of binding to the target nucleic acid. The contacting step requires the reagent exemplified in claim 1 of Kearney and that Larman and Credle are concerned with analysis of RNA from fixed tissue specimens and that the use of a capture is not required for Larman and Credle. And “one of skill in the art would not have any motivation to add a capture probe as this would require that RNA to be extracted first from a fixed tissue sample resulting in further damage to the RNA”
Larman and Credle teach that the sample can be a cell, organ, tissue or a combination there of and that it does not need to be fixed (“In some examples, the sample may be fixed using non-formalin reagents, including, for example, glutaraldehyde, mercurial, oxidizing agents, alcohols, and picrates. In other examples, the sample may include fixed cells in suspension or a fixed tissue culture. The sample may be obtained in a highly degraded form prior to fixation. In particular, the sample may be a formalin fixed paraffin embedded (FFPE) tissue sample.”; bold added for emphasis, ¶0007). Furthermore, Larman and Credle also teach that the method taught can be used to identify RNA in highly degraded tissue. Therefore, one of ordinary skill in the art would use the methods and products taught by Larman and Credle in both fresh and fixed tissue. Additionally, even if RNA is extracted from fixed tissue examples, resulting in further damaged RNA, Larman and Credle in view of Kearny teach that the method will still work with highly degraded RNA.
Applicant contends on page 13 of the Remarks:
Application No. 18/209,992 is also concerned with analyzing RNA from fixed tissue samples. As discussed above, RNA is likely damaged from the harsh conditions used to fix a specimen and any further extraction would result in damaging the RNA even more. Indeed, Larman and Credle and Kearney et al. would require two different capture probes, thereby rendering Larman and Credle inoperable. Applicant submits that claims 1-7, 15-17, and 36 are therefore patentably distinct claims 1, 3-4, 33, 46-47, and 54 of copending Application No. 18209992 in view of Larman and Credle and Kearney et al.
In response: The non-statutory double patenting rejection is maintained.
Larman and Credle teaches that the sample can be a cell, organ, tissue or a combination there of and that it does not need to be fixed (“In an embodiment, the sample may be selected from the group consisting of a cell, an organ, a tissue, and any combination thereof. In some examples, the sample may be fixed using non-formalin reagents, including, for example, glutaraldehyde, mercurial, oxidizing agents, alcohols, and picrates. In other examples, the sample may include fixed cells in suspension or a fixed tissue culture. The sample may be obtained in a highly degraded form prior to fixation.”; bold added for emphasis, ¶0007). Furthermore, Larman and Credle also teach that the method taught can be used to identify RNA in highly degraded tissue. Therefore, one of ordinary skill in the art would use the methods and products taught by Larman and Credle in both fresh and fixed tissue. Additionally, even if RNA is extracted from fixed tissue examples, resulting in further damaged RNA, Larman and Credle in view of Kearny teach that the method will still work with highly degraded RNA.
Conclusion
NO CLAIMS ARE ALLOWED
THIS ACTION IS MADE FINAL. 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 Danyal H Alam whose telephone number is (571)272-1102. The examiner can normally be reached M - F 9am - 5pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Thomas J. Visone can be reached at 571-270-0684. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DANYAL HASSAN ALAM/Examiner, Art Unit 1672
/THOMAS J. VISONE/Supervisory Patent Examiner, Art Unit 1672
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