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 .
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on October 20th, 2022 and June 3rd, 2024 are acknowledged. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements have been considered by the examiner.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-3, 6, 8-11, 14-15, 17-20, 24 and 26, in the reply filed on September 30th, 2025 is acknowledged.
Claims 28-29 and 31 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 reply filed on September 30th, 2025.
Claim Summary
Claims 1, 14, and 28 have been amended. Claims 4-5, 7, 12-13, 16, 21-23, 25, 27, and 30 have been canceled. Claims 1-3, 6, 8-11, 14-15, 17-20, 24, 26, 28-29, and 31 are pending. Claims 28-29 and 31 are withdrawn from consideration as being drawn to a non-elected invention/species. Claims 1-3, 6, 8-11, 14-15, 17-20, 24, and 26 are under examination and discussed in this Office action.
Claim Objections
Claim 1 is objected to because of the following informalities:
Claim 1, at line 7, has a typo in the abbreviation of RNA binding protein. “RPB” should be changed to “RBP”.
Appropriate correction is required.
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.
Claims 1-3, 6, 8-11, 14-15, 17-20, 24, and 26 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 the limitation “profiling the RNA fragment bound by the RPB, thereby determining a translation rate of the RNA in the biological sample”. It is unclear from this recitation how profiling the RNA fragment then leads to determining a translation rate. There’s no calculation or formula to do so indicated in the claim, and therefore there is no clear nexus between “profiling the RNA fragment bound by the RPB” and “thereby determining a translation rate of the RNA in the biological sample”. Turning to the specification, translation rate is not clearly equated to a specific calculation. Page 10, lines 30-21 state, “the normalized Ribo-eCLIP enrichment correlates with translation rate estimates from independent approaches”, but does not clarify what this enrichment or normalization entails, nor how this relates to determining translation rate. Page 13, lines 22-26 state, “profiling includes sequencing of a nucleic acid (e.g., DNA or RNA), wherein the gene expression profile includes information of active translation at a point in time. As used herein, the term "translation rate" can refer to the level of translation of an mRNA in a cell, wherein translation is the process in which ribosomes synthesize proteins after the process of transcription of DNA to RNA. In some embodiments, genetic differences and their subsequent expression as mRNAs impact the translation rate in an RNA-specific matter”. However, this also does not clarify how translation rate is then determined. Finally, Page 18, lines 20-28 state, “[n]ext, it was tested whether Ribo-eCLIP accurately quantitates ribosome-associated RNAs and it was also tested whether per-gene enrichments in Ribo-eCLIP (quantitated as fold-enrichment in IP versus paired input) corresponded to independent measurement of ribosome-associated RNAs obtained by isolation of polysomes followed by RNA-seq. By binning all expressed RNAs into 10 bins based on the ratio of polysome-associated to monosome- or non-ribosome-associated expression, it was observed that Ribo-eCLIP enrichments indeed significantly correlated with polysome-associated RNA enrichments (FIG. 3C). Thus, Ribo-eCLIP recapitulates independent assessments of ribosome-associated RNAs.” This passage from the examples appears to be the most relevant in terms of calculating outcomes from Ribo-eCLIP data. However, it addresses quantification of RNAs and per-gene enrichments, and not specifically determining a rate of translation. Without any further explanation provided, it cannot be clearly determined whether one of these quantifications is actually for determining a translation rate. The cited figure (Figure 3C) appears to relate a translation rate estimate to IP versus input ratio, but it is unclear from this axis label or the figure description what these compared values entail, or even if they are the same as the similar values described in the specification (fold-enrichment in IP versus paired input). Furthermore, even if what is seen in the specification and on the figure was how translation rate is calculated, it would be improper for the Examiner to read limitations from the specification into the claims (See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993)). Overall, there is no clear description of how translation rate can be determined. Claim 14 recites the similar limitation, “profiling the RNA fragment bound by the RNA binding protein, thereby analyzing RNA translation rate in the biological sample”, and is also rejected here for the same issues.
Claims 2-3, 6, 8-11, 15, 17-20, 24, and 26 are also rejected here for their dependence on either claim 1 or claim 14 and not further clarifying the identified issue.
For the purpose of compact prosecution, “profiling the RNA fragment bound by the RPB, thereby determining a translation rate of the RNA in the biological sample”, as well as any other mention of translation rate, will be interpreted as profiling will necessarily determine the translation rate once the profiling of the RNA fragment has been accomplished. “Profiling” as defined in the specification refers to the measurement of an activity (e.g. expression) of one or more genes, and includes sequencing of a nucleic acid to determine a gene expression profile that includes information about translation (Page 13, lines 22-26). Based on this definition, and profiling as claimed, profiling is considered to be sequencing, and determining translation rate is accomplished when sequencing has been accomplished.
Claims 10 and 19 recite the limitation “amplifying the RNA fragment or the cDNA fragment to generate one or more amplification products”. It is unclear from this recitation if there is still supposed to be RNA fragments at this step or not. Claim 18, from which claim 19 depends, recites that profiling comprises isolating the RNA fragment from the RNA-RBP complex and producing a cDNA fragment. Claim 19 itself earlier recites that a DNA adapter is ligated to a 3’ end of the cDNA fragment. It is therefore unclear if there is intended to be RNA fragment at this step, or if all RNA should have been reverse transcribed into cDNA. Claims 11 and 20, which depend from claims 10 and 19 respectively, are also rejected here for their dependence on the claims at issue and for not further clarifying the issues of their respective claims. For the purpose of compact prosecution, “amplifying the RNA fragment or the cDNA fragment to generate one or more amplification products” will be interpreted as amplifying the cDNA fragment to generate one or more amplification products.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-3, 6, 8-11, 14-15, 17-20, 24, and 26 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
In making a determination of whether the application complies with the written description requirement under 35 U.S.C. 112(a) or 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant is claiming and what Applicant has possession of. To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V, v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was “ready for patenting” such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaff v. Wells Eiees., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641,1647 (1998); Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406; Amgen, Inc. v. Chugai Pharm., 927 F. 2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991). See MPEP § 2163.
Claim 1 recites the limitation “[a] method of determining RNA translation rate in a biological sample, the method comprising: (a) crosslinking an RNA binding protein (RBP) to an RNA in a biological sample; (b) identifying an RNA-RNA binding protein (RNA-RBP) complex within the biological sample, wherein the RNA-RBP complex comprises an RNA fragment bound by the RBP; and (c) profiling the RNA fragment bound by the RPB, thereby determining a translation rate of the RNA in the biological sample, wherein the RBP comprises a ribosomal protein.” The claim as written embraces a method wherein RNA is crosslinked to an RNA binding protein, identified, and then profiled to determine a translation rate of the RNA of interest. However, determining a translation rate based on the previous steps is not further defined or described in the claims.
Claim 14 recites the limitation “[a] method of analyzing RNA translation rate in a biological sample, the method comprising: (a) identifying an RNA-RNA binding protein (RBP) complex within a biological sample, wherein the RNA-RBP complex comprises an RNA fragment bound by an RNA binding protein; (b) isolating the RNA-RBP complex; and (c) profiling the RNA fragment bound by the RNA binding protein, thereby analyzing RNA translation rate in the biological sample, wherein the RBP comprises a ribosomal protein.” The claim as written embraces a method wherein an RNA-RBP complex is identified, isolated, and then profiled to analyze a translation rate of the RNA of interest. However, determining a translation rate based on the previous steps is not further defined or described in the claims.
Turning to the specification, there is no description that clearly defines or describes how a translation rate is determined. Page 10, lines 30-21 state, “the normalized Ribo-eCLIP enrichment correlates with translation rate estimates from independent approaches”. This passage does not describe what enrichment or normalization entails, nor how normalized Ribo-eCLIP enrichment correlates or is equivalent to determining translation rate. Page 13, lines 22-26 state, “profiling includes sequencing of a nucleic acid (e.g., DNA or RNA), wherein the gene expression profile includes information of active translation at a point in time. As used herein, the term "translation rate" can refer to the level of translation of an mRNA in a cell, wherein translation is the process in which ribosomes synthesize proteins after the process of transcription of DNA to RNA. In some embodiments, genetic differences and their subsequent expression as mRNAs impact the translation rate in an RNA-specific matter”. This passage appears to indicate that, at most, translation rate is related to expression of mRNA. However, this passage also does not further describe how translation rate is determined. Finally, Page 18, lines 20-28 state, “[n]ext, it was tested whether Ribo-eCLIP accurately quantitates ribosome-associated RNAs and it was also tested whether per-gene enrichments in Ribo-eCLIP (quantitated as fold-enrichment in IP versus paired input) corresponded to independent measurement of ribosome-associated RNAs obtained by isolation of polysomes followed by RNA-seq. By binning all expressed RNAs into 10 bins based on the ratio of polysome-associated to monosome- or non-ribosome-associated expression, it was observed that Ribo-eCLIP enrichments indeed significantly correlated with polysome-associated RNA enrichments (FIG. 3C). Thus, Ribo-eCLIP recapitulates independent assessments of ribosome-associated RNAs.” This passage from the examples appears to be the most relevant in terms of calculating outcomes from Ribo-eCLIP data. However, it addresses quantification of RNAs and per-gene enrichments, and not specifically determining a rate of translation. Without any further explanation provided, it cannot be clearly determined whether one of these quantifications is actually for determining a translation rate. The cited figure (Figure 3C) appears to relate a translation rate estimate to IP versus input ratio, but it is unclear from this axis label or the figure description what these compared values entail, or even if they are the same as the similar values described in the specification (fold-enrichment in IP versus paired input). Furthermore, even if what is seen in the specification and on the figure was how translation rate is calculated, it would be improper for the Examiner to read limitations from the specification into the claims (See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993)). Overall, there is no description that clearly defines or describes how a translation rate is determined.
Based on the above analysis, the Applicant does not have possession of the method as claimed. Claims 1-3, 6, 8-11, 14-15, 17-20, 24, and 26 do not present possession of the method as claimed and do not have support based on the specification.
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.
Claims 1-3, 6, 8-10, 14-15, and 17-19 are rejected under 35 U.S.C. 103 as being unpatentable over Van Nostrand (Robust transcriptome-wide discovery of RNA-binding protein binding sites with enhanced CLIP (eCLIP), Nature Methods, March 2016, 13, 508-514 plus Online Methods; cited on the IDS filed October 20th, 2022), in view of Culver (Meanderings of the mRNA through the Ribosome, Structure, September 2001, 9, 751-758).
Regarding instant claim 1, Van Nostrand teaches a method of determining RNA translation rate in a biological sample, the method comprising: (a) crosslinking an RNA binding protein (RBP) to an RNA in a biological sample (Figure 1A; Online Methods, Page 1, column 1, eCLIP-seq library preparation); (b) identifying an RNA-RNA binding protein (RNA-RBP) complex within the biological sample, wherein the RNA-RBP complex comprises an RNA fragment bound by the RBP (Figure 1A; Online Methods, Page 1, column 1, eCLIP-seq library preparation); and (c) profiling the RNA fragment bound by the RBP, thereby determining a translation rate of the RNA in the biological sample (Figure 1A; Online Methods, Page 1, column 1, eCLIP-seq library preparation; see 112(b) interpretation).
Van Nostrand does not teach wherein the RBP comprises a ribosomal protein.
Culver, in a reasonably pertinent field, teaches that ribosomal proteins can bind to RNA, necessarily indicating that they are RBPs (whole document, but noted at Page 751, Summary and Page 756, column 1, paragraph 4 for specific examples).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the RBP of Van Nostrand with ribosomal proteins from Culver. Since Culver teaches on RNA binding with ribosomal proteins as it relates to the ribosome, which is reasonably pertinent to the RBPs of Van Nostrand, one of ordinary skill in the art would combine the two teachings with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because it is known that ribosomal proteins bind to mRNA (Culver, whole document, but noted at Page 751, Summary and Page 756, column 1, paragraph 4 for specific examples). This would amount to simple substitution of one element for another to obtain predictable results (see MPEP 2141(III)).
Regarding instant claim 2, Van Nostrand, in view of Culver, teaches the method of claim 1. Van Nostrand further teaches wherein the crosslinking comprises UV crosslinking (Figure 1A; Online Methods, Page 1, column 1, eCLIP-seq library preparation).
Regarding instant claim 3, Van Nostrand, in view of Culver, teaches the method of claim 1. Van Nostrand further teaches wherein the method further comprises lysing the biological sample and fragmenting the RNA in the biological sample after step (a), thereby producing a lysate comprising a plurality of RNA fragments, wherein the fragmenting of the RNA comprises using a nuclease (Figure 1A; Online Methods, Page 1, column 1, eCLIP-seq library preparation).
Regarding instant claim 6, Van Nostrand, in view of Culver, teaches the method of claim 1. Van Nostrand further teaches wherein identifying step (b) further comprises contacting the RNA-RBP complex with an RBP specific antibody, thereby allowing immunoprecipitation of the RNA-RBP complex with the RBP specific antibody bound to the RNA-RBP complex (Figure 1A; Online Methods, Page 1, column 1, eCLIP-seq library preparation).
Regarding instant claim 8, Van Nostrand, in view of Culver, teaches the method of claim 1. Van Nostrand further teaches wherein identifying step (b) further comprises dephosphorylating a 3' and a 5' end of the RNA fragment and ligating an RNA adapter to the 3' end of the RNA fragment (Figure 1A; Online Methods, Page 1, column 1, eCLIP-seq library preparation).
Regarding instant claim 9, Van Nostrand, in view of Culver, teaches the method of claim 6. Van Nostrand further teaches wherein profiling step (c) comprises isolating the RNA fragment of the immunoprecipitated RNA-RBP complex and producing a cDNA fragment by reverse transcription (Figure 1A; Online Methods, Page 1, column 1, eCLIP-seq library preparation).
Regarding instant claim 10, Van Nostrand, in view of Culver, teaches the method of claim 9. Van Nostrand further teaches wherein profiling step (c) further comprises ligating a DNA adapter to a 3' end of the cDNA fragment (Figure 1A; Online Methods, Page 1, column 1, eCLIP-seq library preparation); amplifying the RNA fragment or the cDNA fragment to generate one or more amplification products (Figure 1A; Online Methods, Page 1, column 1, eCLIP-seq library preparation; see 112(b) interpretation); and sequencing the one or more amplification products to identify the isolated RNA fragment and determine the translation rate of the RNA in the biological sample (Figure 1A; Online Methods, Page 1, column 1, eCLIP-seq library preparation; see 112(b) interpretation).
Regarding instant claim 14, Van Nostrand teaches a method of analyzing RNA translation rate in a biological sample, the method comprising: (a) identifying an RNA-RNA binding protein (RBP) complex within a biological sample, wherein the RNA-RBP complex comprises an RNA fragment bound by an RNA binding protein (Figure 1A; Online Methods, Page 1, column 1, eCLIP-seq library preparation); (b) isolating the RNA-RBP complex (Figure 1A; Online Methods, Page 1, column 1, eCLIP-seq library preparation); and (c) profiling the RNA fragment bound by the RNA binding protein, thereby analyzing RNA translation rate in the biological sample (Figure 1A; Online Methods, Page 1, column 1, eCLIP-seq library preparation; see 112(b) interpretation).
Van Nostrand does not teach wherein the RBP comprises a ribosomal protein.
Culver, in a reasonably pertinent field, teaches that ribosomal proteins can bind to RNA, necessarily indicating that they are RBPs (whole document, but noted at Page 751, Summary and Page 756, column 1, paragraph 4 for specific examples).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the RBP of Van Nostrand with ribosomal proteins from Culver. Since Culver teaches on RNA binding with ribosomal proteins as it relates to the ribosome, which is reasonably pertinent to the RBPs of Van Nostrand, one of ordinary skill in the art would combine the two teachings with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because it is known that ribosomal proteins bind to mRNA (Culver, whole document, but noted at Page 751, Summary and Page 756, column 1, paragraph 4 for specific examples). This would amount to simple substitution of one element for another to obtain predictable results (see MPEP 2141(III)).
Regarding instant claim 15, Van Nostrand, in view of Culver, teaches the method of claim 14. Van Nostrand further teaches wherein isolating step (b) comprises contacting the RNA-RBP complex with an RBP specific antibody, thereby allowing immunoprecipitation of the RNA-RBP complex with the RBP specific antibody bound to the RNA-RBP complex (Figure 1A; Online Methods, Page 1, column 1, eCLIP-seq library preparation).
Regarding instant claim 17, Van Nostrand, in view of Culver, teaches the method of claim 14. Van Nostrand further teaches wherein isolating step (b) comprises dephosphorylating a 3' and a 5' end of the RNA fragment and ligating an RNA adapter to the 3' end of the RNA fragment (Figure 1A; Online Methods, Page 1, column 1, eCLIP-seq library preparation).
Regarding instant claim 18, Van Nostrand, in view of Culver, teaches the method of claim 15. Van Nostrand further teaches wherein profiling step (c) comprises isolating the RNA fragment of the immunoprecipitated RNA-RBP complex and producing a cDNA fragment by reverse transcription (Figure 1A; Online Methods, Page 1, column 1, eCLIP-seq library preparation).
Regarding instant claim 19, Van Nostrand, in view of Culver, teaches the method of claim 18. Van Nostrand further teaches wherein profiling step (c) further comprises ligating a DNA adapter to a 3' end of the cDNA fragment (Figure 1A; Online Methods, Page 1, column 1, eCLIP-seq library preparation); amplifying the RNA fragment or the cDNA fragment to generate one or more amplification products (Figure 1A; Online Methods, Page 1, column 1, eCLIP-seq library preparation; see 112(b) interpretation); and sequencing the one or more amplification products to identify the isolated RNA fragment and determine the translation rate of the RNA in the biological sample (Figure 1A; Online Methods, Page 1, column 1, eCLIP-seq library preparation; see 112(b) interpretation).
Claims 11 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Van Nostrand (Robust transcriptome-wide discovery of RNA-binding protein binding sites with enhanced CLIP (eCLIP), Nature Methods, March 2016, 13, 508-514 plus Online Methods; cited on the IDS filed October 20th, 2022) and Culver (Meanderings of the mRNA through the Ribosome, Structure, September 2001, 9, 751-758), as applied to claims 1-3, 6, 8-10, 14-15, and 17-19 above, and further in view of Derisi (US20180051320A1).
Regarding instant claim 11, Van Nostrand, in view of Culver, teaches the method of claim 10. Van Nostrand further teaches wherein the sequencing comprises high-throughput sequencing (Figure 1A; Online Methods, Page 1, column 1, eCLIP-seq library preparation).
Neither of these references teaches wherein profiling step (c) further comprises depleting rRNA-containing amplification products before sequencing the one or more amplification products.
Derisi, in a reasonably pertinent field, teaches on depleting rRNA-containing sequencing library products before sequencing by a method called DASH (Page 7, paragraph [0065]), which uses Cas9 proteins combined with gRNAs to cleave unwanted species before sequencing (Page 1, paragraph [0006]).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Van Nostrand, in view of Culver, with the rRNA depletion step of Derisi. Since Derisi teaches on manipulation of sequencing libraries, which is reasonably pertinent to the sequencing libraries of Van Nostrand, one of ordinary skill in the art would combine the two teachings with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because DASH cleaves unwanted species, preventing them from consuming sequencing space (Derisi, Page 1, paragraph [0006]). Furthermore, applying DASH after library generation means the depletion can be performed on any library without regard to starting RNA amount (Page 14, paragraph [0120]).
Regarding instant claim 20, Van Nostrand, in view of Culver, teaches the method of claim 19. Van Nostrand further teaches wherein the sequencing comprises high-throughput sequencing (Figure 1A; Online Methods, Page 1, column 1, eCLIP-seq library preparation).
Neither of these references teaches wherein profiling step (c) further comprises depleting rRNA-containing amplification products before sequencing the one or more amplification products.
Derisi, in a reasonably pertinent field, teaches on depleting rRNA-containing sequencing library products before sequencing by a method called DASH (Page 7, paragraph [0065]), which uses Cas9 proteins combined with gRNAs to cleave unwanted species before sequencing (Page 1, paragraph [0006]).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Van Nostrand, in view of Culver, with the rRNA depletion step of Derisi. Since Derisi teaches on manipulation of sequencing libraries, which is reasonably pertinent to the sequencing libraries of Van Nostrand, one of ordinary skill in the art would combine the two teachings with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because DASH cleaves unwanted species, preventing them from consuming sequencing space (Derisi, Page 1, paragraph [0006]). Furthermore, applying DASH after library generation means the depletion can be performed on any library without regard to starting RNA amount (Page 14, paragraph [0120]).
Claim 24 is rejected under 35 U.S.C. 103 as being unpatentable over Van Nostrand (Robust transcriptome-wide discovery of RNA-binding protein binding sites with enhanced CLIP (eCLIP), Nature Methods, March 2016, 13, 508-514 plus Online Methods; cited on the IDS filed October 20th, 2022) and Culver (Meanderings of the mRNA through the Ribosome, Structure, September 2001, 9, 751-758), as applied to claims 1-3, 6, 8-10, 14-15, and 17-19 above, and further in view of Darnell (US20140378316A1).
Regarding instant claim 24, Van Nostrand, in view of Culver, teaches the method of claim 1
Neither reference teaches wherein the biological sample is a tissue sample.
Darnell, in the same field of endeavor, teaches on a CLIP method wherein the biological sample is a tissue sample (Page 1536, column 2, paragraph 3).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the biological sample of Van Nostrand with the tissue sample of Darnell. Since Van Nostrand and Darnell are in the same field of endeavor (e.g. CLIP techniques for RNA-protein interaction), one of ordinary skill in the art would combine the two teachings with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because it amounts to simple substitution of one known element for another to obtain predictable results (see MPEP 2141(III)).
Claim 26 is rejected under 35 U.S.C. 103 as being unpatentable over Van Nostrand (Robust transcriptome-wide discovery of RNA-binding protein binding sites with enhanced CLIP (eCLIP), Nature Methods, March 2016, 13, 508-514 plus Online Methods; cited on the IDS filed October 20th, 2022) and Culver (Meanderings of the mRNA through the Ribosome, Structure, September 2001, 9, 751-758), as applied to claims 1-3, 6, 8-10, 14-15, and 17-19 above, and further in view of Ingolia (The ribosome profiling strategy for monitoring translation in vivo by deep sequencing of ribosome-protected mRNA fragments, Nature Protocols, July 2012, 7, 1534-1550).
Regarding instant claim 26, Van Nostrand, in view of Culver, teaches the method of claim 1.
Neither reference teaches wherein the biological sample is a fresh, frozen tissue sample that is cryoground into powder.
Ingolia, in a reasonably pertinent field, teaches wherein the biological sample for a similar technique regarding ribosome footprinting can be a fresh, frozen tissue sample that is cryoground into powder (Page 1536, column 2, paragraph 3).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the biological sample of Van Nostrand with the tissue sample of Ingolia. Since Ingolia teaches on downstream applications regarding ribosome associated mRNAs, which is reasonably pertinent to the method of Van Nostrand, in view of Culver, where ribosomal proteins are binding to RNA, one of ordinary skill in the art would combine the two teachings with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to make this modification because cryogenic pulverization of frozen tissue produces effective lysis and homogenization under conditions that block biological responses (Ingolia, Page 1536, column 2, paragraph 3).
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.
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Claims 1-3, 6, 8-11, 14-15, 17-20, 24, and 26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-7, and 9 of copending Application No. 18027478 in view of Van Nostrand (Robust transcriptome-wide discovery of RNA-binding protein binding sites with enhanced CLIP (eCLIP), Nature Methods, March 2016, 13, 508-514 plus Online Methods), Culver (Meanderings of the mRNA through the Ribosome, Structure, September 2001, 9, 751-758), Derisi (US20180051320A1), Darnell (US20140378316A1), and Ingolia (The ribosome profiling strategy for monitoring translation in vivo by deep sequencing of ribosome-protected mRNA fragments, Nature Protocols, July 2012, 7, 1534-1550).
Although the claims at issue are not identical, they are not patentably distinct from each other because both the ’478 application and the instant application claim identifying an RNA that interacts with an RBP, involving crosslinking an RBP to an RNA in a biological sample, identifying an RNA-RBP complex within the biological sample, wherein the RNA-RBP complex comprises an RNA fragment bound by the RBP, isolating the RNA fragment, and profiling the RNA fragment bound by the RBP. Both applications further claim UB crosslinking, contacting the RNA-RBP complex with an RBP specific antibody and immunoprecipitating, and sequencing the isolated RNA fragment.
The ‘478 application claims do not require the aspects of determining RNA translation rate, or the more detailed aspects of the method such as the RBP being a ribosomal protein, lysing the biological sample and fragmenting RNA, dephosphorylating the RNA fragment ends, ligating an adapter to the 3’ end of the RNA fragment, reverse transcribing the RNA fragment to cDNA, ligating another adapter to the 3’ end of the cDNA, amplifying, and depleting rRNA containing amplification products. Then ‘478 application also does not claim specific biological samples like tissue or fresh frozen cryoground tissue. However, Van Nostrand, in view of Culver, Derisi, Darnell, and Ingolia, teaches the claimed limitations as discussed in the above 103 rejections, obviating these variations to the claims of the ‘478 application. Any additional limitations of the claims of copending Application No. 18027478 are encompassed by the open claim language “comprising” found in the instant claims.
This is a provisional nonstatutory double patenting rejection.
Conclusion
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/ALLISON E SCHLOOP/ Examiner, Art Unit 1683
/ANNE M. GUSSOW/ Supervisory Patent Examiner, Art Unit 1683