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 .
Election/Restrictions
Applicant's election with traverse of Group I (claims 1-42) directed to a chemically capped mRNA and methods of linking an oligonucleotide to target RNA molecules in the reply filed on 01/28/2026 is acknowledged. Group II (claims 43-63) directed to methods for enriching and sequencing RNA molecules. The traversal is on the ground(s) that "examination of all pending claims is possible without imposing an undue search burden on the Office" (pg. 12 of remarks, first paragraph). This is not found persuasive because Groups I and II require a different field of search (e.g., different classes/subclasses or electronic resources, or employing different search queries, such as using different search queries and terms for the different features of the claimed inventions. Group I require search queries including capping RNA molecules by using click chemistry azide-alkyne cycloaddition reaction, and enzymatic reactions for capping 5' ends of RNA molecules, while Group Il require search queries including reverse transcription of chemically labeled mRNAs, purification and quantification of chemically labeled cDNAs.
The requirement is still deemed proper and is therefore made FINAL.
Regarding the species election requirement for Group I, Applicant further elected Species A: (iv) oligonucleotide, locked nucleic acid, triazole nucleic acid, phosphorothioate oligonucleotide; and Species B: desthiobiotin; and Species C: 5’-diphosphorylated RNA. Following a search of the prior art, the species election requirement is withdrawn.
Claims 43-63 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected Group II of invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 01/28/2026.
Accordingly, claims 1-42 are pending and under consideration.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. Claims 1, 7, 9-13, 17-18, 20-29, and 35-42 are granted priority to the International Patent Application PCT/US2014/068737 filed on 12/05/2014. However, PCT/US2014/068737 does not provide support for claims 2-6, 8, 14-16, 19, and 30-34.
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 120 and 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application Nos. 62/002,564, 61/920,380, and 61/912,367 fail to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. These applications fail the disclose the structures of claims 1, 12, 13, and 27, and the modifications thereof as recited in the dependent claims.
The disclosure of the prior-filed application, Application No. 15/137,394 fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. The instant application is a CIP of 15/137,394, which claims the benefit of US Provisional Application No. 62/166,190. The ‘394 application provides support for a chemically capped mRNA comprising an oligonucleotide of claim 1 and wherein the oligonucleotide is an oligoribonucleotide or an oligodeoxyribonucleotide, but not a combination thereof or a combination with the other types of oligonucleotides recited in claim 3, 14, and 31. Both ‘394 and ‘190 applications fail to provide support for claims 2-6, 8, 14-16, 19, and 30-34.
The disclosure of the prior-filed application, Application No. 15/908,522, effective filling date of 02/28/2018, provides adequate support for claims 2-6, 8, 14-16, 19, and 30-34. The instant application is a CON of 15/908,522, which is a CIP of 15/786,020 and claims the benefit of US Provisional Application No. 62/166,190; However, both ‘020 and ‘190 applications fail to disclose the structures of claims 1, 12, 13, and 27, and the modifications thereof as recited in the dependent claims.
Accordingly, claims 1, 7, 9-13, 17-18, 20-29, and 35-42 have an effective filling date of 12/05/2014, which is the filling date of PCT/US2014/068737. Claims 2-6, 8, 14-16, 19, and 30-34 have an effective filling date of 02/28/2018, which is the filing date of Application No. 15/908,522.
Specification
The disclosure is objected to because it contains an embedded hyperlink (pg. 71, line 27) and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The use of the following terms which are trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
“Qdot®” and “ITK™ (pg. 39)
“IRDye®”, “Fluor®”, “Quasar®”, “Chromeo™”, “mFluor™” (pg. 40)
“BlackBerry®”, “Quencher™” (pg. 41)
“Int Uni-Link™ Amino Modifier” (pg. 42 and pg. 44)
“5’ Uni-Link™“ (pg. 43)
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Applicant is advised that should claim 23 be found allowable, claim 25 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Applicant is advised that should claim 24 be found allowable, claim 26 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
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.
Claim 12 is 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 12 is vague and indefinite in that the metes and bounds of the phrase "wherein Z is H, OH, SH, NH₂, a lower alkyl, a lower acyloxy, a lower alkylamine, a lower acylamine, or a halogenyl" are unclear. The term "lower" in claim is a relative term which renders the claim indefinite. The term "lower" is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The terms do not have an ordinary meaning in the art. For example, US 2004/0044057 A1 defines "lower alkyl" to mean a hydrocarbon having from 1 to 10 carbon atoms (e.g., paragraph [0100]). Others use the term to mean from 1 to 6 carbon atoms (US Patent No. 5,194,614 A, column 19, lines 4-6). One would not know when an alkyl, acyloxy, alkylamine or acylamine is "lower" or not. The specification provides support for specific groups of methyl, methoxy, acetoxy, methylamine, and acetamide (pg. 9, lines 8-10). Claim 12 may be amended to recite these specific groups.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 6 and 34 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 6 recites, "wherein the oligonucleotide is attached to the linker through an internal nucleotide or a branched spacer arm". Claim 6 depends from claim 1, which recites "an oligonucleotide that is joined by its 3' or 5' end to the 3' position of the sugar of the guanosine via a linker". Thus, dependent claims substitute the joining of the oligonucleotide by its 3' or 5' end with the joining through an internal nucleotide or a branched spacer arm. Claim 6 does not include all of the limitations of the claim from which it depends.
Claim 34 recites "wherein the oligonucleotide is attached to the linker through an internal nucleotide or a branched spacer arm". Claim 34 depends from claim 27 which recites “3’-azido-guanosine capped target RNa molecules with an oligonucleotide comprising an alkyne” indicating that the oligonucleotide is joined by its 3’ or 5’ end to the 3’ position of the sugar of the guanosine via a triazole linker. Thus, dependent claims substitute the joining of the oligonucleotide by its 3' or 5' end with the joining through an internal nucleotide or a branched spacer arm. Claim 34 does not include all of the limitations of the claim from which it depends.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
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 1-5, and 10-11 are rejected under 35 U.S.C. 103 as being unpatentable over Merenkova et al (US 6,022,715; Published Date: Feb 08, 2000) in view of Paredes et al (Click Chemistry for Rapid Labeling and Ligation of RNA; ChemBioChem, 2011, 12:125-131) and Pourceau et al (Azide Solid Support for 30-Conjugation of Oligonucleotides and Their Circularization by Click Chemistry; J. Org. Chem. 2009, 74:6837-6842).
Regarding claims 1, 2, 5, and 10-11, Merenkova et al teach a chemically capped mRNA, comprising a target mRNA comprising a 5'guanosine triphosphate cap; and an oligonucleotide that is joined by its 3' end to the sugar of the guanosine via a linker formed by reaction of amine, in particular hydrazine, with oxidized alcohol groups at the 2’ and 3’ position on the sugar of the guanosine (Col. 7, line 51 to Col. 8, line 44; Col. 9, lines 28-43; Fig. 3 “chemical ligation of nucleic acids to the 5’ end of mRNAs”).
However, Merenkova et al do not teach wherein the oligonucleotide is joined to the 3'position of the sugar of the guanosine and wherein the linker contains a substituted or unsubstituted triazole.
Paredes et al teach production of an RNA-RNA conjugate using a nontemplated click ligation method with a 5'azide and a synthetic RNA bearing a 3'terminal alkyne (paragraph bridging pg. 127-128), which contains a nucleotide modified to contain a 3'-O-propargyl group and a 2'-OH group (Fig. 2(A)(ii); Fig. 3; Table 1). Paredes et al further teach the reaction of azide and alkyne groups forms a covalent triazole linkage (pg. 125, left-column, first paragraph), and this reaction is rapid and can furnish ligated RNAs with no additional optimization in less than two hours (paragraph bridging pg. 127-128).
In addition, Pourceau et al teach that while amine or thiol functions are the most popular groups for conjugation to the ends of oligonucleotides, the alternative approach of using the azide/alkyne system is an efficient and powerful method for conjugation (paragraph bridging pg. 6837-6838). Pourceau et al further teach it is within the skill of the art to synthesize an oligonucleotide with a 3’-azide (pg. 6838, right-column, first paragraph; pg. 6839 left-column, first paragraph).
Thus, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have modified the chemically capped mRNA of Merenkova et al to substitute the linkage of the amine-containing oligonucleotide to the oxidized alcohol groups at the 2’ and 3’ positions of the sugar with the linkage azide/linkage taught by Paredes et al and Pourceau et al to result in a triazole linkage at the 3’ position of the sugar (through the 3’-O’propargyl group), while maintaining the 2’-OH group. This modification would have merely amounted to a simple substitution of prior art elements according to known methods to yield predictable results given that the substituted component (triazole linkage) and its function (conjugating oligonucleotides) were known in the art. One would have been motivated to have done so for the advantage of practicing conjugation via an alternative efficient and powerful method as taught by Pourceau et al. One would have had a reasonable expectation of success in doing so because Merenkova et al teach linking the 3’ end of an oligonucleotide to a modified-guanosine capped mRNA via amine to result in a structure capable of functioning, and Pourceau et al teach it is within the skill of the art to substitute amine for azide/alkyne linker and to provide an azide group at the 3’ end of an oligonucleotide.
Regarding claims 3-4, Merenkova et al teach wherein the oligonucleotide is selected from an oligodeoxyribonucleotide whose 3’ OH end has been modified (Col. 14, lines 32-64).
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Merenkova et al (US 6,022,715; Published Date: 02/08/2000) in view of Paredes et al (Click Chemistry for Rapid Labeling and Ligation of RNA; ChemBioChem, 2011, 12:125-131) and Pourceau et al (Azide Solid Support for 30-Conjugation of Oligonucleotides and Their Circularization by Click Chemistry; J. Org. Chem. 2009, 74:6837-6842) as applied to claim 1 above, and further in view of Fomich et al (Azide Phosphoramidite in Direct Synthesis of Azide-Modified Oligonucleotides; Org. Lett., 2014, 4(16):4590-4593).
Regarding claim 7, the limitations of claim 1 from which claim 7 depends, have been previously addressed and the obviousness to modify the chemically capped mRNA with an oligonucleotide of Merenkova et al by substituting the amine linkage with an azide/alkyne linkage as taught by Paredes et al and Pourceau et al is discussed above as applied to claim 1.
However, neither Merenkova et al, Paredes et al, or Pourceau et al teach wherein the oligonucleotide comprises a fluorophore.
Fomich et al teach that oligonucleotides comprising Cy5-alkyne or FAM-alkyne modifications at the 5’ terminus and an azide phosphoramidite in the oligonucleotide backbone can be linked to 5’-alkyne-modified oligonucleotides to yield oligonucleotide-oligonucleotide conjugates (Scheme 3, pg. 4592). A possible conjugate comprising multi-labeled azide oligonucleotides at various internal nucleotides is illustrated below (Scheme 3). Fomich et al further teach that including fluorophores in oligonucleotides provide easy visualization of the presence and availability of azide functions in oligonucleotide conjugates (pg. 4592, second and third paragraphs).
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Thus, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have modified the chemically capped mRNA of Merenkova et al to further comprise a fluorophore in the oligonucleotide. This modification would have merely amounted to a simple combination of known fluorophores to perform previously known functions in oligonucleotide-oligonucleotide conjugates. One would have been motivated to have done so for the advantage of easy visualization of conjugates and track progress of click ligation as taught by Fomich et al. One would have had a reasonable expectation of success in doing so because Fomich et al teach one or multiple fluorophores attached to 5’-terminus of azide-modified oligonucleotides retain their functions in oligonucleotide-oligonucleotide conjugates, and Merenkova et al in combination with teachings of Paredes et al and Pourceau et al also teach oligonucleotide-RNA conjugates connected via azide-alkyne linkage.
Claims 12-15, 17, 21-22, 27-28, 30-33, 35, and 39-40 are rejected under 35 U.S.C. 103 as being unpatentable over Merenkova et al (US 6,022,715; Published Date: 02/08/2000) in view of Paredes et al (Click Chemistry for Rapid Labeling and Ligation of RNA; ChemBioChem, 2011, 12:125-131) and Pourceau et al (Azide Solid Support for 30-Conjugation of Oligonucleotides and Their Circularization by Click Chemistry; J. Org. Chem. 2009, 74:6837-6842) as applied to claim 1 above, and further in view of Jendrisak et al (CA 2649325 A1; Published Date: 10/25/2007).
Regarding claims 12 and 13, the obviousness to modify the chemically capped mRNA with an oligonucleotide of Merenkova et al by substituting the amine linkage with an azide/alkyne linkage as taught by Paredes et al and Pourceau et al is discussed above as applied to claim 1.
Merenkova et al teach the RNA is obtained by in vitro transcription, followed by capping with m7G(5’)ppp(5’)G via incorporation into the 5’ end of the nascent transcript during the step of initiation of transcription because this compound is recognized by polymerase (Col. 11, lines 15-24).
However, Merenkova et al do not explicitly teach contacting a labeled GTP and a 5’-diphosphorylated or 5’ triphosphorylated 5’ end of the target RNA molecule.
Jendrisak et al teach methods for efficiently generating 5’ capped RNA having a modified cap nucleotide, comprising contacting a modified 3’-deoxyguanosine-5’-triphosphate, wherein the 3’-deoxy position of the deoxyribose sugar moiety is substituted with an azido group (e.g., 3’-azido-3’-dGTP) (claims 10 and 11), with a 5’-diphosphorylated 5’ end of an RNA (claim 1) and a capping enzyme system.
Thus, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have modified the synthesis to obtain the chemically capped mRNA of Merenkova with the capping enzyme system in the method of Jendrisak because it would have merely amounted to a simple substitution of prior art elements according to known methods to yield predictable results. In this modification, the substituted component (capping enzyme) and its function (synthesizing a chemically capped mRNA with the cap is a GTP modified with an azido group at the 3’ position of the sugar of the guanosine) were known in the art. One would have been motivated to have done so for the advantage of in vitro production of 5’ capped mRNA with modified cap nucleotide for in vivo translation of these chemically capped mRNA. One would have had a reasonable expectation of success in doing so because Merenkova et al teach GTP with chemical modifications at the 3’ position of the sugar of the guanosine can be incorporated into 5’ end of mRNA and Jendrisak teach the same results can be achieved using a capping enzyme system.
Regarding claims 14-15, and 17, the teachings of Merenkova et al are discussed above as applied to claims 3-4, and 1, respectively.
Regarding claims 21 and 22, Merenkova et al teach purifying the oligonucleotide-labeled target RNA using exclusion chromatography to remove nonligated oligonucleotides (Col. 16, lines 17-19).
Regarding claims 27 and 30, the obviousness to modify the chemically capped mRNA with an oligonucleotide of Merenkova et al by substituting the amine linkage with an azide/alkyne linkage as taught by Paredes et al and Pourceau et al as discussed above and applied to claim 1. In addition, the teachings of Merenkova et al and Jendrisak et al are discussed above as applied to claims 12 and 13 for the instant step (a). Merenkova et al further teach after mRNAs are 5’ capped by a 3’-amine-GTP, they are purified by oligo-dT chromatography (Col. 9, lines 29-30) (i.e., instant claim 30), followed by oxidization of the 3’-OH end in the presence of periodate and a hydrazine-containing nucleotide tag (i.e., oligonucleotide) is ligated to the oxidized 3’ position on the sugar of the guanosine (Col. 9, lines 28-33; Fig. 3) (i.e., step (b) of instant claim 27).
Regarding claim 28, the obviousness to modify the chemically capped mRNA with an oligonucleotide of Merenkova et al by substituting the amine linkage with an azide/alkyne linkage as taught by Paredes et al and Pourceau et al as discussed above and applied to claim 1, and the obviousness to produce a 3’-capped target RNA using a capping enzyme is discussed above as applied to claims 12 and 13. Paredes et al further teach wherein reacting step (b) further comprises a copper-mediated azide-alkyne cycloaddition reaction (pg. 130, right-column under subsection “nontemplated click ligation”).
Regarding claims 31-33, 35, and 39-40, the teachings of Merenkova et al are discussed above as applied to claims 1-4, and 21-22.
Claims 23-24, and 40 are rejected under 35 U.S.C. 103 as being unpatentable over Merenkova et al (US 6,022,715; Published Date: 02/08/2000) in view of Paredes et al (Click Chemistry for Rapid Labeling and Ligation of RNA; ChemBioChem, 2011, 12:125-131), Pourceau et al (Azide Solid Support for 30-Conjugation of Oligonucleotides and Their Circularization by Click Chemistry; J. Org. Chem. 2009, 74:6837-6842) and Jendrisak et al (CA 2649325 A1; Published Date: 10/25/2007) as applied to claims 13 and 27 above, and further in view of Machida et al (Four Methods of Preparing mRNA 5’ End Libraries Using the Illumina Sequencing Platform; Plos One, July 2014, 9(7):e101812).
Regarding claims 23-24, and 41, the obviousness to modify the chemically capped mRNA with an oligonucleotide of Merenkova et al by substituting the amine linkage with an azide/alkyne linkage as taught by Paredes et al and Pourceau et al is discussed above as applied to claim 1, and the obviousness to link the labeled GTP with a 5’-diphosphorylated 5’end of the RNA using a capping enzyme as taught by Jendrisak et al is discussed above as applied to claim 13. Further, the teachings of Merenkova et al method comprising two steps is discussed above as applied to claim 27.
Regarding enrichment of the oligonucleotide-labeled target RNA, the specification discloses enrichment include purification step for example, gel electrophoresis, size-exclusion, phenol-chloroform extraction, or alcohol precipitation (pg. 6, lines 19-23). Merenkova et al teach that the oligonucleotide-labeled target RNA is ethanol-precipitated (i.e., enriching) and dialyzed against water (Col. 11, line 43), as well as purified using exclusion chromatography (Col. 16, lines 17-19). Regarding sequencing of the oligonucleotide-labeled target RNA, the specification discloses sequencing may be done by ligation of an adaptor to at least the 5’ end of the enriched RNA, synthesis of cDNA using an oligo(dT) primer, amplification of cDNA, and sequencing amplified products (pg. 7, lines 3-12). Merenkova et al teach synthesis and amplification of cDNA. After the chemically capped mRNA comprising an oligonucleotide is made (step 2), reverse transcription (step 3) is performed using oligo-dT of hexamers with random sequences or alternatively primers with specific sequences to yield a first single-strand cDNA comprising the ligated oligonucleotide sequence because reverse transcriptase can cross the cap and recopy the ligated oligonucleotide (e.g., RT tag) (Col. 9, lines 28-44; Fig. 3). Merenkova et al also teach that after elimination of the chemically capped mRNA (step 4), the synthesis of a second strand of cDNAs (step 5) is initiated with a specific primer complementary to the RT tag, leading to production of double-stranded cDNAs containing 5’ end of mRNAs (Col. 9, lines 28-44; Fig. 3). Merenkova et al further teach this method allows isolating whole-length cDNAs corresponding to the entire mRNA (abstract).
However, Merenkova et al do not teach sequencing the oligonucleotide-labeled target RNA.
Machida et al teach methods of profiling 5’ ends of mRNA using Illumina sequencing platform, and the ligation method (Figure. 2) comprises same steps recited by Merenkova including ligation of RNA oligos to the 5’ end of mRNAs (step D), reverse transcription using oligo dT primers to yield a first single-strand cDNA (step E), synthesis of a second-strand cDNA and PCR amplification with biotinylated 5’ end primers (step F), fragmentation and collection of PCR products comprising biotinylated 5’ ends using streptavidin beads (step G), and preparation of sample pool for sequencing (step H) (Figure 2; pg. 3, right-column, last paragraph; pg. 6, left-column, first and second paragraph). Sequencing library preparation is detailed on pg. 8, right-column).
Thus, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have modified method of Merenkova et al to further comprise a sequencing step as taught by Machida et al because it would have merely amounted to a simple combination of known cDNA synthesis and amplification with an additional sequencing step known for mapping mRNA 5’ ends and studying RNA transcripts. One would have been motivated to have done so for the advantage of annotating RNA transcripts, especially full-length transcripts achievable via the method of Merenkova et al. One would have had a reasonable expectation of success in doing so because Merenkova et al teach a method of converting chemically capped mRNA to cDNA and Machida et al teach a method of sequencing mRNa 5’ end libraries comprising essentially the same steps recited in the method of Merenkova et al.
Claims 29 are rejected under 35 U.S.C. 103 as being unpatentable over Merenkova et al (US 6,022,715; Published Date: 02/08/2000) in view of Paredes et al (Click Chemistry for Rapid Labeling and Ligation of RNA; ChemBioChem, 2011, 12:125-131), Pourceau et al (Azide Solid Support for 30-Conjugation of Oligonucleotides and Their Circularization by Click Chemistry; J. Org. Chem. 2009, 74:6837-6842) and Jendrisak et al (CA 2649325 A1; Published Date: 10/25/2007) as applied to claim 27 above, and further in view of Qiu et al (Solid phase click ligation for the synthesis of very long oligonucleotides; Chem. Commun., 2013, 49:6959-6951).
Regarding claim 29, the obviousness to modify the chemically capped mRNA with an oligonucleotide of Merenkova et al by substituting the amine linkage with an azide/alkyne linkage as taught by Paredes et al and Pourceau et al as discussed above and applied to claim 1. In addition, the teachings of Merenkova et al and Jendrisak et al are discussed above as applied to claims 27 and 28.
However, neither Merenkova et al or Jendrisak et al teach wherein reacting (b) of claim 27 further comprises a copper-free azide-alkyne cycloaddition reaction and wherein the alkyne is a dibenzocyclooctyne or a difluorooctyne.
Qiu et al teach copper-free, strain-promoted azide-alkyne cycloaddition (SPAAC) reaction is an excellent alternative to copper-mediated azide-alkyne cycloaddition (CuAAC) reactions because it is extremely fast and does not require copper catalysis (pg. 6960, right-column, second paragraph). Qiu et al further teach using a highly active symmetric bicycle [6.1.0] non-4-yne (BCN) as the strained alkyne component in the SPAAC reaction as it is known to be used for solution-phase oligonucleotide crosslinking and fluorescent labeling, but dibenzocyclooctyne is also a suitable alkyne in solid-phase SPAAC ligation reactions (pg. 6960, right-column, second paragraph). Qiu et al further teach SPAAC conjugation can be conducted between a 3’-BCN oligonucleotide ON9 and a 5’-azide oligonucleotide ON1 (pg. 6960, right-column, third paragraph) or between a 3’-azide oligonucleotide ON14 and a 5’-BCN oligonucleotide ON13 to yield “two long oligonucleotides” ON10 and ON15, respectively (Fig. 3 and Table 3). The resulting SPAAC linkage is illustrate below (Fig. 3b and 3c) wherein the linkage is via 3’-position of the sugar. In addition, Qiu et al teach 5’-azide oligonucleotide ON1 can also be ligated to 3’-propargyl oligonucleotide ON3, differing from 3’-BVN ON9 by a single nucleotide, to yield oligonucleotide conjugate ON4 (Tables 1 and 2). This demonstrates that SPAAC and CuAAC are interchangeable ligation methods for substantially similar oligonucleotide substrates.
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Thus, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have modified method of Merenkova et al to further comprise a copper-free azide-alkyne cycloaddition reaction wherein the alkyne is a dibenzocyclooctyne because it would have merely amounted to a simple substitution of known azide-alkyne cycloaddition reaction with known function of copper-free oligonucleotide ligation. One would have been motivated to have done so for the advantage of avoiding usage of copper that is known to mediate DNA cleavage. One would have had a reasonable expectation of success in doing so because Qiu et al teach oligonucleotide conjugates that differ by a single nucleotide in length can be ligated via SPAAC and CuAAC as they are interchangeable ligation methods.
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 1-6, 8-11, 13-17, 19-21, and 23-24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 7-9-12, 15-23, 30 of U.S. Patent No.11,479,766 B2. Although the claims at issue are not identical, they are not patentably distinct from each other because ‘766 anticipates an RNA-oligonucleotide conjugate with same structural limitations as instant chemically capped mRNA. For compact prosecution, the following table outlines the instant claims that corresponds to claims of ‘766.
Instant claims
Claims of ‘766
1
1, 12
2
2
3
3
4
4
5
5
6
11
8
7
9
8
10
15
11
9
13
12, 16
14
17
15
18
16
19
17
20
19
21-22
20
23
21
22
23
10
24
30
Regarding instant claim 13, the instant method of linking an oligonucleotide to target RNA molecule is also anticipated by step (a) of method recited in claim 40 of ‘766, which teaches incubating an RNA having a 5’ diphosphate or a 5’ triphosphate with an oligonucleotide-labeled guanosine triphosphate (GTP) and a capping enzyme, wherein the oligonucleotide is joined by its 3’ or 5’ end to the 3’ position of the sugar of the guanosine via a linker (i.e., instant step (a)) or is joined by an internal nucleotide or a branched spacer arm to the 3’ position of the sugar of the guanosine via a linker (i.e., instant step (b)).
Allowable Subject Matter
Claims 8-9, 16, 18-20, 36-38, and 42 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Regarding claims 8-9, 18-20, 36-38, and 42, claims require an mRNA comprising a 5’ guanosine triphosphate cap and an oligonucleotide that is joined by its 3’ or 5’ end to the 3’ position of the sugar of the guanosine via a linker. The closest prior art, Merenkova et al (US 6,022,715; Published Date: Feb 08, 2000) discloses joining an oligonucleotide to a 5’ guanosine triphosphate capped RNA, Jendrisak et al (CA 2649325 A1; Published Date: 10/25/2007) discloses joining a biotinylated affinity tag to a 5’ guanosine triphosphate capped RNA (claim 64), and Kore et al (US 2013/0102655 A1; Published Date: Apr 25, 2013) discloses joining a reporter including dye, biotin or peptide to a 5’ guanosine triphosphate capped RNA (FIG. 3), but prior art does not teach or suggest, alone or in combination, an oligonucleotide joined to a 5’ guanosine triphosphate capped RNA and wherein the oligonucleotide comprises an affinity tag. In addition, claims 18 and 20 are directed to a product having the same structure, but it is an RNA rather than a mRNA as in claims 8 and 9. Claims 36-38 are likewise directed to products of similar structure, but further requires a specific azide/alkyne linker between the guanosine and oligonucleotide.
Regarding claim 16, the closest prior art Merenkova et al (US 6,022,715; Published Date: Feb 08, 2000), Paredes et al (Click Chemistry for Rapid Labeling and Ligation of RNA; ChemBioChem, 2011, 12:125-131), and Qiu et al (Solid phase click ligation for the synthesis of very long oligonucleotides; Chem. Commun., 2013, 49:6959-6951) disclose an oligonucleotide is joined by its 3’ or 5’ end to a nucleotide via a linker. Further, Fomich et al (Azide Phosphoramidite in Direct Synthesis of Azide-Modified Oligonucleotides; Org. Lett., 2014, 4(16):4590-4593) discloses an oligonucleotide is joined by its backbone comprising an azide phosphoramidite to a 5’-alkyne-modified oligonucleotide. The prior art does not teach or suggest wherein the oligonucleotide is joined through an internal nucleotide or a branched spacer arm to another nucleotide via a linker.
Conclusion
No claims are allowable.
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QIWEN SU-TOBON
Examiner
Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636
Prosecution Insights