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 .
Claim Status and Formal Matters
This action is in response to claims filed 12/22/20025.
Claim 1, 5, 24, 26, 37-38, 43 have been amended.
Claims 44-45 have been added by amendment.
Claims 1, 5, 12-13, 16-17, 21-22, 24-28, 31-32, 43-45 are being examined.
The instant response is non-compliant with 37 CFR 1.121 as it has added, “i.”, “ii.” and “iii.” have been amended into the independent claim. However the these are not underlined as required by 37 CFR 1.121. Future amendments that are not compliant with 37 CFR 1.121 may not be entered or examined. However, to promote compact prosecution and customer service the instant response is being examined.
The issue with SEQ ID NO in claims and specification have been overcome in view of the amendment.
The previous objection to the claims has been withdrawn in view of the amendment.
Priority
The instant application was filed 12/14/2022 and is a continuation of 15907163 , filed 02/27/2018 which claims priority from provisional application 62464043 , filed 02/27/2017.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/22/2025 and 6/6/2026 are being considered by the examiner.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
It is noted that the IDS contain office actions related to foreign applications, but do not provide a context or specific claims or references that are discussed in the actions. These have been reviewed for what is provided within them, but the relevant application material such as specification, claims and cited references have not been used for the review.
Specification
The specification is objected to as failing to provide proper antecedent basis for the claimed subject matter. See 37 CFR 1.75(d)(1) and MPEP § 608.01(o). Correction of the following is required: Claim 26 has been added by amendment and recites, “facilitate more efficient transcription and/or translation relative to a corresponding wild-type DNA sequence.”.Review and searching of the specification did not reveal antecedent basis for “wild-type sequence.”
Response to Arguments
This is a new ground of objection necessitated by amendment.
Claim Objections
Claim 1, 5, 12-13, 16-17, 21-22, 24-28, 31-32, 43-45 objected to because of the following informalities:
Claim 1 has been amended to recite, “, “i.”, “ii.” and “iii.” MPEP 608.01(m) states: Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations. See Fressola v.Manbeck, 36 USPQ2d 1211 (D.D.C. 1995).
Appropriate correction is required.
Response to Arguments
This is a new ground of rejection necessitated by amendment.
Claim Rejections - 35 USC § 112
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, 5, 12-13, 16-17, 21-22, 24-28, 31-32, 43-45 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.
As set forth in In re Alonso 88 USPQ2d 1849 (Fed. Cir. 2008), at 1851:
The written description requirement of 35 U.S.C. § 112, ¶ 1, is straightforward: “The specification shall contain a written description of the invention ….” To satisfy this requirement, the specification must describe the invention in sufficient detail so “that one skilled in the art can clearly conclude that the inventor invented the claimed invention as of the filing date sought.” Lockwood v. Am. Airlines, Inc., 107 F.3d 1565, 1572 [41 USPQ2d 1961] (Fed. Cir. 1997); see also LizardTech, Inc. v. Earth Res. Mapping, Inc., 424 F.3d 1336, 1345 [76 USPQ2d 1724] (Fed. Cir. 2005); Eiselstein v. Frank, 52 F.3d 1035, 1039 [34 USPQ2d 1467] (Fed. Cir. 1995).
Alonso at 1852:
A genus can be described by disclosing: (1) a representative number of species in that genus; or (2) its “relevant identifying characteristics,” such as “complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics.” Enzo, 323 F.3d at 964.
In applying the test as set forth in Alonso, it is noted that applicant is claiming A method for large-scale production of a composition comprising mRNA molecules, comprising (i) combining reagents comprising:i.SP6 RNA polymerase,ii. an RNA polymerase reaction buffer, and iii. a DNA template to form a reaction mixture; and ii) synthesizing at least 100 mg of mRNA in a single batch, to form the composition, wherein the composition comprises less than 20% of abortive transcripts of less than 30 nucleotides in length.
Thus the claims encompass any mRNA of any of any length. This is an enormous genus.
Mdorek (Nucleic Acids Research (2001) volum 29, pages 2850-2859) teaches there are approximately 2.1 million mRNA and EST.
Further the claims encompass any RNA polymerase buffer. This is an enormous genus of any buffer at any concentration, and NTP at any concentration, any cations or MG at any concentration, etc. Thus this is an enormous genus.
Further the claim encompasses any DNA template. This is an enormous genus as the claim does not require the DNA template provides the sequence of an mRNA or a promoter region.
Further claim 25 demonstrates the independent claim does not require an SP6 promoter or a DNA sequence encoding an mRNA.
Further the claim recites, “wherein the composition comprises less than 20% of abortive transcripts of less than 30 nucleotides in length.” However, the specification teaches:
[0066] As used herein, term "abortive transcript" or "pre-aborted transcript" or the like, in its broadest sense, is any transcript that is shorter than a full-length mRNA molecule encoded by the DNA template. In some embodiments, an abortive transcript may be less than 90% of the length of the full-length mRNA molecule that is transcribed from the target DNA molecule, e.g., less than 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%, 1% of the length of the full-length mRNA molecule.
{0128} As used herein, the term "shortmers" or "abortive transcripts" refers to any transcripts that are less than full-length. In some embodiments, "shortmers" or "abortive transcripts" are less than 100 nucleotides in length, less than 90, less than 80, less than 70, less than 60, less than 50, less than 40, less than 30, less than 20, or less than 10 nucleotides in length. In some embodiments, shortmers are detected or quantified after adding a 5'-cap, and/or a 3'-poly A tail.
Thus the limitation appears to be contradictory of the definition of abortive transcript of the claim.
The teachings of the specification are limited to FFL, Human EPO, {AH, CFTR, ASS1, and OTC transcribed from DNA templates under specific conditions.
The specification teaches:
[0166] The IVT reaction is scaled up in the following manner: Briefly, for each gram of mRNA transcribed, a reaction containing 20 mg of a linearized double stranded DNA plasmid with an RNA polymerase-specific promoter, 10 mg RNA polymerase, RNase inhibitor, pyrophosphatase, 5mM NTPs, 10mM DTT and a reaction buffer (lOx - 250 mM Tris-HCl, pH 7.5, 20 mM spirmidine,50 mM NaCI,) was used and quantity sufficient (QS) to 200 ml with RNase-free water then incubated at 37 C for 60min. The reaction was then quenched by the addition of DNase I and a DNase I buffer (lOx - 100 mM Tris-HCl, 5 mM MgCl2 and 25 mM CaCl2, pH 7.6) to facilitate digestion of the double-stranded DNA template in preparation for purification. The final reaction volume was 226m1. Cap and Tail (C/F) reaction
Burgin (Journal of Mammalogy, 99(1):1–14, 2018) teaches, “We found 6,495 species of currently recognized mammals.”
Further Nam (The Journal of Biological Chemistry (1988) volume 263, pages 18123-18127) teaches
Effects of mutations around the phage SP6 transcription initiation site on SP6 RNA polymerase’s selection of initiation site were studied. In the in vitro transcription reactions, the limiting concentration of a ribonucleotide causes the SP6 RNA polymerase to stall long enough only at the positions of the limited nucleotide and dissociate from the elongation complex. As a result, a series of RNA oligomers comprises a sequencing lad- der, and abortive initiation cycling products up to 6- mer are made in high yield. Precise sizing of the prod- uct RNAs from the elongation pausings determined the initiation site of each mutant. When the wild-type +1 G is changed to C or A without change in the upstream sequence including TATA from -4 to -1, transcription still starts only at the +1 site. But, the mutant contain ing TATCC from -4 to +1 starts transcription at both positions -1 C and +1 C. We propose that the phage SP6 RNA polymerase selects the initiation site precisely at a certain distance from a direct contact point in the upstream promoter sequence, regardless of the species of initiating nucleotide. It is also suggested that the sequence-dependent perturbations of DNA helical structure, for example D toto B form, may shift the initiation site.
Thus the specification does not provide adequate written description for any DNA template, any transcription conditions, and RNA or mRNA which provide for wherein the composition comprises less than 20% of abortive transcripts of less than 30 nucleotides in length., and wherein at least 100 mg of mRNA is synthesized in a single batch as they have not provided a representative number of species for the genus encompassed in humans, let alone the thousands of mammalian species, as well as microorganisms, plants, etc.
Response to Arguments
The response begins traversing the rejection by asserting, “Contrary to the Office's assertion, Applicant submits that the specification provides adequate support for the pending claims, which encompass any mRNA that can be synthesized using an SP6 RNA polymerase, because the production of short abortive transcripts is largely linked to the RNA polymerase and not the protein coding sequence of the mRNA encoded by the template. As explained in the specification, "abortive cycling" results in the production of abortive transcripts, which is known to be common to all RNA polymerases.” This argument has been thoroughly reviewed but is not considered persuasive as Nam (The Journal of Biological Chemistry (1988) volume 263, pages 18123-18127) teaches, “Effects of mutations around the phage SP6 transcription initiation site on SP6 RNA polymerase’s selection of initiation site were studied. In the in vitro transcription reactions, the limiting concentration of a ribonucleotide causes the SP6 RNA polymerase to stall long enough only at the positions of the limited nucleotide and dissociate from the elongation complex. As a result, a series of RNA oligomers comprises a sequencing lad- der, and abortive initiation cycling products up to 6- mer are made in high yield. Precise sizing of the product RNAs from the elongation pausings determined the initiation site of each mutant. When the wild-type +1 G is changed to C or A without change in the upstream sequence including TATA from -4 to -1, transcription still starts only at the +1 site. But, the mutant contain ing TATCC from -4 to +1 starts transcription at both positions -1 C and +1 C. We propose that the phage SP6 RNA polymerase selects the initiation site precisely at a certain distance from a direct contact point in the upstream promoter sequence, regardless of the species of initiating nucleotide. It is also suggested that the sequence-dependent perturbations of DNA helical structure, for example D toto B form, may shift the initiation site.”
.
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, 5, 12-13, 16-17, 21-22, 24-28, 31-32, 43-45 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 has been amended to recite, ““wherein the composition comprises less than 20% of abortive transcripts of less than 30 nucleotides in length.” However, the specification teaches:
[0066] As used herein, term "abortive transcript" or "pre-aborted transcript" or the like, in its broadest sense, is any transcript that is shorter than a full-length mRNA molecule encoded by the DNA template. In some embodiments, an abortive transcript may be less than 90% of the length of the full-length mRNA molecule that is transcribed from the target DNA molecule, e.g., less than 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%, 1% of the length of the full-length mRNA molecule.
{0128} As used herein, the term "shortmers" or "abortive transcripts" refers to any transcripts that are less than full-length. In some embodiments, "shortmers" or "abortive transcripts" are less than 100 nucleotides in length, less than 90, less than 80, less than 70, less than 60, less than 50, less than 40, less than 30, less than 20, or less than 10 nucleotides in length. In some embodiments, shortmers are detected or quantified after adding a 5'-cap, and/or a 3'-poly A tail.
Thus the limitation appears to be contradictory of the definition of abortive transcript of the claim. Thus the limitation is confusing and unclear in view of the definitions of 0066 and 0128.
Claim 5 has been amended to recite, “wherein the compositioncomprises undetectable amounts of abortive transcripts as detected by agarose gel electrophoresis, glyoxal agarose gel electrophoresis or capillary electrophoresis.” The claim is confusing and unclear as the claim does not provide a positive active step. Further the recited means of electrophoresis do not inherently detect anything. The electrophoresis merely separates the nucleic acids based on size/charge. Further the recitation of “undetectable amount” is a relative term. The amount of RNA detected is dependent on the means of detecting and how detection is done. More specifically staining of RNA with ethidium bromide and providing a short shutter time for the camera may in the short products being undetectable, however a longer shutter timer or the use of radioactive probes would detect what is not detected by with ethidium bromide with a short shutter time.
Claim 12 is unclear in view of the amendment to claim 1. Claim 12 recites, “wherein the relative amount of full- length or abortive transcripts of synthesized mRNA is determined by the relative peak areas corresponding to the full-length or abortive transcripts.” However, claim 1 has been amended to recite, ““wherein the composition comprises less than 20% of abortive transcripts of less than 30 nucleotides in length.” However, the specification teaches:
[0066] As used herein, term "abortive transcript" or "pre-aborted transcript" or the like, in its broadest sense, is any transcript that is shorter than a full-length mRNA molecule encoded by the DNA template. In some embodiments, an abortive transcript may be less than 90% of the length of the full-length mRNA molecule that is transcribed from the target DNA molecule, e.g., less than 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%, 1% of the length of the full-length mRNA molecule.
{0128} As used herein, the term "shortmers" or "abortive transcripts" refers to any transcripts that are less than full-length. In some embodiments, "shortmers" or "abortive transcripts" are less than 100 nucleotides in length, less than 90, less than 80, less than 70, less than 60, less than 50, less than 40, less than 30, less than 20, or less than 10 nucleotides in length. In some embodiments, shortmers are detected or quantified after adding a 5'-cap, and/or a 3'-poly A tail.
Thus it is unclear if the abortive transcripts of claim 12 are only those of less than 30 nucleotides or encompass anything less than full length, as the definition in the specification appear to require.
Claim 26 recites, “wherein the DNA sequence is optimized to facilitate more efficient transcription and/or translation relative to a corresponding wild-type DNA sequence.” The recitation of optimized, efficient, and wild-type are relative terms. While the claim has been amended to limit optimize to efficient transcription and/or translation relative to corresponding wild-type. However, efficient and wild-type are relative terms which are not defined by the specification and claims. Thus it is unclear what optimized, efficient, and wild-type are relative to.
Claim 37 recites, “wherein a protein coding sequence of the mRNA is codon optimized for expression in human cells relative to a corresponding wild-type protein coding sequence.” The recitation of optimized and wild-type are relative terms. While the claim has been amended to limit optimize to expression relative to corresponding wild-type. However, wild-type are relative terms which are not defined by the specification and claims. Thus it is unclear what optimized, and wild-type are relative to.
Claim 38 has been amended to recite, ““wherein the composition comprises less than 20% of abortive transcripts of less than 30 nucleotides in length.” However, the specification teaches:
[0066] As used herein, term "abortive transcript" or "pre-aborted transcript" or the like, in its broadest sense, is any transcript that is shorter than a full-length mRNA molecule encoded by the DNA template. In some embodiments, an abortive transcript may be less than 90% of the length of the full-length mRNA molecule that is transcribed from the target DNA molecule, e.g., less than 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%, 1% of the length of the full-length mRNA molecule.
{0128} As used herein, the term "shortmers" or "abortive transcripts" refers to any transcripts that are less than full-length. In some embodiments, "shortmers" or "abortive transcripts" are less than 100 nucleotides in length, less than 90, less than 80, less than 70, less than 60, less than 50, less than 40, less than 30, less than 20, or less than 10 nucleotides in length. In some embodiments, shortmers are detected or quantified after adding a 5'-cap, and/or a 3'-poly A tail.
Thus the limitation appears to be contradictory of the definition of abortive transcript of the claim. Thus the limitation is confusing and unclear in view of the definitions of 0066 and 0128.
Claim 43 has been amended to recite, ““the composition comprises less than 20% of abortive transcripts of less than 30 nucleotides in length.” However, the specification teaches:
[0066] As used herein, term "abortive transcript" or "pre-aborted transcript" or the like, in its broadest sense, is any transcript that is shorter than a full-length mRNA molecule encoded by the DNA template. In some embodiments, an abortive transcript may be less than 90% of the length of the full-length mRNA molecule that is transcribed from the target DNA molecule, e.g., less than 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%, 1% of the length of the full-length mRNA molecule.
{0128} As used herein, the term "shortmers" or "abortive transcripts" refers to any transcripts that are less than full-length. In some embodiments, "shortmers" or "abortive transcripts" are less than 100 nucleotides in length, less than 90, less than 80, less than 70, less than 60, less than 50, less than 40, less than 30, less than 20, or less than 10 nucleotides in length. In some embodiments, shortmers are detected or quantified after adding a 5'-cap, and/or a 3'-poly A tail.
Thus the limitation appears to be contradictory of the definition of abortive transcript of the claim. Thus the limitation is confusing and unclear in view of the definitions of 0066 and 0128.
Claim 44 has been amended to recite, “wherein the composition
Claim 45 has been amended to recite, “wherein the compositionstaining of RNA with ethidium bromide and providing a short shutter time for the camera may in the short products being undetectable, however a longer shutter timer or the use of radioactive probes would detect what is not detected by with ethidium bromide with a short shutter time.
Response to Arguments
The response traverses with rejection with respect to full length in view of the amendment. This argument has been thoroughly reviewed but is not considered persuasive as ““the composition comprises less than 20% of abortive transcripts of less than 30 nucleotides in length.” However, the specification teaches:
[0066] As used herein, term "abortive transcript" or "pre-aborted transcript" or the like, in its broadest sense, is any transcript that is shorter than a full-length mRNA molecule encoded by the DNA template. In some embodiments, an abortive transcript may be less than 90% of the length of the full-length mRNA molecule that is transcribed from the target DNA molecule, e.g., less than 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%, 1% of the length of the full-length mRNA molecule.
{0128} As used herein, the term "shortmers" or "abortive transcripts" refers to any transcripts that are less than full-length. In some embodiments, "shortmers" or "abortive transcripts" are less than 100 nucleotides in length, less than 90, less than 80, less than 70, less than 60, less than 50, less than 40, less than 30, less than 20, or less than 10 nucleotides in length. In some embodiments, shortmers are detected or quantified after adding a 5'-cap, and/or a 3'-poly A tail.
Thus the limitation appears to be contradictory of the definition of abortive transcript of the claim. Thus the limitation is confusing and unclear in view of the definitions of 0066 and 0128.
The response traverses the rejections in view of the amendments. While the amendment has addressed some issues it has raised new issues as detailed above.
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.
Claim(s) 1, 5, 16-17, 24-25, 28, 38, 43 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wochner (WO2015188933).
The specification teaches, “[0072] As used herein, "full-length mRNA" is as characterized when using a specific assay, e.g., gel electrophoresis and detection using UV and UV absorption spectroscopy with separation by capillary electrophoresis. The length of an mRNA molecule that encodes a full- length polypeptide is at least 50% of the length of a full-length mRNA molecule that is transcribed from the target DNA, e.g., at least 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%,95%, 96%, 97%, 98%, 99%, 99.01%, 99.05%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9% of the length of a full-length mRNA molecule that is transcribed from the target DNA. “ The specification further teaches, “[0066] As used herein, term "abortive transcript" or "pre-aborted transcript" or the like, in its broadest sense, is any transcript that is shorter than a full-length mRNA molecule encoded by the DNA template. In some embodiments, an abortive transcript may be less than 90% of the length of the full-length mRNA molecule that is transcribed from the target DNA molecule, e.g., less than 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%,1% of the length of the full-length mRNA molecule.” Thus the claims are confusing as to what is require of full-length mRNA.
With regards to claim 1, 5, 24-25, 38 Wochner teaches, “According to the present invention, the term “large scale” refers to a reaction yield of said RNA molecule in the order of milligram quantities, preferably of at least one gram. “ (page 33, lines 30-31). Wochner teaches transcription with T7 polymerase produces:
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Wochner does not specifically exemplify production of over 100 mg of mRNA using SP6 polymerase.
However, Wochner teaches, “According to the invention the RNA molecule is prepared by in vitro transcription of a corresponding DNA molecule. This DNA template preferably comprises a suitable promoter, e.g. a T7 or SP6 promoter, for in vitro transcription, which is followed by the desired nucleotide sequence coding for the RNA molecule to be prepared and a termination signal for in vitro transcription. The DNA molecule, which forms the template of the at least one RNA of interest, may be prepared by fermentative proliferation and subsequent isolation as part of a plasmid which can be replicated in bacteria. Plasmids which may be mentioned as suitable for the present invention are e.g. the plasmids pUC18, pUC19, pBR322, pT7Ts (GenBank accession number U26404; Lai et al., Development 1995, 121: 2349 to 2360), PGEM® series, e.g. pGEM®-1 (GenBank accession number X65300; from Promega) and pSP64 (GenBank accession number X65327); cf. also Mezei and Storts, Purification of PCR Products, in: Griffin and Griffin (ed.), PCR Technology: Current Innovation, CRC Press, Boca Raton, FL, 2001.”
Wochner teaches, “According to a preferred embodiment of the invention, said RNA molecule is longer than 100 nucleotides. It is equally preferred that the RNA has a length between 100 and 15.000 nucleotides, 100 and 12.500 nucleotides,, 100 and 10.000 nucleotides, 100 and 7.500 25 nucleotides, 100 and 5.000 nucleotides, 100 and 2.500 nucleotides, 100 and 1.500 nucleotides, or 100 and 1.000 nucleotides.” (page 33, lines 21-26).
Wochner teaches, “In view of the above, there is a continued need for improved and economical means and methods of RNA production, especially for the production of full-length capped RNA molecules that can be translated into proteins.” (page 6, lines 9-11).
Therefore it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claims to produce milligrams to grams of mRNA using SP6 polymerase for RNA of 100 nucleotides or more. The artisan would be motivated as Wochner specifically suggests SP6 RNA polymerase can be used. The artisan would have a reasonable expectation of success as the artisan is merely using known methods.
With regards to claim 16, Wochner teaches, “According to a preferred embodiment of the invention, said RNA molecule is longer than 100 nucleotides. It is equally preferred that the RNA has a length between 100 and 15.000 nucleotides, 100 and 12.500 nucleotides,, 100 and 10.000 nucleotides, 100 and 7.500 25 nucleotides, 100 and 5.000 nucleotides, 100 and 2.500 nucleotides, 100 and 1.500 nucleotides, or 100 and 1.000 nucleotides.” (page 33, lines 21-26).
With regards to claim 17, Wochner teaches, “According to the present invention, the term “large scale” refers to a reaction yield of said RNA molecule in the order of milligram quantities, preferably of at least one gram. “ (page 33, lines 30-31).
With regards to claims 28, Wochner teaches, “Preferably the start nucleotide is added with an initial concentration in the range of about to 20 mM, 1 to 17.5 mM, 1 to 15 mM, 1 to 12.5 mM, 1 to 10 mM, 1 to 7.5 mM, 1 to 5 mM or 1 to 2.5 mM. Even more preferred the start nucleotide is added with an initial 25 concentration of about 5 to 20 mM or 7.5 to 17.5 mM.” (page 23) Wochner teaches, “According to a preferred embodiment of the invention, the RNA polymerase comprised in the sequence-optimized reaction mix is selected from the group consisting of T3, T7 and SP6 RNA polymerase. Preferably, the concentration of the RNA polymerase is from about 1 to 100 nM, 1 to 90 nM, 1 to 80 nM, 1 to 70 nM, 1 to 60 nM, 1 to 50 nM, 1 to 40 nM, 1 to 30 nM, 1 to 20 nM, or about 1 to 10 nM. Even more preferred, the concentration of the RNA polymerase is from about 10 to 50 nM, 20 to 50 nM, or 30 to 50 nM. Most preferred is a RNA polymerase concentration of about 40 nM. In this context a concentration of 500 to 10000 U/ml of the RNA polymerase is preferred. More preferred is a concentration of 1000 to 7500 U/ml and most preferred is a concentration of 2500 to 5000 Units/ml of the RNA polymerase. The person skilled in the art will understand that the choice of the RNA polymerase concentration is influenced by the concentration of the DNA template. According to a preferred embodiment of the invention, the concentration of the DNA template comprised in the sequence-optimized reaction mix is in a range from about 1 to 50 nM, 1 to 40 nM, 1 to 30 nM, 1 to 20 nM, or about 1 to 10 nM. Even more preferred the concentration of the DNA template is from about 10 to 30 nM. Most preferred the concentration of the DNA template is about 20 nM. In this context it is particularly 15 preferred to have a concentration of the DNA template of about 1 to 200 µg/ml and more preferably of about 10 to 100 µg/ml, and most preferably of about 20 to 50 µg/ml (e.g. 25 or 50 µg/ml).” (page 24-25)
MPEP 2144.05 II A States:
II. ROUTINE OPTIMIZATION
A. Optimization Within Prior Art Conditions or Through Routine Experimentation
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In reAller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)
Therefore it would have been prima facie obvious to one of ordinary skill in the art prior the effective filing date of the claims to optimize the concentration of SP6 polymerase, NTP and DNA template. The artisan would be motivated as Wochner suggests ranges to optimize transcription of mRNA production. The artisan would have a reasonable expectation of success as the artisan is merely using known methods and concentrations to produce mRNA.
With regards to claim 43, Wochner teaches, “Therapeutic ribonucleic acid (RNA) molecules represent an emerging class of drugs. RNAbased therapeutics include mRNA molecules encoding antigens for use as vaccines (FotinMleczek et al. 2012. J. Gene Med. 14(6):428-439). In addition, it is envisioned to use RNA molecules for replacement therapies, e.g. providing missing proteins such as growth factors or enzymes to patients (Karikó et al., 2012. Mol. Ther. 20(5):948-953; Kormann et al.,. 2012. Nat. Biotechnol. 29(2):154-157). Furthermore, the therapeutic use of noncoding
immunostimulatory RNA molecules (WO2009/095226) and other noncoding RNAs such
as microRNAs and long noncoding RNAs is considered (Esteller, 2011. Nat. Rev. Genet. 12(12):861-74).”
Therefor it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claims to introduce the mRNA produced by the methods of Wochner for in vivo protein production. The artisan would be motivated as Wochner suggests mRNA for encoding antigens. The artisan would have a reasonable expectation of success as the artisan is merely following direction of art.
Response to Arguments
The response traverses the rejection asserting, “Applicant submits that the instant claims are not obvious over Wochner. Wochner does not teach or disclose "[a] method for large-scale production of a composition" "wherein the composition comprises less than 20% of abortive transcripts," as required by the instant claims. Further, Wochner does not teach or disclose that the use of different RNA polymerases could result in reducing the amounts of abortive transcripts in mRNA, let alone that such an effect could be achieved using an SP6 RNA polymerase at a large scale.” This argument has been thoroughly reviewed but is not considered persuasive as "wherein the composition comprises less than 20% of abortive transcripts," is vague and unclear. Further the arguments with respect to different RNA polymerases having different amount of abortive transcription is a limitation not required of the claims.
The response continues by asserting, “Applicant notes that T7 RNA polymerase is the only polymerase disclosed in the examples of Wochner, and SP6 RNA polymerase is only mentioned in a list among different RNA polymerases. See, e.g., Wochner, page 24, lines 12 and 31-32.” This argument has been thoroughly reviewed but is not considered persuasive as while Wochner exemplifies a single RNA polymerase, Wochner suggests other RNA polymerases including SP6 RNA polymerase can be used, rendering the instant claims obvious.
The response continues by asserting, “Notably, Wochner is not focused on the large-scale synthesis of mRNA using SP6 polymerase, but rather on improving mRNA yield using "sequence- optimized" transcription reactions in which the ribonucleoside triphosphates (NTP) composition is adjusted based on the nucleotide composition of the mRNA. For instance, Examples 1 and 4 of Wochner show that the mRNA yield of "sequence-optimized" transcription reactions is higher than that of "standard" transcription reactions. See Wochner, Example 1 (p. 55, line 15; p. 56, line 5), Example 4 (p. 58, line 30; p. 59, line 3).” This argument has been thoroughly reviewed but is not considered persuasive as applicant attempts to claim optimized sequences in claim 26 and thus it is consistent. Further Wochner teaches the production of mRNA using T7 RNA polymerase of the scale required by the claims and suggests SP6 RNA polymerase can also be used.
The response continues by providing arguments with respect to the examples. These arguments have been thoroughly reviewed but are not considered persuasive as the examples require a DNA template with an SP6 promoter, specific buffer conditions, specific amounts of DNA template, specific co-factors, etc. Thus these claims are not commensurate in scope with the breadth of the claims.
Claim(s) 26-27, 31-32, 37 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wochner (WO2015188933). as applied to claims 1, 5, 16-17, 24-25, 28, 38, 43 above, and further in view of Liu (US20110081708)
While Wochner teaches optimized in vitro transcription of mRNA by use of SP6 polymerase.
Wochner does not specifically teach optimizing mRNA sequence or minimizing secondary structure.
However, Liu teaches, “[0040] To boost protein translation efficiency, the gene sequences is preferably optimized so that codon usages are optimized according to the tRNAs abundance or the availability of the different tRNAs. Generally the optimal range for CAI is preferably from 0.8 to 1.0. A second method to quantitatively analyzing codon usage bias is codon context index (CCI) derived from "codon pair" theory (Irwin B, Heck J D and Hatfield G W, 1995, Codon pair utilization biases influence translational elongation step times. Journal of Biological Chemistry, 270 (39), 22801-22806) and the optimal range for CCI is preferably from 0.7 to 1.0.” Liu teaches, “[0044] According to embodiments of the present invention, the local secondary structures of mRNA with a low free energy (.DELTA.G<-18 Kcal/mol) or a long complementary stem (>10 bp) are defined as too stable for efficient translation. The gene sequences is preferably optimized to make the local structure not so stable.”
Therefore it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claims to use optimized DNA sequences for transcription of RNA. The artisan would be motivated as Liu suggests optimized codon sequences and minimizing stem loop structures (hairpins) increases translation efficiency. The artisan would have a reasonable expectation of success as the artisan is merely using known methods to optimize RNA for protein production.
With regards to claim31, Wochner teaches, “The percentage of the modified nucleotide in the mix can be varied from 0% to 100% of the natural nucleotide that it replaces.” (page 57).
With regards to claim 32, Wochner teaches nucleotide analogs (page 9).
Response to Arguments
The response traverses the set forth with respect to the independent claims. These arguments are not persuasive for the reasons of record.
Claim(s) 5, 12-13, 44-45 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wochner (WO2015188933). as applied to claims 1, 5, 16-17, 24-25, 28, 38, 43 above, and further in view of Melton (nucleic Acid research (1984) page 7035-) and Rio (Adapted from RNA: A Laboratory Manual by Donald C. Rio, Manuel Ares Jr, Gregory J. Hannon, and Timothy W. Nilsen. CSHL Press, Cold Spring Harbor, NY, USA, 2011. © 2015 Cold Spring Harbor Laboratory Press Cite this protocol as Cold Spring Harb Protoc; doi:10.1101/pdb.prot081000)
The specification teaches, “[0072] As used herein, "full-length mRNA" is as characterized when using a specific assay, e.g., gel electrophoresis and detection using UV and UV absorption spectroscopy with separation by capillary electrophoresis. The length of an mRNA molecule that encodes a full- length polypeptide is at least 50% of the length of a full-length mRNA molecule that is transcribed from the target DNA, e.g., at least 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%,95%, 96%, 97%, 98%, 99%, 99.01%, 99.05%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9% of the length of a full-length mRNA molecule that is transcribed from the target DNA. “ The specification further teaches, “[0066] As used herein, term "abortive transcript" or "pre-aborted transcript" or the like, in its broadest sense, is any transcript that is shorter than a full-length mRNA molecule encoded by the DNA template. In some embodiments, an abortive transcript may be less than 90% of the length of the full-length mRNA molecule that is transcribed from the target DNA molecule, e.g., less than 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%,1% of the length of the full-length mRNA molecule.” Thus the claims are confusing as to what is require of full-length mRNA.
While Wochner teaches optimized in vitro transcription of mRNA by use of SP6 polymerase.
Wochner does not specifically teach agarose gel electrophoresis, glyoxal .electrophoresis or determining relative peak areas to determine full length or abortive transcripts.
The specification teaches, “[0072] As used herein, "full-length mRNA" is as characterized when using a specific assay, e.g., gel electrophoresis and detection using UV and UV absorption spectroscopy with separation by capillary electrophoresis. The length of an mRNA molecule that encodes a full- length polypeptide is at least 50% of the length of a full-length mRNA molecule that is transcribed from the target DNA, e.g., at least 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%,95%, 96%, 97%, 98%, 99%, 99.01%, 99.05%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9% of the length of a full-length mRNA molecule that is transcribed from the target DNA. “ The specification further teaches, “[0066] As used herein, term "abortive transcript" or "pre-aborted transcript" or the like, in its broadest sense, is any transcript that is shorter than a full-length mRNA molecule encoded by the DNA template. In some embodiments, an abortive transcript may be less than 90% of the length of the full-length mRNA molecule that is transcribed from the target DNA molecule, e.g., less than 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%,1% of the length of the full-length mRNA molecule.” Thus the claims are confusing as to what is require of full-length mRNA.
However, Melton teaches in vitro transcription of RNA and running on formaldehyde gel (7038-7039). Melton teaches scanning of gels and densitomery (figure 2).
Rio teaches, “This protocol is used to denature and separate large mRNA molecules (0.5–10 kb) on agarose gels by electrophoretic size fractionation. Glyoxal (also called diformyl or ethanedial), the agent responsible for maintaining denaturation in this protocol, contains two carbonyl groups that react to form a cyclic ring structure with the imino and amino groups of guanine. It can also react with the amino groups of adenine and cytidine. When RNA is denatured in the presence of glyoxal, this covalent adduct prevents normal base pairing and maintains the RNA in a denatured state in agarose gels. Once formed, these adducts are stable at room temperature at pH “
Therefore it would have been prima facie obvious to one of skill in the art prior to the effective filing date of the claims to use glyoxal agarose electrophoresis to separate full RNA products from abortive mRNA and scan the gets to use peak areas to determine relatives amount. The artisan would be motivated as Melton and Rio suggest electrophoresis of RNA to characterize RNA. The artisan would have reasonable expectation of success merely using know techniques to characterize RNA products.
Response to Arguments
The response traverses the set forth with respect to the independent claims. These arguments are not persuasive for the reasons of record.
Claim(s) 21-22 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wochner (WO2015188933). as applied to claims 1, 5, 16-17, 24-25, 28, 38, 43 above, and further in view of He (Protein Expression and Purification Volume 9, Issue 1, February 1997, Pages 142-151)
While Wochner teaches optimized in vitro transcription of mRNA by use of SP6 polymerase.
Wochner does not specifically a recombinant or tagged SP6 RNA polymerase.
However, He teaches, “We have developed plasmid-based expression sys- and purification of T7 and other phage RNA polymertems that encode modified forms of T7 RNA polymerase (RNAP) having 6–12 histidine residues fused to the Previous methods for purification of T7 RNAP have amino terminus. The histidine-tagged RNAPs (His-T7 included selective precipitation with salt, size-excluRNAPS) are indistinguishable from the wild-type (WT) sion chromatography, chromatography on ion exchange enzyme in nearly all biochemical assays. Similar plas- columns, and affinity chromatography on columns such mids that encode His-tagged T3 and SP6 RNAPs have as Affi-Gel blue or GTP–agarose (1–9). In general, also been constructed.”
Therefore it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claims to use a recombinant SP6 polymerase with a tag. The artisan would be motivated to identify mutations in SP6 polymerase with improved processivity. Alternatively the artisan would be motivated to use the tag to immobilize polymerase instead of DNA in the method of Wochner. The artisan would have a reasonable expectation of success as the artisan is merely using known reagents in known methods.
Response to Arguments
The response traverses the set forth with respect to the independent claims. These arguments are not persuasive for the reasons of record.
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, 5-6, 8, 12-13, 16-17, 21-22, 24-28, 31-32, 43 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 11,253, 605. Although the claims at issue are not identical, they are not patentably distinct from each other because they are coextensive in scope.
The instant claims are drawn to claiming A method for large-scale production of a composition comprising mRNA molecules, comprising (i) combining reagents comprising:i.SP6 RNA polymerase,ii. an RNA polymerase reaction buffer, and iii. a DNA template to form a reaction mixture; and ii) synthesizing at least 100 mg of mRNA in a single batch, to form the composition, wherein the composition comprises less than 20% of abortive transcripts of less than 30 nucleotides in length.
.The claims of 605 are drawn to a method of producing codon optimized mRNA encoding a Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein, comprising in vitro synthesizing codon optimized CFTR mRNA using a SP6 RNA polymerase, wherein at least 80% of the synthesized codon optimized CFTR mRNA molecules are full-length and wherein at least 100 mg of codon optimized mRNA is synthesized at a single batch..
Thus it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claims the instant claims encompass those of 605 as at least 80% full length appears to be obvious over less than 20% abortive sequences. The claims of 605 are a species which render the instant claims obvious.. The artisan would have a reasonable expectation of success as the artisan is merely using known methods.
Dependent claims are obvious as they are co-extensive in scope with the dependent claims of 605 and/or in view of the cited prior art cited above.
Response to Arguments
The response traverses the rejection the rejection does not provide a claim by claim analysis and provide a prima facie case. This argument has been thoroughly reviewed as the rejection as provided both claims and asserted the reference claims are a species encompassed by the instant claims. Thus the rejection is maintained.
Claims 1, 5-6, 8, 12-13, 16-17, 21-22, 24-28, 31-32, 43 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 11,560,562 Although the claims at issue are not identical, they are not patentably distinct from each other because they are coextensive in scope.
The instant claims are drawn A method for large-scale production of a composition comprising mRNA molecules, comprising (i) combining reagents comprising:i.SP6 RNA polymerase,ii. an RNA polymerase reaction buffer, and iii. a DNA template to form a reaction mixture; and ii) synthesizing at least 100 mg of mRNA in a single batch, to form the composition, wherein the composition comprises less than 20% of abortive transcripts of less than 30 nucleotides in length.
The claims of 562 are drawn to a A method for large-scale production of a composition enriched for full-length mRNA molecules comprising synthesizing in vitro mRNA using a recombinant SP6 RNA polymerase having 90% identity to SEQ ID NO: 1, wherein the mRNA is synthesized in about 1 gram to 250 gram quantities in a single batch in a reaction mixture comprising NTPs at a concentration ranging from 1-10 mM each NTP, a DNA template at a concentration ranging from 0.01-0.5 mg/ml, the recombinant SP6 RNA polymerase at a concentration ranging from 0.01-0.1 mg/ml, and a salt or buffering agent, at pH 6.5-8.0, and wherein the reaction is incubated for 60-120 minutes at between 37° C.−42° C..
Thus it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claims the instant claims encompass those of 562 as enriched renders obvious less then 20% abortive transcripts. The claims of 562 are a species which render the instant claims obvious.. The artisan would have a reasonable expectation of success as the artisan is merely using known methods.
Dependent claims are obvious as they are co-extensive in scope with the dependent claims of 562 and/or in view of the cited prior art cited above.
Response to Arguments
The response traverses the rejection the rejection does not provide a claim by claim analysis and provide a prima facie case. This argument has been thoroughly reviewed as the rejection as provided both claims and asserted the reference claims are a species encompassed by the instant claims. Thus the rejection is maintained.
Claims 1, 5-6, 8, 12-13, 16-17, 21-22, 24-28, 31-32, 43 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 10,975, 369. Although the claims at issue are not identical, they are not patentably distinct from each other because they are coextensive in scope.
The instant claims are drawn to A method for large-scale production of a composition comprising mRNA molecules, comprising (i) combining reagents comprising:i.SP6 RNA polymerase,ii. an RNA polymerase reaction buffer, and iii. a DNA template to form a reaction mixture; and ii) synthesizing at least 100 mg of mRNA in a single batch, to form the composition, wherein the composition comprises less than 20% of abortive transcripts of less than 30 nucleotides in length.
The claims of 369 are drawn to a A method for large-scale purification of mRNA, comprising steps of: providing a suspension comprising at least about 10 grams of precipitated mRNA manufactured by in vitro synthesis; and centrifuging the suspension at a speed of about 1000 to 5000 RPM in a centrifuge comprising a porous substrate such that the precipitated mRNA is captured on the porous substrate and contaminants are removed from the precipitated mRNA to provide a purified mRNA, wherein the purified mRNA yield is at least about 80% and is substantially free of one or more enzyme reagents used in in vitro synthesis. Claim 9 recites, “The method of claim 1, wherein the purified mRNA is substantially free of prematurely aborted RNA sequences, DNA templates, and enzyme reagents used in in vitro synthesis.” Claim 10 depends from claim 9 and requires wherein the enzyme reagents used in in vitro synthesis comprise T7 RNA polymerase, SP6 RNA polymerase, DNAse I, pyrophosphatase, and/or RNAse inhibitor.
Thus it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claims the instant claims are encompassed by those of 369. The claims of 369 render the instant claims obvious as they require the active steps of the claims. The artisan would have a reasonable expectation of success as the artisan is merely using known methods.
Dependent claims are obvious as they are co-extensive in scope with the dependent claims of 369 and/or in view of the cited prior art cited above.
Response to Arguments
The response traverses the rejection the rejection does not provide a claim by claim analysis and provide a prima facie case. This argument has been thoroughly reviewed as the rejection as provided both claims and asserted the reference claims are a species encompassed by the instant claims. Thus the rejection is maintained.
Claims 1, 5-6, 8, 12-13, 16-17, 21-22, 24-28, 31-32, 43 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 12,410,422. Although the claims at issue are not identical, they are not patentably distinct from each other because they are coextensive in scope.
The instant claims are drawn to A method for large-scale production of a composition enriched for full-length mRNA molecules comprising synthesizing in vitro mRNA using an SP6 RNA polymerase, wherein at least 80% of the synthesized mRNA molecules are full-length, and wherein at least 100 mg of mRNA is synthesized in a single batch.
The claims of 422 are drawn to a composition comprising at least 10 grams of dried purified mRNA, wherein said mRNA is obtained by a method for large-scale purification of mRNA, comprising the steps of: providing a suspension comprising precipitated mRNA manufactured by in vitro synthesis; and centrifuging the suspension at a speed of about 1000 to 5000 RPM in a centrifuge comprising a porous substrate such that the precipitated mRNA is captured on the porous substrate, and contaminants are removed from the precipitated mRNA to provide captured purified mRNA; washing the captured purified mRNA composition with a solvent; and drying the captured purified mRNA, thereby obtaining dried purified mRNA in the form of a solid, wherein the purified mRNA yield is at least about 80% and is substantially free of prematurely aborted RNA sequences, DNA templates, and one or more enzyme reagents used in in vitro synthesis; wherein the dried purified mRNA is collected and stored as a solid at a temperature of or below about 0° C. for a period of at least about one week to about two years; and wherein the dried purified mRNA has substantially the same integrity as prior to storage. Claim 3 recites, wherein the enzyme reagents used in in vitro synthesis comprise T7 RNA polymerase, SP6 RNA polymerase, DNAse I, pyrophosphatase, and/or RNAse inhibitor.
Thus it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claims the claims of 422 encompass a product produced by the claim process. Thus the instant claims are obvious over a product made by the claimed method, The artisan would have a reasonable expectation of success as the artisan is merely using known methods.
Dependent claims are obvious as they are co-extensive in scope with the dependent claims of 422 and/or in view of the cited prior art cited above.
Response to Arguments
The response traverses the rejection the rejection does not provide a claim by claim analysis and provide a prima facie case. This argument has been thoroughly reviewed as the rejection as provided both claims and asserted the reference claims are a species encompassed by the instant claims. Thus the rejection is maintained.
Summary
No claims are allowed.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEVEN C POHNERT PhD whose telephone number is (571)272-3803. The examiner can normally be reached Monday- Friday about 6:00 AM-5:00 PM, every second Friday off.
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/Steven Pohnert/ Primary Examiner, Art Unit 1683
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