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 .
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No.15/317,579, filed on 12/09/2016.
Applicant’s claim to priority from International Application No. PCT/EP2015/001164 filed 06/15/2015 and from Foreign Application No. PCT/EP2014/001577 filed 06/10/2014 is hereby acknowledged.
Application Status
This Application is a CON of US Application No. 17/071,279 filed 10/15/2020 (now abandoned), itself the CON of US Application No. 15/317,579 filed 12/09/2016 (now patented, US Patent No. 10,837,039).
Claims 1-23 are currently pending and are under consideration in this Office Action.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 05/22/2024 is hereby acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
However, 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.
Drawings
The Drawings filed 02/20/2024 are hereby acknowledged.
The drawings are objected to as failing to comply with 37 CFR 1.84(p)(5) because they include the following reference character(s) (1 to 51) not mentioned in the description of the Figures on page 42 (the characters are explained much later in Example 9, pages 63-64). Corrected drawing sheets in compliance with 37 CFR 1.121(d), or amendment to the specification to add the reference character(s) in the description in compliance with 37 CFR 1.121(b) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The abstract of the disclosure is objected to because of undue length. The current abstract is over 200 words in length. The requirements according to MPEP 608.01(b) specify that the Abstract should not exceed 150 words. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (see page 5, lines 5-6 and 12). 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 term “Lipofectamine” (page 73, lines 10-16), “BD FACS Canto”, “FlowJo” (page 73, line 29), “Graph Pad Prism” (page 73, line 30; page 74, line 13), “FCAP Array” (page 74, line 12) which are trade names or marks used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore, the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
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
Claim 8 is objected to because of the following informalities: The claim
recites “The composition of claim 1, wherein the NTPs in the sequence-optimized reaction mix comprise tris(hydroxymethyl)-aminomethane (Tris) counterions”. The claim should read “The composition of claim 1, wherein the NTPs comprised within the sequence-optimized reaction mix are provided with tris(hydroxymethyl)-aminomethane (Tris) counterions”.
NOTE: Examiner respectfully proposes this corrected phraseology based on the paragraph found with the only recitation of “counterion” in the Specification, which reads: “Another preferred embodiment of the invention relates to the form in which the NTPs are added to the sequence-optimized NTP mix or sequence-optimized reaction mix. The ribonucleoside triphosphates (NTPs) GTP, ATP, CTP and UTP or analogs thereof may be provided with a monovalent or divalent cation as counterion. Preferably the monovalent cation is selected from the group consisting of Li+ , Na+ , K+ , NH4+ or tris(hydroxymethyl)-aminomethane (Tris). Preferably, the divalent cation is selected from the group consisting of Mg++, Ba++ and Mn++.” (see page 27, lines 13-18).
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-23 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.
MPEP 2163.II.A.3.(a).i) states, “Whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention”.
For claims drawn to a genus, MPEP § 2163 states the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
Nature of the Invention:
Claim 1 recites “A composition comprising a capped mRNA molecule of a
given sequence, wherein the capped mRNA molecule was made by a method comprising the following steps:
determining the fraction for each of the four nucleotides G, A, C and U
in said mRNA molecule of the given sequence, and
synthesizing said mRNA molecule comprising an open reading frame
by in vitro transcription in a sequence-optimized reaction mix, wherein said sequence optimized reaction mix comprises the four ribonucleoside triphosphates (NTPs) GTP, ATP, CTP and UTP and/or analogs thereof, wherein the relative proportion of each of the four ribonucleoside triphosphates in the sequence-optimized reaction mix corresponds to the fraction of the respective nucleotide in said mRNA molecule determined in step (a), a buffer, a DNA template encoding the mRNA molecule, and an RNA polymerase,
wherein the mRNA molecule is between 100 and 10,000 nucleotides in length
and comprises an open reading frame (ORF) encoding a protein and a Poly(A) sequence positioned 3' of the ORF,
wherein:
before the start of the in vitro transcription a cap analog is added to the
sequence-optimized reaction mix to produce the capped mRNA molecule; or
after the in vitro transcription a capping enzyme is used to produce the capped mRNA molecule.”
Claim 18 is also drawn to the same elements within a pharmaceutical composition with an acceptable carrier.
Therefore, the claims are drawn to a product-by process. The product may not be
structurally different from any capped mRNA molecule of any sequence, wherein the mRNA molecule is between 100 and 10,000 nucleotides in length and comprises an open reading frame (ORF) encoding a protein and a Poly(A) sequence positioned 3' of the ORF. These are the only structural requirements claimed, the other limitations are methods steps to a method of making said structure.
Therefore, Applicant claims any capped mRNA molecule of any sequence, with a length between 100 to 10,000 nucleotides in length comprising an ORF and a polyA tail.
It is therefore expected in the instant application a disclosure of many types of mRNAs of genes belonging to yeast, plant, or eukaryotic cells, of any signal pathways, and mRNAs from recombinant molecules used for therapeutics, such as mRNA vaccines, ORF encoding for antibodies or fragments thereof, hormone peptides, enzymes for replacement therapy of genetic disorders, metabolic disorders etc.… .
The State of the Art:
Xiao (Xiao, C. et al. “mRNAs of plants and green algae lack the m7G cap-1
structure”. New Phytologist, Vol. 246 (2025), pp: 396-401) teaches that plant and algae also have capped mRNAs, although the cap is a Cap-0 type and lack the Cap-1 and Cap-2 forms (see Figure 1, and page 398, left column, lines 4-5 and 24-27).
Xiao teaches that mammalian cells have mainly Cap-1 and Cap2 forms, which are for immune self-tolerance, with additional roles in mRNA stability and increase translation (see page 396, left column, lines 30-39).
Therefore, yeast and plant cells have capped mRNAs, which are encompassed by the claims; also, a recombinant mRNA from plants lacking Cap-1 would need to be further modified and capped with a Cap-1 or Cap-2, to be used as a therapeutics agent in mammalian cells.
Vavilis (Vavilis, T. et al. “mRNA in the context of protein replacement therapy”.
Pharmaceutics, Vol. 15 (2023), p: 166) teaches mRNA for rapid in vivo production of antigens from exogenously administered mRNA (see abstract). Figure 2 shows that capped mRNA obtained via In Vitro Transcription can be used as therapeutics. Vavilis teaches the use of mRNA for protein replacement therapy for a wide variety of diseases, liver diseases, lung diseases, blood disorders among others (see section 5; pages 9-11), which also means a wide variety of genes encoding for hormones, enzymes, blood clotting factors, interferons (see page 2, “Protein Replacement Options__Why choose mRNA?” section).
Chen (Chen, H. et al. “Chemical and topological design of multicapped mRNA
and capped circular RNA to augment translation”. Nature Biotechnology, Vol. 43 (2025), pp: 1128-1143) teaches that there is a rapid development of mRNA vaccines since the adoption of mRNA as a powerful and programmable expression of proteins in vivo. However, mRNA-based therapies were limited by its short half-life and low translation capacity. Therefore, increasing the translatability through enhancement benefits therapeutics, from vaccination to functional protein delivery, gene editing and protein replacement therapies (see page 1128, introductory paragraphs). Chen teaches a method of engineering a capped mRNA named LEGO (ligation-enabled mRNA-oligonucleotide assembly) (see page 1129, left column, last paragraph before “results” section). Chen teaches a method of making capped mRNA that results in higher stability and production up to 10-fold in vivo, and up to 17-fold in prime dose for antibody production.
Therefore, Chen teaches capped mRNAs, and these new types of capped mRNA would be encompassed by Applicant’s claim, even though it was obtained using a different method, according to MPEP 2113.
What the Specification does and does not teach:
The Specification teaches two traditional protocols for making capped mRNAs. In
the first method, capping occurs simultaneously to the initiation of transcription, and a cap analog m7G(5’)ppp(5’)G(m7G) is added to the reaction mixture in a proportion in excess to favor the competition with GTP for incorporation as start nucleotide (page 2, lines 13-24). In the second protocol, capping is performed in a separate reaction after the in vitro transcription with an enzyme, the Vaccinia Virus Capping Enzyme (VCE), leading to the synthesis of a m7G cap structure. Additional type 1 cap can be created by adding a second Vaccinia enzyme, 2’-O-methyltransferase to the capping reaction (page 2, lines 26-30 and page 3, lines 1-2).
The Specification is also drawn at explanation and rationale for economically
favorable methods avoiding contaminants, false start transcription, depletion of GTP and low yield, for improving on existing methods of producing capped mRNAs using a bioreactor (pages 3-6; and “Summary of the Invention” page 6 and 7).
The Specification is drawn to a generic method for “an RNA molecule of a given sequence” using a bioreactor, in the Summary of the Invention” on page 5 and 6.
The novelty is about improvements on already existing methods with commercially available kits (see page 4, lines 17-23); it is about economically favorable method to perform the known reaction.
The novelty is not about a specific mRNA and a specific gene, or a specific new composition. The cap analogs were described in previously known methods (see page 8, 13-20).
The Specification teaches a preferred embodiment for an immunostimulatory RNA molecule, i.e., formula (I): (NuG1XmGnNv)a (see page 30, lines 31-31, page 31, lines 1-20, page 32, lines 1-13). Applicant teaches examples of sequences (SEQ ID Nos:1- 4) and Figures 1-5 present these examples. The Specification teaches a human Prostate Stem Cell antigen (SEQ ID NO: 1), a Photinus pyralis luciferase (SEQ ID NO: 2), a recombinant human EGFR/Mucin 1 fusion protein (SEQ ID NO: 3), and a non-coding RNA (SEQ ID NO: 4). The Specification also teaches a hammerhead ribozyme HHNUH2d (SEQ ID NO: 5) and a sequence-optimized HA from Influenza A H1N1 virus (SEQ ID NO: 6).
There is no RNA from a plant or a yeast presented.
Conclusion:
Therefore, the Specification and the claims are not about a specific composition
comprising a specific mRNA.
The claims are drawn to a much larger genus, including mRNAs of any sequence within the composition, or resulting from the composition used in a method described in the Specification, while the Specification is drawn to RNAs of formula (I), and specific examples of such “sequence-optimized” antigens and a reporter gene.
Taking into consideration the factors outlined above, including the nature of the
invention, the state of the art, the guidance provided by the Applicant and the specific examples based on one specific formula, it is the conclusion that Applicant does not possess the whole scope of the claimed invention, i.e., an mRNA of any given sequence. There is no specific written example within the Specification that would lead one with ordinary skills in the art to a different conclusion.
Claims 2-17 and 19-23 are dependent from claims 1 and 18. The dependent
claims do not remedy the deficiencies of claims 1 and 18, therefore they are rejected as well.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 7, 16, 18 and 23 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 7, it recites “The composition of claim 2, wherein in the course of the in vitro transcription the sequence-optimized reaction mix is supplemented with the sequence-optimized ribonucleoside triphosphate (NTP) mix as defined in claim 54 b1).”
Therefore, the claim is limited with elements cited in claim 54 b1), which does not exist in this Application, rendering the claim incomplete and indefinite.
Regarding claims 16 and 23, the claims recite “ wherein after the in vitro transcription a capping enzyme is used to produce the capped mRNA”. The claims depend from claims reciting a product-by process, and the “capped mRNA” seems to be an end-result of the process. A further limitation to the process and the method of “use of the enzyme” are not described in claims 16 and 23. It is not clear what and how many additional steps are part of the process of making the composition.
Regarding claim 18, the claim recites “c) formulating the capped mRNA molecule in a pharmaceutically acceptable carrier to provide the pharmaceutical composition comprising a capped mRNA molecule,
wherein the pharmaceutical composition comprising the capped mRNA, upon
administration to a cell provides improved expression and/or reduced IL-6 release
relative to a composition comprising a capped mRNA having the same nucleotide
sequence as the capped mRNA produced in step b) but that was produced in a
standard transcription reaction using equimolar amounts of the four NTPs.”
It is unclear whether the “upon administration to a cell” is a required limitation and additional step to the method by which the product is made.
The claim limitations in c) seem to describe a method of use of the composition and an end-result of a method linked to an experiment comparing two conditions. It is not clear what further limitation on the composition’s structure is required to allow the experiment’s method steps; it is not clear what these steps are either.
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 1-8 and 18 are rejected under 35 U.S.C. §103 as being unpatentable over Gruegelsiepe (Gruegelsiepe, H. et al. “Enzymatic RNA synthesis using Bacteriophage T7 RNA polymerase”. Handbook of RNA Biochemistry, ed. R. K. Hartmann, Part 1.1, (2005), pp: 3-21; cited in the IDS filed 05/22/2024), in view of Labourier (Labourier, E. et al. WO 2006/004648 Al; published January 2006; cited in the IDS filed 05/22/2024), Chin ( Chin et al. US 2014/0227300 Al; filed June 2012; cited on IDS filed 05/22/2024) and Munroe (Munroe et al. Mol. Cell. Biol., vol. 10, pp. 3441-3455, 1990; cited in the IDS filed 05/22/2024).
Regarding claims 1, 2, 7-8 and 18, Gruegelsiepe teaches RNA synthesis by in vitro transcription using sequence-optimized reaction mix in which a fraction of nucleotides in the reaction mix corresponds to a fraction of nucleotides in an RNA molecule (page 13, last two paragraphs; page 14, first paragraph). Gruegelsiepe teaches RNA molecules in the range between 100 to 30,000 nucleotides (page 4, last paragraph).
Regarding claim 7, for the purpose of prior-art-based rejection, Examiner interprets that the claim depends on claim 2b1). Gruegelsiepe teaches RNA synthesis by in vitro transcription using sequence-optimized reaction mix and preparing a mix comprising the four NTPs wherein the relative proportion of each of the four NTP in the mix corresponds to fraction of the respective nucleotide in said mRNA molecule (see Figure 1.1. and page 13, two last paragraphs).
Regarding claims 3-4, Gruegelsiepe teaches start nucleotides (page 6, last paragraph; page 9, third paragraph; page 11, second paragraph). Gruegelsiege teaches that “Normally, transcription by T7 RNAP is initiated with GTO, resulting in 5’ triphosphate ends. If, however, 5’-OH ends or 5’-monophosphate termini are preferred, T7 RNAP can be prompted to initiate transcripts with guanosine or 5’-ApG ( to generate 5’-OH ends for direct end-labeling with 32P) or 5’-GMP (to generate 5’-monophosphates), when these components are added to reaction mixtures in excess over GTP” (page 6, last paragraph).
Regarding claims 5 and 6, Gruegelsiepe teaches modified nucleotides,
including 4-thiouridine-5' -triphosphate (page 7, Table 1.1; first and second paragraph).
Regarding claim 8, Gruegelsiepe teaches Tris as counter ion for nucleotides (page 17, first paragraph).
Regarding claim 18, Gruegelsiepe et al. teach adding mRNA to a pharmaceutically acceptable carrier (page 3, third paragraph).
Gruegelsiepe teaches synthesis on RNA of various lengths but does not specifically teach synthesis of mRNA or using cap analogs.
However, Labourier teaches synthesis of mRNA in vitro using T7 RNA polymerase in the presence of a cap analog (page 2, second and third paragraph; page 3, first and second paragraph). Labourier also teaches that using uncapped RNA in transfection experiments into eukaryotic cells or microinjections into cells or embryos, may lead to quick degradation and low translation efficiency (page 3, second paragraph).
Therefore, it would have been obvious to one of ordinary skills in the art before the effective filing date of the claimed invention to have used cap nucleotide analogs to add to the in vitro synthesized mRNA in the method of Gruegelsiepe as suggested by Labourier. One with ordinary skills in the art motivated in using the synthetic mRNA for translation in cells and avoiding quick degradation and low translation efficiency, could have performed this modification with a reasonable expectation of success and would have arrived at the claimed invention.
However, neither of Gruegelsiepe nor Labourier teaches addition of poly(A) tail to the mRNA produced in vitro.
Regarding claim 1, Chin teaches addition of poly(A) tails to mRNAs produced by in vitro transcription before introducing the mRNAs into cells ([0061]; [0063]; [0105]; [0106]).
Munroe teaches that presence of poly(A) tail on mRNA enhances its stability and increases translation (Abstract; page 3444, sixth paragraph).
Therefore, it would have been obvious to one of ordinary skills in the art before the effective filing date of the claimed invention to have added poly(A) tails as suggested by Chin to mRNAs produced in vitro in the method of Gruegelsiepe modified by Labourier. One with ordinary skills in the art motivated in ensuring mRNA stability and increased translation could have performed this modification with a reasonable expectation of success and would have arrived at the claimed invention.
Claims 9-12 are rejected under 35 U.S.C. §103 as being unpatentable over Gruegelsiepe (Gruegelsiepe, H. et al. “Enzymatic RNA synthesis using Bacteriophage T7 RNA polymerase”. Handbook of RNA Biochemistry, ed. R. K. Hartmann, Part 1.1, (2005), pp: 3-21; cited in the IDS filed 05/22/2024), in view of Labourier (Labourier, E. et al. WO 2006/004648 Al; published January 2006; cited in the IDS filed 05/22/2024), Chin ( Chin, C. et al. US 2014/0227300 Al; filed June 2012; cited on IDS filed 05/22/2024) and Munroe (Munroe, D. et al. Mol. Cell. Biol., vol. 10, pp. 3441-3455, 1990; cited in the IDS filed 05/22/2024), as applied to claim 1 above, and in further view of Marble (Marble, H. WO 95/08626 published March 30, 1995; cited on IDS filed 05/22/2024).
The rejection of claim 1 is described above. The combination of references Gruegelsiepe, Labourier, chin and Munroe renders the elements of claim 1 obvious.
However, the combination of references does not render obvious the separation and quantification of any unincorporated NTP (claim 9), nor the carrying out the in vitro reaction in a bioreactor (claim 10). The combination of references does not render obvious a DNA template immobilized on a solid support (claim 11), nor a bioreactor comprising a filtration membrane for separation of nucleotides from the reaction mix (claim 12).
But, regarding claims 9-12, Marble does teach all these elements within a method for producing RNA enzymatically in a bioreactor using a DNA template immobilized to a solid support (see title and abstract).
Regarding claim 9, Marble teaches that nucleotides are the second most-expensive component of the transcription reaction and that using a bioreactor allows components to be recycled or reused (page 4, second paragraph; page 13, third paragraph; page 32, claim 35).
Regarding claims 9-12, Marble teaches in vitro transcription of RNA molecules
using a bioreactor comprising a membrane and a DNA template immobilized on solid support (Fig. 1 and 2; page 7, second and third paragraph; page 8, second paragraph; page 9, third paragraph). Marble teaches that the bioreactor comprises filtration membrane (microfiltration or ultrafiltration membrane) at the exit port (see page 32, claims 36-39).
Therefore, it would have been obvious to one with ordinary skills in the art before the effective filing date of the claimed invention, to have used a bioreactor as suggested by Marble in the method of mRNA production of Gruegelsiepe modified by Labourier, Chin and Munroe. One with ordinary skills in the art motivated in producing mRNA in an economical and practical industrial upscaling could have performed this modification, recycling costly reagents, while eliminating the need for subsequent purification by using filtration membrane of the bioreactor, thereby decreasing the cost of RNA production. One with ordinary skills in the art could have made this modification with a reasonable expectation of success and would have arrived at the claimed invention.
Claims 13-17 and 19-23 are rejected under 35 U.S.C. §103 as being unpatentable over Gruegelsiepe (Gruegelsiepe, H. et al. “Enzymatic RNA synthesis using Bacteriophage T7 RNA polymerase”. Handbook of RNA Biochemistry, ed. R. K. Hartmann, Part 1.1, (2005), pp: 3-21; cited in the IDS filed 05/22/2024), in view of Labourier (Labourier, E. et al. WO 2006/004648 Al; published January 2006; cited in the IDS filed 05/22/2024), Chin ( Chin, C. et al. US 2014/0227300 Al; filed June 2012; cited on IDS filed 05/22/2024) and Munroe (Munroe, D. et al. Mol. Cell. Biol., vol. 10, pp. 3441-3455, 1990; cited in the IDS filed 05/22/2024), as applied to claims 1, 5, 6 and 18 above, and in further view of Bancel (Bancel, S. et al. US 2014/0105966 A1, published April 17, 2014; cited on IDS filed 05/22/2024).
The rejection of claims 1, 5, 6 and 18 is described above. The combination of references Gruegelsiepe, Labourier, chin and Munroe renders the elements of claim 1 obvious.
However, the combination of references does not teach all elements from claims 13, 14, 16-17,19, and 21-23, i.e., a capping enzyme added after the in vitro transcription reaction (claim 13) to produce a capped mRNA (claims 16 and 23), UTPs replaced with 1-methylpseudouridine-5’-triphosphate in the reaction mix (claims 14 and 19), a pharmaceutically acceptable carrier added to the capped mRNA to provide a pharmaceutical composition (claim 17), a cap analog that is a m7GpppN cap, a Cap 1 (claims 21 and 22).
Regarding claims 15 and 20, Labourier teaches synthesis of mRNA in vitro using T7 RNA polymerase in the presence of a cap analog, therefore added before the start of transcription (page 2, second and third paragraph; page 3, first and second paragraph).
However, Labourier and the combination of references does not teach enzymatically adding a cap onto mRNA post transcription or replacing all UTP nucleotides with 1-methylpseudouridine-5'-triphosphate (N1mpU).
However, Bancel teaches these elements:
Regarding claims 14, 16-17, 19 and 21-23, Bancel teaches production of modified mRNA molecules to be used in cell transfection in vitro and in vivo to express proteins encoded by the mRNA in the transformed cells ([0035]; [0606]; [0832]).
Regarding claims 14 and 19, Bancel teaches that the modified nucleobase in some embodiments is uracil, and examples of replacements include N1-methyl-pseudouridine N1mpU (see [0456]; Figure 8). Bancel teaches synthetic mRNA with replacement at each uridine (see [1172]).
Regarding claims 13, 16 and 23, Bancel teaches a capping enzyme added after the in vitro transcription reaction (see [1157]-[1159]) to produce a capped mRNA (see [1157]-[1160]).
Regarding claim 17, Bancel teaches a pharmaceutically acceptable carrier added to the capped mRNA to provide a pharmaceutical composition (see [0487]-[0492], [1091], claims 19-20).
Regarding claims 21 and 22, Bancel teaches that the cap analog can be a m7GpppN cap and a Cap-1 (see [0169]-[0170], [1163], [1166], [1168], [1191], [1193]-[1194]).
Bancel also teaches that “While cap analog allow for the concomitant capping of a nucleic acid molecule in an in vitro transcription reaction, up to 20% of transcripts can remain uncapped.” (see [0171]). Therefore, Bancel’s teachings suggest adding a capping enzyme after the in vitro transcription assay for efficient capping of produced mRNAs as shown in [1157]-[1159].
Bancel also teaches that using a modified 5-methylcytosine/N1-methyl-pseudouridine human G-CSF mRNA generally demonstrates increased G-CSF protein production ( see [1351]).
In KSR Int 'l v. Teleflex, the Supreme Court, indicated that “The principles underlying [earlier] cases are instructive when the question is whether a patent claiming the combination of elements of prior art is obvious. When a work is available in one field of endeavor, design incentives and other market forces can prompt variations of it, either in the same field or a different one. If a person of ordinary skill can implement a predictable variation, § 103 likely bars its patentability” KSR Int'l v. Teleflex lnc., 127 S. Ct. 1727, 1740 (2007).
Applying the KSR standard of obviousness to Gruegelsiepe, Labourier, Chin, Munroe and Bancel, it is concluded that the combination of the references represents a combination of known elements which yield the predictable result. At the time of invention, a practitioner could have combined the teachings of Gruegelsiepe, Labourier, chin and Munroe on a method to produce a synthetic mRNA in in vitro transcription assay and further modified the method using the teachings of Bancel, adding a cap analog prior to the start of transcription and using a capping enzyme after the start to enhance the percentage of capped mRNAs obtained. One with ordinary skills in the art motivated in obtaining efficient protein production from a stable capped mRNA could have performed these modifications with a reasonable expectation of success and the predictable result of obtaining an optimal modified mRNA producing higher yield of proteins would be achieved. Such a combination is merely a "predictable use of prior art elements according to their established functions." KSR Int’l 7, 127 S. Ct. at 1740.
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 1-13, 15-16, 18, 20 and 23 are rejected on the ground of non-statutory double patenting as being unpatentable over claims 1-3, 6, 9-10, 13, 15-19, 53-55 and 57-58 of U.S. Patent No. 10,837,039 (USPAT’039). Although the claims at issue are not identical, they are not patentably distinct from each other because claims of the '039 patent anticipate instant claims.
Regarding claim 1, claim 1 of USPAT’039 is drawn to a method for synthesizing a capped mRNA molecule of a given sequence, comprising the following steps:
a) determining the fraction for each of the four nucleotides G, A, C and U in said mRNA molecule, and
b) synthesizing said mRNA molecule by in vitro transcription in a sequence-optimized reaction mix, wherein said sequence-optimized reaction mix comprises the four ribonucleoside triphosphates (NTPs) GTP, ATP, CTP and UTP, wherein the relative proportion of each of the four ribonucleoside triphosphates in the sequence-optimized reaction mix corresponds to the fraction of the respective nucleotide in said mRNA molecule determined in step (a), a buffer, a DNA template, and an RNA polymerase,
wherein:
before the start of the in vitro transcription a cap analog is added to the sequence optimized reaction mix to produce the capped mRNA; or
after the in vitro transcription a capping enzyme is used to produce the capped mRNA”.
Claims 13 and 54 of USPAT’039 is drawn to a method wherein said mRNA molecule is longer than 100 nucleotides, and between 100 and 10,000 nucleotides in length.
Claim 55 of USPAT’039 is drawn to mRNA comprising a Poly(A) tail sequence.
Regarding instant claim 2, claim 2 of USPAT’039 is drawn to the same limitations in b1) and b2).
Regarding instant claims 3, 15 and 20, claim 3 of USPAT’039 is drawn to the same limitations, i.e., a cap analog added before the start of the in vitro transcription.
Regarding instant claim 4, claim 6 of USPAT’039 is drawn to the same limitation.
Regarding instant claim 5, claim 8 of USPAT’039 is drawn to replacing at least one NTP with a modified nucleoside triphosphate.
Regarding instant claim 6, claim 9 of USPAT’039 is drawn to a composition, wherein said modified nucleoside triphosphate is selected from the group consisting of pseudouridine-5' -triphosphate, l-methylpseudouridine-5' -triphosphate, 2-thiouridine-5' -triphosphate, 4-thiouridine-5' -triphosphate and 5-methylcytidine-5' -triphosphate.
Regarding instant claim 7, claim 10 of USPAT’039 is drawn to the composition of claim 2, wherein m the course of the in vitro transcription the sequence-optimized reaction mix 1s supplemented with the sequence-optimized ribonucleoside triphosphate (NTP) mix as defined in claim 2b1).
Regarding instant claim 8, claim 15 of USPAT’039 is drawn to an NTP counterion that is TRIS.
Regarding instant claim 9, claim 16 of USPAT’039 is drawn to the composition of claim 1, wherein the synthesizing of said mRNA molecule by in vitro transcription is followed by separating and quantifying any unincorporated NTPs.
Regarding instant claim 10, claim 17 of USPAT’039 is drawn to the composition of claim 1, wherein the synthesizing of said mRNA molecule by in vitro transcription is carried out in a bioreactor.
Regarding instant claim 11, claim 18 of USPAT’039 is drawn to said bioreactor comprises a DNA template immobilized on a solid support.
Regarding instant claim 12, claim 19 of USPAT’039 is drawn to a bioreactor comprising a filtration membrane for separating nucleotides from the reaction mix.
Regarding instant claims 13, 16 and 23, claim 53 of USPAT’039 is drawn to adding a capping enzyme after the in vitro transcription to produce the capped mRNA.
Regarding claim 18, the combination of claims 1, 13, 54, 55, 57 and 58 of USPAT’039 teaches all the elements of claim 18.
Conclusion
No claim is allowed.
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/A.D./Examiner, Art Unit 1636
/NANCY J LEITH/Primary Examiner, Art Unit 1636
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