Detailed Action
► The applicant's response (filed 22 JAN 2026) to the Office Action has been entered. Following the entry of the claim amendment(s), Claim(s) 40, 43-46, 48, 50, 52-63 and 120-127 is/are pending. Rejections and/or objections not reiterated from the previous office action are hereby withdrawn. The following rejections and/or objections are either newly applied or reiterated. They constitute the complete set presently being applied to the instant application.
► The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . 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 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.
35 U.S.C. 102
► The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that may form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
35 U.S.C. 103
► The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
► 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.
Claim Rejection(s) under 35 U.S.C. 103
► Claim(s) 40, 43-46, 48, 50, 52-59 and 120-127 is/are rejected under 35 U.S.C. 103 as being unpatentable over Woolf et al. [US 2009/0093433 – hereinafter Woolf”] in view of Fodor [US 2001/0053519 – hereinafter Fodor”] and/or Minshull et al. [US 2002/0025517 – hereinafter “Minshull”].
Claim 40 is drawn to a composition 1) a polynucleotide having a coding and a non-coding region, and 2) a complementary stabilizing oligonucleotide hybridized to at least a portion of the non-coding region of the polynucleotide mRNA, wherein the stabilizing oligonucleotide comprises at least one modified nucleobase and is at least about 1 to about 50 nucleotides in length, and wherein the stabilizing oligonucleotide and the polynucleotide are present at about 0.001:1 to about 100:1 parts stabilizing oligonucleotide to polynucleotide.
Woolf describe methods and compositions for stabilizing mRNA molecules (ie. therapeutic mRNA). In particular, Woolf teach a method/composition comprising a polynucleotide having a coding and a non-coding region (i.e. a mRNA coding for a therapeutically relevant protein). In one embodiment the method of Woolf, a complementary stabilizing oligonucleotide(s) is/are hybridized to at least a portion of the non-coding region of the polynucleotide mRNA, wherein the stabilizing oligonucleotide comprises at least one modified nucleobase in order to stabilize/protect said mRNA from degradation . See at least paras 7-12 and 17-19 recited below :
[0007] The present invention is directed to methods of altering eukaryotic, preferably mammalian, mRNA which result in its stabilization against nucleases and enable its use in sense RNA therapy to provide a protein of interest. The invention also pertains to compositions comprising such modified mRNAs and their methods of use. The modified RNAs of the present invention retain the ability to encode proteins.
[0008] In one aspect the invention pertains to modified, eukaryotic mRNA molecule encoding a therapeutically relevant protein, the mRNA molecule having a nucleotide sequence which comprises at least one chemical modification which renders the modified mRNA molecule stable, wherein the modified mRNA is translatable.
[0009] In one embodiment, the chemical modification comprises at least one end blocking modification. In one embodiment, the end blocking modification comprises the inclusion of a non-nucleotide blocking group blocking group. In another embodiment, the end blocking modification comprises the inclusion of a modified blocking group. In another embodiment, the end blocking modification comprises the inclusion of a 3' blocking modification. In another embodiment, the end blocking modification comprises the inclusion of a 5' blocking modification. In yet another embodiment, the 5' modification comprises the inclusion of a modified diguanosine (m7) cap being linked to the mRNA by a chemically modified linkage.
[0010] In another embodiment, the chemical modification comprises the inclusion of at least one modified nucleotide. In one embodiment, the modified nucleotide is selected from the group consisting of a 2' modified nucleotide and a phosphorothioate modified nucleotide.
[0011] In another aspect, the invention pertains to a modified, eukaryotic mRNA molecule encoding a therapeutically relevant protein, the mRNA molecule having a nucleotide sequence which comprises at least one modification which renders the modified mRNA molecule stable against nucleases, wherein the modification comprises the inclusion of a polyA tail of greater than about 50 bases in length, the mRNA molecule being translatable.
[0012] In another aspect, the invention pertains to a modified, eukaryotic mRNA molecule encoding a therapeutically relevant protein, the mRNA molecule having a nucleotide sequence which comprises at least one modification which renders the modified mRNA molecule stable against nucleases, wherein the modification of the mRNA molecule comprises complexing the mRNA with an agent to form an mRNA complex, the modified mRNA being translatable.
[0017] In another aspect, the invention pertains to a modified, eukaryotic mRNA molecule encoding a therapeutically relevant protein, the mRNA molecule having a nucleotide sequence which nucleotide sequence comprises at least one modification which renders the modified mRNA molecule stable against nucleases, wherein the modification of the mRNA molecule comprises the incorporation of 3' or 5' sequences which naturally flank a second mRNA molecule which encodes a protein selected from the group consisting of: globin, actin GAPDH, tubulin, histone, and a citric acid cycle enzyme, the modified mRNA being translatable.
[0018] In another aspect, the invention pertains to a modified, eukaryotic mRNA molecule encoding a therapeutically relevant protein, the mRNA molecule having a nucleotide sequence which nucleotide sequence comprises at least one modification which renders the modified mRNA molecule stable against nucleases, wherein the modification of the mRNA molecule comprises the incorporation of an internal ribosome entry site selected from the group consisting of: a vascular endothelial growth factor IRES, encephalo myocardial virus IRES, a picornaviral IRES, a adenoassociated virus IREF, and a c-myc IRES.
[0019] In one embodiment the mRNA has a length of between about 500 to about 2000 nucleotides. In another embodiment, the mRNA has a length of between about 500 to about 1000 nucleotides.
[0050] In one embodiment, the mRNA to be stabilized is eukaryotic in origin. Preferably the mRNA to be stabilized is mammalian in origin. In preferred embodiments, the subject sense mRNA molecules comprise characteristics of eukaryotic mRNAs, e.g., the presence of a 5' diguanosine (7 m) cap, and/or the presence of a poly A tail.
[0051] mRNAs for stabilization using the instant methods can be isolated from cells, can be made from a DNA template, or can be chemically synthesized using methods known in the art prior to alteration using the instant methods. In preferred embodiment, mRNAs for modification are synthesized in vitro from a DNA template In one embodiment, the modified mRNAs of the invention are made using a high yield technology known in the art.
[0052] For stabilization using the described methods, sense mRNA molecules can be of any length. Preferably, sense mRNA molecules for stabilization are longer than about 50 nucleotides. In a preferred embodiment, sense mRNA sequences to be stabilized are longer than about 100 nucleotides. In another preferred embodiment, sense mRNA sequences are longer than about 250 nucleotides. In other preferred embodiments, the coding region of an mRNA molecule to be stabilized is between about 500 and about 1000 nucleotides in length. In another preferred embodiment, the coding region of an mRNA molecule to be stabilized is between about 1000 and 2000 nucleotides. In another preferred embodiment, the coding region of an mRNA molecule to be stabilized is between about 2000 and 3000 nucleotides. In another preferred embodiment, the coding region of an mRNA molecule to be stabilized is between about 3000 and 4000 nucleotides. In another preferred embodiment, the coding region of an mRNA molecule to be stabilized is between about 5000 and 6000 nucleotides. In another preferred embodiment, the coding region of an mRNA molecule to be stabilized is between about 6000 and 7000 nucleotides. In another preferred embodiment, the coding region of an mRNA molecule to be stabilized is between about 7000 and 8000 nucleotides.
As noted above, Woolfe, in at least para 112 teach the use of "complementary nucleic acid molecule(s) (i.e. stabilizing oligos). There Woolfe expressly teaches “Since most coding regions of mRNA molecules are relatively long, a series of tandem complementary 2'-O-methyl modified complementary oligomers can be designed to hybridize to the sense mRNA molecule downstream of the start AUG codon. These complementary nucleic acid molecules can hybridize to the entire coding region and, in some embodiments, to portions of the 3' untranslated region. Woolfe further teaches "Alternatively, a longer protecting oligomer made by in vitro transcription" can be used. Finally, Woolf in para 52 teach the length of some representative coding region lengths.
That said, Woolf does not expressly teach the length of their stabilizer oligos and, in particular, Woolf does not expressly teach that said stabilizing oligos are to be at least about 1 to about 50 nucleotides in length as required by Claim 40. Regardless oligos in the range recited were known, consider at least Fodor. At para 101 Fodor teach all possible oligonucleotides comprising at least about 10 nucleotides as well as all possible oligos comprising about 25 nucleotides (i.e. about 50 nucleotides in length) . Also note, Minshull who teach 50 -mers and the use thereof, see at least para 222. Accordingly, absent an unexpected result it would have been prima facie obvious to the PHOSITA at the time of the invention to substitute oligos comprising at least about 10 to about 50 nucleotides as disclosed by Fodor and/or Minshull for those of Woolfe. Please note that substitution of one known second method/reagent with known properties for a first known method/reagent with known properties would have been prima facie obvious to the ordinary artisan at the time of the invention in the absence of an unexpected result. As regards the motivation to make the substitution recited above, the motivation to combine arises from the expectation that the prior art elements will perform their expected functions to achieve their expected results when combined for their common known purpose. Support for making this obviousness rejection comes from the M.P.E.P. at 2144.07 and 2144.09, as well as, the SCOTUS decision in KSR International. Co. V. Teleflex, Inc., et al., 550 U.S.398 (2007).
Claim 43 is drawn to an embodiment of the composition of Claim 40 wherein the nuclease resistant mRNA encodes a protein selected from a defined group which includes CFTR and EPO.
Woolf teach these limitation(s), see at least para 133.
Claim 44 is drawn to an embodiment of the composition of Claim 40 wherein the stabilizing oligo is fully complementary to at least a portion of the non-coding region of the mRNA. Claim 45 is drawn to an embodiment of the composition of Claim 40 wherein the stabilizing oligo is perfectly complementary to at least a portion of the coding region of the mRNA.
Woolf teach these limitations, see especially para 112.
As regards Claim 46, see para 112 in Woolfe.
As regards Claim(s) 48 and 50, see especially paras 25-26.
As regards Claim 52, see at least para 101 in Fodor.
As regards Claim(s) 53-59, see especially paras 91 and 112 in Woolfe
As regards Claim 62, Woolf teach non-coding regions comprising poly(A) tails, see especially para 11, 14 and 24.
As regards Claims 120-127, Woolf teach using stabilizing oligos at a ratio of 1:1 or greater but does not teach the ratios recited by Claims 120-127. However, where the general conditions of a claim are disclosed in the prior art, it is not inventive, in the absence of an unexpected result, to discover the optimum or workable ranges by routine experimentation. In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
► Claim(s) 60-61 is/are rejected under 35 U.S.C. 103 as being unpatentable over Woolfe in view of Fodor and/or Minshull as applied above against Claim 40 and further in of Kariko et al. [Modern Therapy 16(11) 1833(2208) - hereinafter "Kariko] and/or Shohda et al. [Bioorganic & Medicinal Chemistry Letters 10 :1795 (2000) - hereinafter "Shohda"].
As regards Claim(s) 60-61 , Woolfe teach nucleobase modifications, see for example paras 111-113. Woolfe do not teach the use of pseudouridine and/or 2-thiouridine, as required, in part, by Claim 61. However, these nucleobase modifications were well known, consider at least the abstracts of Kariko and/or Shohda. Accordingly, absent an unexpected result it would have been prima facie obvious to the PHOSITA at the time of the invention to substitute the nucleobase modifications of Kariko and/or Shohda for those of Woolfe in view of Fodor and/or Minshull. Please note that substitution of one known second method/reagent with known properties for a first known method/reagent with known properties would have been prima facie obvious to the ordinary artisan at the time of the invention in the absence of an unexpected result. As regards the motivation to make the substitution recited above, the motivation to combine arises from the expectation that the prior art elements will perform their expected functions to achieve their expected results when combined for their common known purpose. Support for making this obviousness rejection comes from the M.P.E.P. at 2144.07 and 2144.09, as well as, the SCOTUS decision in KSR International. Co. V. Teleflex, Inc., et al., 550 U.S.398 (2007).
► Claim(s) 63 is/are rejected under 35 U.S.C. 103 as being unpatentable over Woolfe in view of Fodor and/or Minshull and Kariko or Shohda as applied above against Claims 40 and 62 and further in of Venkatesan et al. [Nucleic Acids Research 3(8) : 1925(1976) - hereinafter "Venkatesan"].
As regards Claims 63 , Woolfe in view of Fodor and/or Minshull and Kariko or Shohda reasonably suggest using stabilizing oligos hybridizing to at a non-coding portion of a therapeutic mRNA in order to stabilize/protect said mRNA as outlined above. That said, these documents do not expressly teach stabilizer oligos comprising poly(U) sequences. However, oligos comprising poly U nucleobases were known, as was as their ability to hybridize to the poly A regions of mRNA molecules, consider for example Venkatesan. Accordingly, absent an unexpected result it would have been prima facie obvious to the PHOSITA at the time of the invention to substitute the poly U containing oligos of Venkatesan for those of Woolfe in view of Fodor and/or Minshull and Kariko or Shohda which are to hybridize to the non-coding region of a therapeutic mRNA in order to stabilize/protect said mRNA from deterioration. Please note that substitution of one known second method/reagent with known properties for a first known method/reagent with known properties would have been prima facie obvious to the ordinary artisan at the time of the invention in the absence of an unexpected result. As regards the motivation to make the substitution recited above, the motivation to combine arises from the expectation that the prior art elements will perform their expected functions to achieve their expected results when combined for their common known purpose. Support for making this obviousness rejection comes from the M.P.E.P. at 2144.07 and 2144.09, as well as, the SCOTUS decision in KSR International. Co. V. Teleflex, Inc., et al., 550 U.S.398 (2007).
Response to Applicant’s Amendment / Arguments
► Applicant's arguments with respect to the claimed invention have been fully and carefully considered but are moot in view of the new ground(s) of rejection.
Conclusion
C1. Applicant's amendment necessitated the new grounds of rejection. Accordingly, THIS ACTION IS MADE FINAL. See M.P.E.P. § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 C.F.R. § 1.136(a).
A SHORTENED STATUTORY PERIOD FOR RESPONSE TO THIS FINAL ACTION IS SET TO EXPIRE THREE MONTHS FROM THE DATE OF THIS ACTION. IN THE EVENT A FIRST RESPONSE 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 EXTENSION FEE PURSUANT TO 37 C.F.R. § 1.136(a) WILL BE CALCULATED FROM THE MAILING DATE OF THE ADVISORY ACTION. IN NO EVENT WILL THE STATUTORY PERIOD FOR RESPONSE EXPIRE LATER THAN SIX MONTHS FROM THE DATE OF THIS FINAL ACTION.
C2. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Ethan Whisenant whose telephone number is (571) 272-0754. The examiner can normally be reached Monday-Friday from 8:30 am -5:30 pm EST or any time via voice mail. If repeated attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Anne Gussow, can be reached at (571) 272-6047.
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/ETHAN C WHISENANT/Primary Examiner, Art Unit 1683 ethan.whisenant@uspto.gov