DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Claims 1, 3-4, 12, 25-26, 28-29, 34-37, 42, 47, 50, 54-55, 81-82 are pending.
Applicant’s election without traverse of group I, claims 1, 3-4, 8, 12, 25-26, 28-29, 34-37, 42, 47, 50, 81, and 82 in the reply filed on 02/10/2022 is acknowledged.
Claims 54-55 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 02/10/2022.
Claims 1, 3-4, 12, 25-26, 28-29, 34-37, 42, 47, 50, 81, 82 are under consideration.
Priority
This application is a divisional of U.S. Application No. 16/523214, filed 12/29/2015, which is a divisional of U.S. Application No. 15/540,610, filed June 29, 2017, which is a national phase application under 35 U.S.C. § 371 of International Application No. PCT/EP2015/081366, filed December 29, 2015, which claims the priority of International5 Application No. PCT/EP2014/003479, filed on December 30, 2014. As such the effectively filed date for the instant application is December 30, 2014.
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 1,3,4,12,25-26,28-29,34-37,42,47,50 and 81-82 remain rejected and newly added claim 83 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the claimed nucleic acid comprising the full 3’UTR of a transcript of GNAS (SEQ ID NO:2), does not reasonably provide enablement for the nucleic acid comprising fragments of the 3’UTR of GNAS. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). The court in Wands states: "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is 'undue,' not 'experimentation.' " (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all of these factors are considered, a sufficient amount for a prima facie case are discussed below.
The invention relates to artificial nucleic acid sequences that combines a GNAS 3’UTR to a coding sequence to provide greater stability to the coding sequence. The specification, however, fails to teach what sequences within the 3’UTR confer an unexpected level of stability. The specification presents 2 species of GNAS 3’UTR, mouse and human. The alignment of the mouse and human 3’UTR shows 81.5% sequence identity.
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The specification does not provide the guidance necessary to determine which 50 nucleotide fragments in either the mouse or human 3’UTR would have properties that render it enabled to use. The Specification does not support the functionality of 50-mer fragments of the 350+ nucleotide 3’UTR, at all. The claims broadly encompass fragments of the GNAS 3’UTR that may have no effect on mRNA stability and therefore fail to provide an enabled use.
While the skilled artisan can readily envision all fragments of the human or mouse GNAS 3’UTR for their sequence, it cannot be determined which of those sequences will provide an enabled use without undue experimentation.
Applicant’s remarks have been fully considered but are not persuasive. Applicant argues that experimentation to determine 50-mers that would function as an effective 5’UTR would have been routine. The issue set forth above is that the claims encompass 50-mers that lack function and the skilled artisan would not know how to use them. Applicant also provides post-filing evidence that 4 70-mers provide similar prolonged expression compared to the full length 3’UTR sequence set forth in SEQ ID NO:2. Two 5’ fragments and two 3’ fragments are used but the actual sequence or position within the full length are not provided. This data supports that less than the full length can be useful and that stability can be conferred from each of the 5’ and 3’ end. A 72-mer 3’ fragment confers greater stability than full length and more than any of the other fragments. Applicant argues the rejection under 35 USC 103, below, stating that the full length 3’UTR unexpectedly and robustly prolong protein production. Because this unexpected, it would also be unpredictable which 50-mers would produce this unexpected, robust and prolonged expression.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1,3,4,12,25-26,28-29,34-37,42,47,50 and 81-82remain rejected and newly added claim 83 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 remains unclear as it refers to the “RNA sequence of SEQ ID NO: 2”. However, SEQ ID NO:2 sets forth a DNA sequence. Claims 3,4,12,25-26,28-29,34-37,42,47,50 and 81-83 depend from claim 1 and are unclear based on this dependency and their failure to clarify claim 1.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1, 3-4, 25, 28-29, 34,36, 42, 47, 50 remain rejected and newly added claim 83 is rejected under 35 U.S.C. 103 as being unpatentable over Tanguay (Molecular and Cellular Biology, Jan. 1996, p. 146–156 ) and Schlake (RNA Biology 9:11, 1319–1330; November 2012) in view of Genbank XM_006498777.2 (https://www.ncbi.nlm.nih.gov/nucleotide/XM_006498777.2?report=genbank&log$=nuclalign&blast_rank=1&RID=B0W211X2015, ROD 07-Feb-2024, Accessed on 08/28/2025; pdf attached).
Claim 1 is drawn to an ORF and a 3’UTR comprising at least 50 consecutive nucleotides of the RNA sequence of SEQ ID NO:2. Tanguay taught an artificial nucleic acid comprising an ORF encoding luciferase and a 3’UTR. Tanguay taught that all polyadenylated mRNAs contain a 3’UTR between the coding region and the polyA tail. Tanguay taught inclusion of a 3’UTR could increase expression by up to 97-fold. Taguay taught delivery of mRNA by transfecting cells with a plasmid vector encoding the mRNA under the control of a promoter (claims 36, 42 and 47). Schlake taught that in designing mRNA for therapy, 3’UTRs are included following the ORF to increase both translation and stability. Schlake teaches that elements of 3’UTRs from a variety of genes can be used and that completely novel UTRs can be discovered by screening. Schlake taught that, “…5'- and 3'-UTRs were demonstrated to impart much greater translational efficiency on heterologous mRNA…” (claim 3-4). Schlake also teaches that a 5’-cap can enhance translation efficiency (claim 34) and that the nucleic acid can be delivered as a pharmaceutical composition (claim 50) to cells to express the protein (claim 47).
Neither Tanguay nor Schlake taught the GNAS 3’UTR that is the claimed sequence set forth by SEQ ID NO:2.
However, Genbank XM_006498777 taught the sequence of the mouse (claim 8) GNAS gene and 3’UTR which is 100% identical to the mouse GNAS 3’UTR set forth by SEQ ID NO:2 (claim 25) and is 370 nucleotides in length with a polyA tail (claims 28-29).
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It would have been obvious at the time of filing to generate an artificial nucleic acid comprising an ORF encoding any gene of interest and a stabilizing 3’UTR as taught by Tanguay and by Schlake using the 3’UTR sequence of GNAS to arrive at the invention as claimed. One would have been motivated to use the GNAS 3’UTR as Tanguay taught that the stabilizing effect of the 3’UTR is largely sequence independent and the GNAS 3’UTR sequence was known and readily available. One would have been motivated to use the GNAS 3’UTR with an ORF encoding luciferase as taught by Tanguay as it is a means for screening the stabilizing effect of the GNAS 3’UTR.
Furthermore, the combination of prior art cited above in all rejections under 35 U.S.C. 103 satisfies the factual inquiries as set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966). Once this has been accomplished the holdings in KSR can be applied (KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. ___, 82 USPQ2d 1385 (2007): "Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
In the present situation, rationales A, B and E are applicable. The modification of Tanguay and Schlake with the 3’UTR sequence taught by Genbank XM_006498777 represents combining prior methods to yield predictable results, substitution for one known element for another, and choosing from a finite number of identified, predictable results. The teachings of the cited prior art in the obviousness rejection above provide the requisite teachings and motivations with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR.
Applicant argues that the claimed 3’UTR unexpectedly and robustly prolong protein production. This argument is not persuasive because the claims encompass fragments of the 3’UTR that yields the unexpected results. Applicant has not shown that 50-mer fragments would yield similar unexpected results.
Claim(s) 1,12,35,37 and 81-82 remain rejected under 35 U.S.C. 103 as being unpatentable over Tanguay (Molecular and Cellular Biology, Jan. 1996, p. 146–156; IDS ) and Schlake (RNA Biology 9:11, 1319–1330; November 2012; IDS) in view of Genbank XM_006498777.2 (https://www.ncbi.nlm.nih.gov/nucleotide/XM_006498777.2?report=genbank&log$=nuclalign&blast_rank=1&RID=B0W211X2015, ROD 07-Feb-2024, Accessed on 08/28/2025; pdf attached) as applied to claims 1, 3-4, 8, 25, 28-29, 34, 36, 42, 47, 50 above, and further in view of Thess (WO2013143700; IDS).
Tanguay, Schlake and Genbank XM_006498777.2 meet the limitations of claim 1 as set forth above. The references do not teach the additional nucleic acid elements required by claims 12, 35, 37, 81 and 82.
However, Thess discloses an artificial nucleic acid molecule comprising
i) at least one 5'-UTR element which comprises or consists of a nucleic acid sequence which is derived from the 5'-UTR of a TOP gene (i.e. a gene providing mRNA which contains a stretch of pyrimidine nucleotides located at the 5' terminal region, see page 22).
ii) at least one open reading frame (e.g. a therapeutic protein), and further comprises
iii) at least one 3'-UTR element which comprises or consists of a nucleic acid sequence derived from the 3'-UTR of a mammalian gene, most preferably a human gene (abstract; claims 1, 2, 33, 4, 57; page 65 lines 5-20; page 80, lines 10-26). More preferably, the artificial nucleic molecule of Thess consists of three sequence parts that are derivable from three different genes, i.e. three elements heterologous to each other: the 5'-UTR element which is derivable from a TOP gene, the open reading frame which is derivable from the gene encoding the desired gene product and the 3'UTR element which may be derivable from a gene that relates to an mRNA with an enhanced half-life (page 39, lines 28-33).
Regarding claim 12, Thess discloses the 5'UTR element, preferably the artificial nucleic acid molecule, does not comprise a complete TOP-motif or 5'TOP sequence. Thus, the 5'UTR element, preferably the artificial nucleic acid molecule, does not comprise the 15 complete TOP-motif of the TOP gene from which the nucleic acid sequence of the 5'UTR element is derived (see page 28. Lines 11-16). Regarding claim 37, Thess discloses the 5'UTR element may comprise or consist of a nucleic acid sequence which starts at its 5' end with a pyrimidine residue that corresponds to residue 2, 4, 5, 6, 7, 8, 9, 10 etc. of the TOP-motif or 5'TOP of the TOP gene from which the nucleic acid sequence of the 5'UTR element is derived (see page 28, lines 20-24). Regarding claim 47, Thess discloses a cell comprising the artificial nucleic acid molecule according to any one of claims 1-32 or the vector according to any one of claims 33-67 (see p 282 claim 68).
Regarding claim 35, the instant claimed SEQ ID NO:34 is a histone stem loop disclosed by Thess as SEQ ID NO:1394, which increases expression.
Regarding claims 81 and 82, the instant claimed SEQ ID NO:33 is “5'-UTR of human ribosomal protein Large 32 lacking the 5'terminal oligopyrimidine tract” where the TOP has been removed. Thess discloses SEQ ID NO:1368, which is identical to SEQ ID NO:33. Thess discloses that the TOP can be removed to decrease expression ass the 5’TOP UTR and the 3’UTR act synergistically to increase expression to high levels.
It would have been obvious to alter the nucleic acid taught by Tanguay, Schlake and Genbank to arrive at the more specifically claimed nucleic acids of claims 12, 37, 81 and 82 by employing the additional regulatory and structural elements taught by Thess to arrive at the invention a claimed. One would have been motivated to make such a combination as Thess taught making stable RNAs using various 5’- and 3’ UTRs and that the 5’ TOP can be removed to adjust expression levels. One would have a reasonable expectation of success in making such a combination as the requisite technology and materials to make the nucleic acid were readily available to the ordinary skilled artisan.
Applicant relies upon the arguments of unexpected results that are addressed above. For the same reasons, these are no sufficient to overcome this rejection.
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 VALARIE BERTOGLIO whose telephone number is (571)272-0725. The examiner can normally be reached M-F 6AM-2:30PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Peter Paras can be reached on 571-272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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VALARIE E. BERTOGLIO, Ph.D.
Examiner
Art Unit 1632
/VALARIE E BERTOGLIO/Primary Examiner, Art Unit 1632