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
This action is in response to the papers filed on 10/15/2025. Claims 1-2, 4,7, 9-11, 13-15, 17, 19, 23, 25-26, 30, 32, 35-36 and 38 are currently pending as per claims filed on 07/21/2022.
Applicant’s election of Group I, which include claims 1-2, 4, 7, 9-11, 13-15, and 17 in the reply filed on 10/15/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 19, 23, 25-26, 30, 32, 35-36, and 38 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10/15/2025.
The requirement for restriction between Groups I-III is still deemed proper and is therefore made FINAL.
Therefore, claims 1-2, 4, 7, 9-11, 13-15, and 17, are subject to examination to which the following grounds of rejection are applicable.
Priority
The instant application is a CON of PCT/IL2021/050074 filed 01/24/2021, which claims priority to PRO 62/964,859 filed 01/23/2020.
Thus, the earliest possible priority for the instant application is 01/23/2020
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 05/16/2024 was filed before the mailing date of the non-final office action. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Interpretation
Multiple regions are recited in the instant application claims. The “first region” as recited in claim one is interpreted as being the last 90 nucleotides within the sequence prior to the stop codon. The transcriptional start site (TSS) as recited in claim 13 is understood to be the first nucleotide of the start codon and a single nucleotide position. The “second region” as recited in claim 13 is understood to be a position between the TSS to 10 or 20 nucleotides downstream (5’ → 3’ prime direction) and “third region” as recited claim 15 is a distinct region between the first and second region. Although the third region is a distinct region, the nucleotides of the third region may overlap with the first or second region. Prior art that reads on nucleotides falling within these regions will be considered.
Claim objections
Claims 4, 14 and 17 are objected to because of the following informalities: claims 4, 14 and 17 are a Markush-type claim which recites “selected from” ; the proper format requires the use of the phase “ selected from the group consisting of “. Amending claims 4, 14 and 17 to insert the phrase “the group consisting of” after “selected from” will overcome this aspect of the objection.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 7, 9 15 and 17 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.
Claim 7 is rejected because of its recitation of “said substitution”. There is not proper antecedent bases for “said substitution” in the claim or parent claim. Claim 1 requires “a mutation”.
Claim 7 recites the phrase “increases folding energy of said first region to above a predetermined threshold.” It is unclear what the intended meaning or numerical value would be for a “predetermined threshold”. This threshold is not defined by the claims, thus rendering the metes and bounds indefinite. Therefore, the claim is indefinite.
Claim 7 is vague and indefinite in the recitation of the word “optionally". The recitation of the word “optionally” is an opened ended word and renders the claim indefinite. As such the metes and bounds of the claim cannot be determined.
Claim 7 recites the term “would be significant”. The recitation of term “significant” is a relative term and renders the claim indefinite. The term "threshold" is not defined by the claim. The specification does not provide any closed definition as to what is meant by “threshold”. What thresholds are considered "significant" varies widely in the art depending on the individual situation as well as the person making the determination. As such the metes and bounds of the claim are indefinite.
Claim 9 is dependent upon and inherits the deficiencies of claim 7. Claim 9 references a table from within the specification, which renders the claim indefinite, “wherein said threshold is species-specific and is selected from a threshold provided in Tables 5 or said threshold is domain-specific and is selected from a threshold provided in Table 1. "Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table 'is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience.' Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993)" (MPEP 2173.05(s)).
Claim 15 and by dependence claim 17 are indefinite in the recitation of “a third region between said first and said second regions” as it is unclear the structure encompassed by the third region. The recitation of “a region” implies that there is at least one or more residues in this region which is indefinite. Amending the claim to recite the amino acids comprising the domain of a third region would obviate the rejection.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that 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.
Claim(s) 1, 2 and 4, and 13-14 are rejected under 35 U.S.C. 102 as being unpatentable over Hunt et al. (WO 2015/184466 Al, IDS filed 05/13/2024; hereafter “Hunt”).
Claim 1 of the instant application recites, “A method for optimizing a coding sequence, the method comprising introducing a mutation into a first region from 90 nucleotides upstream of a stop codon of said coding sequence to said stop codon; wherein said mutation increases folding energy of said first region or of RNA encoded by said first region, thereby optimizing a coding sequence.”
Hunt teaches methods and metric suitable for use in modulating the expression of a polypeptide encoded by a nucleic acid sequence. “In certain aspects, the invention also relates to methods for introducing modifications in a polypeptide, for example through substitution of one or more nucleic acids in an untranslated sequence or in a coding sequence of a nucleic acid sequence encoding a polypeptide to increase the expression of the polypeptide.” (Abstract).
Moreover, Hunt teaches tail folding affects expression (Pg. 68, Paragraph [00216]; Figure 9), synonymous mutations (substitutions) can increase predicted free energy of folding (Pg. 2, Paragraph [0006]), and predicted free energy of folding (termed ΔG) of both head (Pg. 6-7, Paragraphs [0016]-[0021]) and tail regions (defined as nucleotides 49 through the stop codon) (Pg. 68, Paragraph [00216]) of coding sequence affect protein expression level. This tail region would include nucleotides as recited in claim 1 of the instant application “a first region from 90 nucleotides upstream”. Hunt teaches mutations within the tail region to include eliminating codons that reduce expression (Pg. 34-35, Paragraph [00123]) and introducing one or more synonymous nucleic acid substitutions into the tail region to alter predicted free energy of folding (Claim 3 of Hunt).
Regarding Claim 2 and 4, Hunt teaches “A method for increasing the expression of a recombinant polypeptide in an expression system by introducing one or more synonymous substitutions” (Claim 1 and 3 of Hunt). The method can be performed in an expression system, including using E.coli or mammalian cells as target cells (Claims 59-60 of Hunt).
Regarding claim 13, Hunt teaches “A method for increasing the expression of a recombinant polypeptide in an expression system by introducing one or more synonymous substitutions, the method comprising providing a nucleic acid sequence comprising a coding sequence encoding the polypeptide and a 5' UTR comprising a ribosome binding site and wherein the 5' UTR is functionally linked to said coding sequence, and (a) introducing one or more substitutions in the 5'UTR or one or more synonymous nucleic acid substitutions in a head sequence consisting essentially of the first 48 nucleic acids of the coding sequence, wherein the one or more substitutions in the 5'UTR and the one or more synonymous nucleic acid substitutions increase the predicted free energy of folding of the RNA sequence corresponding to the head sequence and the 5' UTR functionally linked to said coding sequence…” (Claim 1 of HUNT). +20nt recited by instant claim 13 is a subset of the first 48nt recited by Hunt, therefore the region recited by instant claim 13 is inherently included.
Regarding Claim 14, The method can be performed in an expression system, including using E.coli or mammalian cells as target cells (Claims 59-60 of Hunt). The regions recited in claim 14 would be inherently included in the first 48nt recited by Hunt as discussed in the rejection to claim 13.
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.
Claim(s) 10-11 are rejected under 35 U.S.C. 103 as being unpatentable over Hunt et al. (WO 2015/184466 Al, IDS filed 05/13/2024; hereafter “Hunt”) as applied to claim 1 above.
Regarding claim 1, Hunt et al. renders obvious the claimed methodology, as iterated above in the 102 rejection the content of which is incorporated herein, in its entirety.
Regarding Claims 10-11, Hunt teaches mutations within the tail region to include eliminating codons that reduce expression (Pg. 34-35, Paragraph [00123]) and introducing one or more synonymous nucleic acid substitutions into the tail region to alter predicted free energy of folding (Claim 3 of Hunt). Moreover, Hunt teaches optimization strategies to determine optimum free folding energy of the tail region (Pg. 84, Paragraph [00257]).
Although Hunt teaches optimizing folding energy, they do not specifically teach each mutation to increase folding energy of said first region as in instant claim 11, rather they seek to determine the most optimum folding energy that is neither too high or low.
It would have been prima facie obvious to someone having ordinary skill in the art at the time of the instant application using the methods of optimization taught by Hunt to produce an RNA molecule with a higher folding energy than the base molecule through introduction of mutations. A person would have been motivated to determine to introduce synonymous mutations and adjust the number and specific placement to specifically tune the folding energy of the region into an optimal range known to influence translation efficiency.
There would have been a reasonable expectation of success incorporating known elements to produce an expected result.
"[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 re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.") See MPEP 2144.05 II. A.
Conclusion
Claims 1-2, 4, 7, 9-11 and 13 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KODYE LEE ABBOTT whose telephone number is (703)756-1111. The examiner can normally be reached M-F 8-5.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Maria G. Leavitt can be reached at (571) 272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KODYE LEE ABBOTT/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634