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
Applicant’s election of Group I, claims 38-45, codons exchanges with alternative codons that occur with the highest frequency in the human genome, and codon exchange Table 1B in the reply filed on 17 December 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Claims 42 and 46-59 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 17 December 2025.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code on pg. 6-13. 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.
Claim Objections
Claim 45 is objected to because of the following informalities: the claim recites the phrase “any one of the codon exchange tables 1A, 1B, 2A, 2B, 2C, 2D” in line 2 of the claim. The phrase should read “any one of the codon exchange tables 1A, 1B, 2A, 2B, 2C, or 2D” Appropriate correction is required.
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.
Claim 38-41 and 43-45 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Regarding claim 38, the claim is broadly drawn towards a method of decreasing the immunogenicity of an RNA molecule and/or at least maintaining the translation efficacy thereof via the reduction of at least 10% of the cytidines in the RNA molecule when compared to a wildtype RNA molecule. Therefore, the claim is interpreted as claiming a genus of RNA molecules that have been modified such that the RNA molecule has at least 10% less cytidines than a wildtype RNA molecule and comprises the claimed reduced immunogenicity or maintained translation efficiency.
The instant specification does not provide support for the generation of an RNA molecule, via the method as claimed, that had reduced immunogenicity when compared to a wildtype RNA molecule. The instant specification does not provide support for the generation of the broad genus of RNA molecules not limited by structure, via the method as claimed, that had maintained translation efficacy when compared to a wildtype RNA molecule.
The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include "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. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would leave one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient." MPEP 2163. A claimed genus may be satisfied through sufficient descriptions of a representative number of species or disclosure of relevant, identifying characteristics such as functional characteristics coupled with known or disclosed correlation between function and structure. MPEP 2163(3)a(II). The number of species that describe the genus must be adequate to describe the entire genus; if there is substantial variability, a large number of species must be described.
The analysis for adequate written description considers (a) actual reduction to practice, (b) disclosure of drawings or structural chemical formulas, (c) sufficient relevant identifying characteristics in the way of complete/partial structure or physical and/or chemical properties or functional characteristics when coupled with known or disclosed correlation with structure, and (d) representative number of samples.
As the claim currently recites, as described above, the claim is directed towards a method of decreasing the immunogenicity of an RNA molecule and/or at least maintaining the translation efficacy thereof via the reduction of at least 10% of the cytidines in the RNA molecule when compared to a wildtype RNA molecule (see Claim 38). While claiming a genus of structures (i.e., RNA molecules) by a function (i.e., a method of decreasing the immunogenicity of an RNA molecule and/or at least maintaining the translation efficacy thereof) is not prohibited, there must be a sufficient structure-function relationship described in the specification such that the claimed genus was represented by a representative number of species or the teachings of the specification, or, the prior art can be used to support a well-known structure-function relationship.
In the instant case, the instant specification does not provide support that the claimed method of altering an RNA molecule’s sequence could perform the claimed function. Further, the prior art demonstrates that the ability for a codon exchange table to be utilized in order to at least maintaining the translation efficacy of an RNA molecule is unpredictable.
Working Examples
With regard to working examples, the specification provides little evidence on the possession of a sufficient number of species which are encompassed by the entirety of the claim.
MPEP 2163 teaches that “for some arts, there is an inverse correlation between the level of skill and knowledge in the art and the specificity of disclosure necessary to satisfy the written description requirement. Information which is well known in the art need not be described in detail in the specification. See, e.g., Hybritech, Inc. v. Monoclonal Antibodies, Inc., 802 F.2d 1367, 1379-80, 231 USPQ 81, 90 (Fed. Cir. 1986). However, sufficient information must be provided to show that the inventor had possession of the invention as claimed [emphasis added].”
In the instant case, the specification teaches the use of codon exchanges tables 1A and 2C to generate C2-depleted or UC-depleted variants of secNLuc, mEPO, and eGFP (pg. 20-21; see Example 1). The specification also teaches that C2-depleted and UC-depleted variants of specific RNA molecules were able to maintain protein expression (i.e., translation efficiency) when compared to a WT RNA molecule (pg. 18-19; see Figure 4). The specification also teaches that the codon exchange tables 1B, 2A, 2B, and 2D were generated “by the algorithm” (pg. 39). However, the instant specification does not provide support for the utilization of codon exchange tables 1B, 2A, 2B, and 2D to perform the claimed function. The instant specification does not disclosure how codon exchange tables 1B, 2A, 2B, and 2D relate to Figure 4 nor how the codon exchange tables were utilized in order to decreasing the immunogenicity of an RNA molecule and/or at least maintaining its translation efficacy. It is also noted that the instant specification’s working examples are limited to individual sequences in replicate.
Further, the instant specification does not provide any description of the reduced immunogenicity of the claimed RNA molecules, specifically. FIGS. 3-7 are directed towards charts demonstrating the activity and expression levels of reporter molecules that have had their sequences altered according to codon exchange tables when compared to a wildtype RNA molecule’s activity and expression levels. Neither the figures nor specification provide evidence for the reduced immunogenicity of the modified RNA molecules, as claimed.
Thus, when taken as a whole, the set of codon exchange tables 1A and 2C present in the specification that were utilized to produce modified RNA molecules that comprised maintained translation efficacies is not representative of the entirety of the claimed genus of modified RNA molecules claimed in claim 38. The instant specification does not disclosure how codon exchange tables 1B, 2A, 2B, and 2D could be utilized to perform the claimed method nor how the variants present in Figure 4 relate to codon exchange tables 1B, 2A, 2B, and 2D. Further, it is noted that the instant specification’s working examples are limited to individual sequences in replicate while the claim is broadly drawn towards a genus of any such codon optimized sequence whose specific codons are not specifically defined. The instant specification also does not provide any description of the reduced immunogenicity of the claimed RNA molecules.
Therefore, the instantly claimed method of decreasing the immunogenicity of an RNA molecule and/or at least maintaining the translation efficacy thereof is not adequately described in the specification as being able to decreasing the immunogenicity of an RNA molecule and/or at least maintaining its translation efficacy.
Thus, the instant specification does not provide written description for the entirety of the claimed method (see Claim 38).
Prior Art
Regarding the state of the prior art, the prior art demonstrates that utilizing a codon exchange table to alter the sequence of a translated RNA molecule and the successful use of the exchange table to maintain the translation efficacy thereof is unpredictable and requires testing.
Gonzalez (Nucleic acids research 32.17 (2004): 5198-5205) is directed towards a study concerned with the influences that different codons at different positions downstream of an initiation codon have on gene expression (Abstract). Gonzalez teaches that utilizing certain codon exchanges (i.e., a codon exchange table) did not result in an RNA molecule that had a maintained expression level (i.e., a maintained translation efficacy) (pg. 5200-52001; see Figures 2-4). Gonzalez teaches that many alternate codon sequences for a single codon result in a lower expression level of the RNA molecule and that testing of each specific codon sequence permutation was required in order to determine if the translation efficacy of the RNA molecule was maintained (pg. 5200-52001; see Figures 2-4).
Thus, the prior art shows that prior to the effective filing date of the claimed invention it was not predictable that any codon exchange table would be utilized to maintain the translation efficacy of an RNA molecule. Rather, the prior art shows that multiple codon sequence permutations at a specific position resulted in a lower expression of an RNA molecule and that testing was required in order to determine if a specific codon sequence substitution would maintain translation efficacy.
Conclusion
The specification does not identify a representative number of species of the claimed codon exchange tables that possess the claimed function of maintain the translation efficacy of an RNA molecule modified by the codon exchange tables. Further, the prior art shows that prior to the effective filing date of the claimed invention that determining if a particular codon sequence permutation resulted in the claimed function was unpredictable and highly specific. Therefore, a person of ordinary skill in the art would not have concluded that Applicant was in possession of the invention as claimed. Thus, claim 45 is rejected under 35 U.S.C. 112(a).
Regarding claims 39-41 and 43-45, as the claims are ultimately dependent on claim 38 and do not rectify the 35 USC 112(a) rejection above, the claims are rejected under 35 USC 112(a).
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 38-41 and 43-45 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 38, the claim recites the limitation "the translation efficacy thereof" in line 2, “the coding sequence” in line 5, “the sense DNA strand” in lines 5-6, “the ATG start codon” in line 6, “the first in-frame stop codon” in lines 6-7. There is insufficient antecedent basis for these limitations in the claim. The limitations are unclear because the genus of an “RNA molecule” does not inherently have these claimed terms because not all transcribed RNA molecules comprise coding sequences.
Claim 38 further recites the following phrase: “exchanging one or more codons […] resulting in a similar amino acid” in part d) of the claim. As the specification does not provide a specifical definition for “a similar amino acid”, it is unclear what is encompassed by the term. It is unclear if “a similar amino acid” requires that the substituted amino acid has a similar biochemical property, a specific sequence requirement, or if the substituted amino acid may be any amino acid, so long as the claimed function is performed.
Regarding claim 45, the claim recites “codon exchange tables 1A, 1B, 2A, 2B, 2C, 2D” in line 2 of the claim. MPEP 2173.05(s) states "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". Accordingly, the claim is rejected under 35 USC 112(b) because it is practical to amend the claim to list the specific codon substitution sequences listed in the tables.
Regarding claims 39-41 and 43-44, as the claims are ultimately dependent on claim 38 and do not rectify the currently 35 USC 112(b) rejections above, the claims are also rejected under 35 USC 112(b).
Claim Rejections - 35 USC § 102
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.
Claim(s) 38-41 and 44 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Martini (PG Pub No. WO 2017201346 A1).
Regarding claim 38, Martini is drawn towards an invention concerned with mRNAs that encode human porphobilinogen deaminase (PBGD) (Abstract). Martini teaches a method of incorporating modified nucleotides within therapeutic mRNAs to optimize the translation efficiency of mRNA to protein (i.e., Martini teaches a method of at least maintaining the translation efficacy of an mRNA molecule) ([0009]). Martini teaches (a) the use of a wild-type DNA molecule comprising an open reading frame encoding a PBGD polypeptide (i.e., (b) a coding sequence from a sense strand of a DNA sequence that comprises a start codon to a first in-frame stop codon) ([0271], [0564]). Martini teaches that the open reading frame encoding the PBGD polypeptide can be sequence-optimized ([0272]). Martini teaches that the sequence-optimized nucleotide sequence is a codon-optimized sequence encoding the PBGD polypeptide that comprises at least one synonymous nucleobase substitution with respect to a reference wild type sequence (i.e., Martini teaches the codon-optimization of a wild-type DNA sequence encoding a PBGD polypeptide) ([0282]). Martini teaches (c)-(d) the use of a codon optimization table that provides for alternative DNA nucleotide codons that can be utilized to generate a codon-optimized RNA molecule encoding the PBGD polypeptide ([0285], [0326]; see Table 1). Martini teaches that the optimization of the RNA sequence may result in a decrease in the cytosine content by at least about 10% (i.e., the modified, codon-optimized, mRNA sequence produced from the DNA molecule with the codon-optimized open reading frame comprises at least 10% less total cytidine content when compared to a non- optimized wild type mRNA sequence) ([0369]).
Regarding claim 39, Martini teaches that reducing the amount off uridine content in the modified RNA molecule is advantageous to avoid adverse effects on translation ([0338]). Martini teaches an embodiment of optimizing the amount of uridine in a modified RNA molecule wherein the uridine content in the modified RNA molecule is 20% less than the reference sequence ([0335]).
Regarding claim 40, Martini teaches the use of multiple, different, codon options for single amino acids (i.e., Martini teaches the use of alternative codons that encode the same amino acid) ([0285]; see Table 1).
Regarding claims 41 and 44, Martini teaches the use of alternative codons for a singular amino acid wherein the cytidine nucleotides and thymidine nucleotides in a codon are replaced with a guanosine or adenosine nucleotide (i.e., the available alternative codon comprising less cytidine nucleotides encodes the same amino acid) ([0285]; see Table 1).
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) 43 is/are rejected under 35 U.S.C. 103 as being unpatentable over Martini (PG Pub No. WO 2017201346 A1) as applied to claims 38-41 and 44 above, and further in view of Lavner (Gene 345.1 (2005): 127-138).
Regarding claim 43, Martini anticipates claims 38-41 and 44 as described above. Martini further teaches that the mRNA encoding the PBGD polypeptide can be administered to a human subject ([0014]). Martini further teaches that sequence optimized nucleic acids can be generated by applying a codon substitution map ([0323])
Martini does not teach or suggest that the codon are exchanged with alternative codons that occur with the highest frequency in the human genome (Claim 43).
However, one of ordinary skill in the art would have considered the teachings of Lavner as both references are common fields of endeavor pertaining to the use of codon exchange tables.
Lavner is drawn towards a study concerned with codon bias as a factor in regulating expression via translation rate in the human genome (Abstract). Lavner teaches the use of a codon exchange table that weighs alternative codons by their frequency in the human genome and ranks the alternative codons as occurring more frequently within the human genome (pg. 132; see Table 3). Lavner teaches that when amino acid frequencies were considered, a highly significant positive correlation was found for their presence in highly expressed genes (pg. 131).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the codon exchange table of Martini for a codon exchange table wherein codons are exchanged with alternative codons that occur with the highest frequency in the human genome, as described by Lavner. A person of ordinary skill in the art would have been motivated to do so in order to utilize codons that were correlated with a higher expression level. A person of ordinary skill in the art would have had a reasonable expectation of success because Martini teaches that alternative codon exchange tables may be utilized while Lavner teaches the use of a specific codon exchange table.
Claim(s) 45 is/are rejected under 35 U.S.C. 103 as being unpatentable over Martini (PG Pub No. WO 2017201346 A1) as applied to claims 38-41 and 44 above.
Regarding claim 45, Martini anticipates claims 38-41 and 44 as described above.
Martini does not teach or suggest that the codon are exchanged according to codon exchange table 1B (Claim 45).
However, one of ordinary skill in the art would have further considered the teachings of Martini as the reference further provides evidence for the modification of the RNA molecules.
It is noted that one of ordinary skill in the art would recognize that there are a finite number of codons that encode for amino acids, specifically 61 codons.
The applicable teachings of Martini are discussed above as applied to claim 38. Martini teaches that an RNA sequence may be codon-optimized such that its translation efficacy is at least maintained ([0009]). Martini teaches that the optimization of the RNA sequence may result in a decrease in the cytosine content by at least about 10% ([0369]). Martini teaches that a reduction in G/C content of an RNA molecule resulted in the improved stability of the RNA molecule ([0284]). Martini teaches the generation of codon exchange tables and teaches that one of ordinary skill in the art could optimize an RNA sequence such that the RNA molecule comprised improved properties (0284]).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to try to exchange the codons according to the claimed codon exchange table 1B, as described by Martini. A person of ordinary skill in the art would have recognized that Martini identified a need in the art to modify codons of an RNA molecule such that its G/C content was reduced in order to improve stability of the RNA molecule. A person of ordinary skill in the art would have recognized that there are a finite number of possible codons encoding amino acids that had at least a 10% reduction in cytidine, as described by Martini. A person of ordinary skill in the art would have recognized that the known potential solutions could have been pursued through routine experimentation and optimization because Martini teaches the generation of codon exchange tables and teaches that one of ordinary skill in the art could generate a codon exchange table such that the sequence RNA molecule comprised improved properties.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KYLE T REGA whose telephone number is (571)272-2073. The examiner can normally be reached M-R 8:30-4:30, every other F 8:30-4:30 (EDT/EST).
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/KYLE T REGA/Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636