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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 08/03/2026 has been entered.
Election/Restrictions
Applicant’s election without traverse of Group I (Claims 1-2, 5-6, and 12-13), drawn to a nucleic acid molecule product and a bacterial cell product containing said molecule having at least one mutation for modulating interaction strength of the molecule with 16S ribosomal RNA in the reply filed on 07/21/2025 is acknowledged.
Claims 19-21, 24-31 (Group II), and 37-39 (Group III) are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Groups II and III, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 07/21/2025.
Claims Status
Claims 1-2, 5-6, 12-13, 19-21, 24-31, 37-39 and 42-44 are pending.
Claims 19-21, 24-31 and 37-39 are withdrawn.
Claims 1-2, 5-6, 12-13 and 42-44 are currently under examination.
Priority
This application is a continuation of PCT Patent Application No. PCT/IL2020/050367 having International filing date of March 26, 2020, which claims the benefit of priority of U.S. Provisional Patent Application No. 62/825,143 filed March 28, 2019. The priority date of the claim set, filed on Sept. 28, 2021, is determined to be March 28, 2019.
Claim Objections
Claim 42 is objected to because of the following informalities: Regarding claim 42, “translational termination site (TTS)” should be amended to “TTS”. 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.
Claims 1-2, 5-6, 12-13 and 42-44 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims are broadly drawn to a nucleic acid molecule comprising a coding sequence, wherein said nucleic acid molecule comprises at least one mutation within a region of said molecule, wherein said mutation modulates interaction strength of said nucleic acid molecule to a 16S ribosomal RNA (rRNA); and wherein said region is selected from the group consisting of:
a) positions 26 downstream of a translational start site (TSS) of said coding sequence through position -13 upstream of a translational termination site (TTS) of said coding sequence and said mutation modulates interaction strength to an intermediate interaction strength; b) positions -8 through -17 upstream of a TTS of said coding sequence and said mutation increases interaction strength; and c) a position downstream of a TTS of said coding sequence and said mutation increases interaction strength.
Relevant to the lack of particular structural limitations in the rejected claims drawn to nucleic acids, MPEP 2163 states:
The claimed invention as a whole may not be adequately described if the claims require an essential or critical feature which is not adequately described in the specification and which is not conventional in the art or known to one of ordinary skill in the art.
In the case of the instant claims, the functionality of the mutation in a particular region of the nucleic acid molecule modulates the interaction strength of the nucleic acid molecule to a 16S ribosomal RNA (rRNA), such as the mutation increases interaction strength or modulates the interaction strength to intermediate as a critical feature of the claimed methods.
The specification teaches “We then defined each gene by two values: a. Minimum interaction strength (i.e. strongest interaction) from region 1) distribution. b. Minimum interaction strength from region 2) distribution.” (Para 244). However the specification does not teach the structure of nucleic acid molecules and mutation within regions thereof that are capable of modulating interaction strength.
While the skilled artisan may be capable of developing nucleic acid molecules comprising at least one mutation in mutation within regions thereof with the claimed functionality of modulating interaction strength, possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features. See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895.
Further, while a particular agent may be an inhibitor of TERT, for example, there is no indication, teaching, guidance, or expectation that ALL inhibitors of the recited biomarker would be capable of "treating" cancer, as is broadly claimed.
The claims encompass a genus of structurally undefined nucleic acid molecules which require a specific functionality. However, the specification fails to teach how to distinguish members of the claimed genus of nucleic acid molecules which possess the claimed functionality: a nucleic acid molecule comprises at least one mutation within a region of said molecule, wherein said mutation modulates interaction strength of said nucleic acid molecule to a 16S ribosomal RNA (rRNA) as broadly claimed, from nonmembers.
In analysis of the claims for compliance with the written description requirement of 35 U.S.C. 112, first paragraph, and particularly for claims drawn to a genus, the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species. A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus."). The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]." See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615.
Further, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 held that:
To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.
An adequate written description of a DNA, such as the cDNA of the recombinant plasmids and microorganisms of the '525 patent, "requires a precise definition, such as by structure, formula, chemical name, or physical properties," not a mere wish or plan for obtaining the claimed chemical invention. Fiers v. Revel, 984 F.2d 1164, 1171, 25 USPQ2d 1601, 1606 (Fed. Cir. 1993). Accordingly, "an adequate written description of a DNA requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it; what is required is a description of the DNA itself." Id. at 1170, 25 USPQ2d at 1606.
Thus, considering the breadth of the nucleic acid molecules and mutations of regions thereof required by the claims, their specific required functionalities, and the teachings of the instant specification, it is the conclusion that the specification does not provide an adequate written description of the broadly claimed subject matter. So one of skill in the art cannot envision the detailed chemical structure of the nucleic acid molecule and mutation within regions thereof encompassed by the claimed.
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 1-2, 5-6, 12-13 and 42-44 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 1 is indefinite over the limitation “intermediate interaction strength” (ln 8). It is unclear as to what is considered intermediate interaction strength. Claims 2, 5-6, 12-13 and 42-44 depend on claim 1.
Claim 1 is indefinite over the limitation “increases interaction strength” (ln 10 and ln 12). It is unclear as to what is considered an increase in the interaction strength. Claims 2, 5-6, 12-13 and 42-44 depend on claim 1.
Claim 2 recites “said interaction strength to a 16S rRNA is to an anti-Shine Dalgarno (aSD) sequence of said 16S rRNA and is determined from Table 3" (ln 6-7), it is unclear what “Table 3” (ln 7) is referring to as the claim should be complete and clear by limitations recited in the claims without referring to any tables or drawings disclosed in the specification. See MPEP § 2173.05(s). Furthermore, Table 3 is unclear as to what the values listed indicate, what each section indicates and the metes of bounds of what is indicated by Table 3.
Claim 5 recites “wherein strong, weak and intermediate interaction strengths are determined from Table 1" (ln 3-4), it is unclear what “Table 1” (ln 4) is referring to as the claim should be complete and clear by limitations recited in the claims without referring to any tables or drawings disclosed in the specification. See MPEP § 2173.05(s). Furthermore, Table 1 is unclear as to what the values listed indicate, what the organisms indicate and what interactions are taking place to receive the values listed.
Claim 5 is indefinite over the limitation “wherein said increasing increases interaction strength to a strong interaction strength, decreasing decreases interaction strength to a weak interaction strength” (ln 1-3). It is unclear what is meant by “increasing increases” (ln 1-2) and “decreasing decreases”(ln 2). Furthermore, it is unclear as to the metes and bounds of claim 5.
Claim 13 recites “a cell of a bacterium recited in Table 1" (ln 3), it is unclear what “Table 3” (ln 3) is referring to as the claim should be complete and clear by limitations recited in the claims without referring to any tables or drawings disclosed in the specification. See MPEP § 2173.05(s). Furthermore, Table 1 is unclear as to what the values listed indicate and what interactions are taking place to receive the values listed.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 5 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. As claim 5 depends on claim 1, claim 1 does not recite “increasing” or “decreasing”. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-2, 5-6, 12-13 and 42-44 are rejected under 35 U.S.C. 101 because the claimed invention is directed towards a natural phenomenon of nucleic acid molecule comprising at least one mutation and well understood, conventional elements, without significantly more. The claim(s) recite(s) natural phenomena. This judicial exception is not integrated into a practical application because no additional elements integrate the judicial exceptions into a practical application. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because no additional elements are considered significantly more than the judicial exceptions.
Claim analysis
The instant claim 1 is directed towards: A nucleic acid molecule comprising a coding sequence, wherein said nucleic acid molecule comprises at least one mutation within a region of said molecule, wherein said mutation modulates interaction strength of said nucleic acid molecule to a 16S ribosomal RNA (rRNA); and wherein said region is selected from the group consisting of: a) positions 26 downstream of a translational start site (TSS) of said coding sequence through position -13 upstream of a translational termination site (TTS) of said coding sequence and said mutation modulates interaction strength to an intermediate interaction strength; b) positions -8 through -17 upstream of a TTS of said coding sequence and said mutation increases interaction strength; and c) a position downstream of a TTS of said coding sequence and said mutation increases interaction strength.
The “nucleic acid molecule comprising a coding sequence, wherein said nucleic acid molecule comprises at least one mutation” is considered to be a product of nature or natural phenomenon.
The “mutation modulates interaction strength of said nucleic acid molecule to a 16S ribosomal RNA (rRNA) is considered to lack markedly different characteristics from any naturally occurring counterpart because nucleic acid molecules naturally comprise variants/mutations and also sequences naturally vary by species of organism/taxonomic group. Additionally, the interaction strength of a nucleic acid molecule to a 16S ribosomal RNA (rRNA) naturally vary by sequence-structure composition in various species of organism/taxonomic groups and thus is considered a natural phenomenon that lacks markedly different characteristics.
Dependent claims set forth further limitations about the mutation, interaction strength, region, and cell.
According to the 2019 Patent Eligibility Guidance an initial two step analysis is required for determining statutory eligibility.
Step 1. Is the claim directed to a process, machine, manufacture, or composition of matter? In the instant case, the Step 1 requirement is satisfied as the claims are directed towards a composition of matter.
Step 2A Prong one. Does the claim recite a law of nature, a natural phenomenon or an abstract idea? Yes, natural phenomena.
With regard to claim 1, the claim recites “A nucleic acid molecule comprising a coding sequence, wherein said nucleic acid molecule comprises at least one mutation within a region of said molecule, wherein said mutation modulates interaction strength of said nucleic acid molecule to a 16S ribosomal RNA (rRNA); and wherein said region is selected from the group consisting of: a) positions 26 downstream of a translational start site (TSS) of said coding sequence through position -13 upstream of a translational termination site (TTS) of said coding sequence and said mutation modulates interaction strength to an intermediate interaction strength; b) positions -8 through -17 upstream of a TTS of said coding sequence and said mutation increases interaction strength; and c) a position downstream of a TTS of said coding sequence and said mutation increases interaction strength.” The “nucleic acid molecule comprising a coding sequence, wherein said nucleic acid molecule comprises at least one mutation” is considered to be a product of nature and/or natural phenomenon. The “mutation modulates interaction strength of said nucleic acid molecule to a 16S ribosomal RNA (rRNA) is considered to lack markedly different characteristics from any naturally occurring counterpart because nucleic acid molecules naturally comprise variants/mutations and also sequences naturally vary by species of organism/taxonomic group. Additionally, the interaction strength of a nucleic acid molecule to a 16S ribosomal RNA (rRNA) naturally vary by sequence-structure composition in various species of organism/taxonomic groups and thus is considered a natural phenomenon that lacks markedly different characteristics.
Step 2A prong two. Does the claim recite additional elements that integrate the judicial exception into a practical application? No, there are no additional steps that integrate the claims into a practical application.
Step 2B. Does the claim recite additional elements that are significantly more than the judicial exceptions? No, there are no additional elements that are significantly more than the judicial exceptions.
Regarding claim 1, the claim requires the well understood features of nucleic acid molecule comprising a coding sequence, wherein said nucleic acid molecule comprises at least one mutation within a region of said molecule, wherein said mutation modulates interaction strength of said nucleic acid molecule to a 16S ribosomal RNA (rRNA) similar to that of Ramseier et al. (“Ramseier”; Patent App. Pub. No. WO 2009020899 A1, Feb. 12, 2009).
Ramseier discloses “The present invention provides methods and compositions for producing heterologous protein with improved yield and/or quality. A library of randomized ribosomal binding site sequences is provided for the identification of a translation initiation region sequence optimal for expression of the heterologous protein. Also provided are novel ribosomal binding site sequences, and vectors and host cells having those sequences. The library of randomized sequences is useful for screening for improved expression of any protein of interest, including therapeutic proteins, hormones, a growth factors, extracellular receptors or ligands, proteases, kinases, blood proteins, chemokines, cytokines, antibodies and the like.” (Abstract).Thus, the claim does not provide additional steps which are significantly more.
Dependent claims require the mutation, interaction strength, region, and cell which are well understood, conventional elements based on Ramseier et al. (“Ramseier”; Patent App. Pub. No. WO 2009020899 A1, Feb. 12, 2009).
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 1-2, 5-6, 12-13 and 42-44 are rejected under 35 U.S.C. 103 as being unpatentable over Ramseier et al. (“Ramseier”; Patent App. Pub. No. WO 2009020899 A1, Feb. 12, 2009).
Claim Interpretations: The claims are drawn to nucleic acid molecule which is interpreted as a product. The claims with the limitations comprising “or” in claim 2 (ln 5), claim 6 (ln 4), claim 13 (ln 6) indicate each of the alphabets prefixes is alternative of one another.
Ramseier discloses “The present invention provides methods and compositions for producing heterologous protein with improved yield and/or quality. A library of randomized ribosomal binding site sequences is provided for the identification of a translation initiation region sequence optimal for expression of the heterologous protein. Also provided are novel ribosomal binding site sequences, and vectors and host cells having those sequences. The library of randomized sequences is useful for screening for improved expression of any protein of interest, including therapeutic proteins, hormones, a growth factors, extracellular receptors or ligands, proteases, kinases, blood proteins, chemokines, cytokines, antibodies and the like.” (Abstract).
Regarding claims 1 and 42-44, Ramseier teaches a nucleic acid molecule comprising “Modulating translation strength by altering the translation…region” (Pg. 3 ln. 25). Ramseier teaches a nucleic acid molecule comprising “The RBS (also referred to herein as the Shine- Dalgarno sequence) is located on the … Because of the role of the RBS sequence in translation, there is a direct relationship between the efficiency of translation and the efficiency (or strength) of the RBS sequence” (Pg. 4 ln. 10-16). Ramseier teaches a nucleic acid molecules comprising “In addition to altering the RBS sequence for optimizing expression, several additional approaches are also encompassed that can be used to control protein translation levels. For example, using promoters with a range of translation strengths, modulating promoter activity by titrating induction, using plasmids with different copy numbers, improving transcript stability, and manipulating sequences other than the RBS sequence in the translation initiation region” (Pg. 12 ln. 13-18). Ramseier teaches a nucleic acid molecule comprising “A single base pair mutation was introduced by PCR amplification to create the silent codon mutation” (Pg. 3 ln. 4-5; Figure 1). Ramseier teaches a nucleic acid molecule comprising “oligonucleotide sequences are useful for optimizing expression of a heterologous protein in a host cell where the translation efficiency is decreased when compared to the translation efficiency of the protein encoded by a gene comprising the canonical RBS sequence” (Pg. 5 ln.12-15). “Modulating translation strength by altering the translation…site” reads on any type of change (e.g. mutation) relative to any position of the coding sequence within a region from upstream or downstream of the TSS causing any type of change in the interaction strength of the nucleic acid molecule to a 16s rRNA. “manipulating sequences other than the RBS sequence in the translation initiation region” reads on wherein said region is a position as recited in claim options a, b, or c. Thus, Ramsier suggests a nucleic acid molecule comprising a coding sequence, wherein said nucleic acid molecule comprises at least one mutation within a region of said molecule, wherein said mutation modulates interaction strength of said nucleic acid molecule to a 16S ribosomal RNA (rRNA); and wherein said region is selected from the group consisting of: a) positions 26 downstream of a translational start site (TSS) of said coding sequence through position -13 upstream of a translational termination site (TTS) of said coding sequence and said mutation modulates interaction strength to an intermediate interaction strength; b) positions -8 through -17 upstream of a TTS of said coding sequence and said mutation increases interaction strength; and c). a position downstream of a TTS of said coding sequence and said mutation increases interaction strength.
The prior art, Ramseier et al., is considered to be analogous to the claimed invention because they are in the same field of altering protein translation. Therefore, the invention as recited in claims 1 and 42-44 is prima facie obvious over the prior art Ramseier et al. The ordinary artisan would have been motivated, based on the teachings of Ramseier stated above in the 35 USC 103 rejection in addition to the suggestion that it will be obvious that certain changes and modifications may be practiced within the scope of the appended claims, to provide a nucleic acid molecule to modulate the translation strength to control protein translation levels by manipulating sequences in and/or out of the translational initiation region. One of ordinary skill in the art would have had a reasonable expectation of success given the obviousness of the claim limitations to modulate the translation initiation region in addition to manipulating sequences other than the RBS sequence in the translation initiation region. One of ordinary skill in the art would have had a reasonable expectation of success given the obviousness of the claims. These claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome according to the limitations of claims 1 and 42-44. Hence, it would have been obvious to have a nucleic acid molecule comprising a coding sequence, wherein said nucleic acid molecule comprises at least one mutation within a region of said molecule, wherein said mutation modulates interaction strength of said nucleic acid molecule to a 16S ribosomal RNA (rRNA) according to the limitations of the instant application claims 1 and 42-44 based on Ramseier et al. (Patent App. Pub. No. WO 2009020899 A1).
The teachings of Ramseier are documented above in the rejection of claims 1 and 42-44 under 35 U.S.C. 103. Claim 2, 5-6, 12, and 42-44, depends on claim 1. Claim 13 depends on claim 12, which depends on claim 1.
Regarding claim 2, Ramseier teaches a nucleic acid molecule comprising “Modulating translation strength by altering the translation initiation region” (Pg. 3 ln. 25). Ramseier teaches a nucleic acid molecule comprising “The translation initiation region has been defined as the sequence extending immediately upstream of the ribosomal binding site (RBS) to approximately 20 nucleotides downstream of the initiation codon…In prokaryotes, alternative RBS sequences can be utilized to optimize translation levels of heterologous proteins by providing translation rates that are decreased with respect to the translation levels using the canonical, or consensus, RBS sequence … described by Shine and Dalgarno ((1974) Proc. Natl Acad. Sci USA 71: 1342-1346)... In most prokaryotes, the Shine-Dalgarno sequence assists with the binding and positioning of the 30S ribosome component relative to the start codon on the mRNA through interaction with a pyrimidine-rich region of the 16S ribosomal RNA (Pg. 3 ln. 32-34, Pg. 4 ln 1-10). Ramseier teaches a nucleic acid molecule comprising “The RBS (also referred to herein as the Shine- Dalgarno sequence) is located on the mRNA … upstream from the start of translation, typically from 4 to 14 nucleotides upstream of the start codon, and more typically from 8 to 10 nucleotides upstream of the start codon. Because of the role of the RBS sequence in translation, there is a direct relationship between the efficiency of translation and the efficiency (or strength) of the RBS sequence” (Pg. 4 ln. 10-16). Ramseier teaches a nucleic acid molecules comprising “RBS sequence fragment wherein one or more nucleotides corresponding to the canonical RBS sequence (SEQ ID NO: 1) has been fully randomized” (Pg. 5 ln. 22-23). Ramseier teaches a nucleic acid molecule wherein “strength ribosome binding site” (Pg. 48 ln. 32). Thus, Ramsier suggests a nucleic acid molecule wherein a) said mutation modulates interaction strength of a six-nucleotide sequence containing said mutation to said 16S rRNA; b) said interaction strength to a 16S rRNA is to an anti-Shine Dalgarno (aSD) sequence of said 16S rRNA; or c) said interaction strength to a 16S rRNA is to an anti-Shine Dalgarno (aSD) sequence of said 16S rRNA and is determined from Table 3.
Regarding claim 5, Ramseier teaches a nucleic acid molecule wherein “randomized RBS sequences for optimizing heterologous expression of a polypeptide of interest in a host cell” (Pg. 2 ln. 14-16) and “useful in host cells … including bacterial cells” (Pg. 2 ln. 21-23). Ramseier teaches “the host cell can be a member of any of the bacterial taxa” (Pg. 16 ln 1). Ramseier teaches a nucleic acid molecule wherein “the RBS sequence variants described herein can be classified as resulting in high, medium, or low translation efficiency. In one embodiment, the sequences are ranked according to the level of translational activity compared to translational activity of the canonical RBS sequence” (Pg. 25 ln. 13-15). Thus, Ramsier suggests a nucleic acid molecule wherein said increasing increases interaction strength to a strong interaction strength, decreasing decreases interaction strength to a weak interaction strength and wherein strong, weak and intermediate interaction strengths are determined from Table 1.
Regarding claim 6, Ramseier teaches a nucleic acid molecule comprising “The translation initiation region has been defined as the sequence extending immediately upstream of the ribosomal binding site (RBS) to approximately 20 nucleotides downstream of the initiation codon… In most prokaryotes, the Shine-Dalgarno sequence assists with the binding and positioning of the 30S ribosome component relative to the start codon on the mRNA through interaction with a pyrimidine-rich region of the 16S ribosomal RNA (Pg. 3 ln. 32-34, Pg. 4 ln 7-10). Ramseier teaches a nucleic acid molecule comprising “The RBS (also referred to herein as the Shine- Dalgarno sequence) is located on the mRNA … upstream from the start of translation, typically from 4 to 14 nucleotides upstream of the start codon … Because of the role of the RBS sequence in translation, there is a direct relationship between the efficiency of translation and the efficiency (or strength) of the RBS sequence” (Pg. 4 ln. 10-16). Ramseier teaches a nucleic acid molecules comprising “the library comprises a plurality of oligonucleotides comprising an RBS sequence fragment wherein one or more nucleotides corresponding to the canonical RBS sequence (SEQ ID NO: 1) has been fully randomized. In another embodiment ... or wherein only 1, 2, 3, 4, or 5 nucleotide positions corresponding to the canonical RBS sequence have been fully randomized” (Pg. 5 ln. 2-8; Pg. 5 ln 21-30). Thus, Ramsier suggests a nucleic acid molecule wherein a) said region from position 26 downstream of the TSS through position -13 upstream of the TTS comprises the first 400 base pairs of said region; b) said molecule comprises at least a second mutation, wherein said second mutation is in a different region than said at least one mutation; c) said at least one mutation is within said coding sequence and mutates a codon of said coding sequence to a synonymous codon; d) wherein said mutation improves the translation potential of said coding sequence; e) wherein said mutation does at least one of: increasing translation initiation efficiency, increasing translation initiation rate, increasing diffusion of the small subunit to the initiation site, increasing elongation rate, optimization of ribosomal allocation, increasing chaperon recruitment, increasing termination accuracy, decreasing translational read-through and increasing protein yield; f) said nucleic acid molecule is a messenger RNA (mRNA); or g) a combination thereof.
Regarding claim 12-13, Ramseier teaches oligonucleotides comprising “novel RBS sequence fragments useful for the heterologous expression of a protein or polypeptide of interest in a bacterial host cell” (Pg. 4 ln. 29-31). Ramseier teaches bacterial cells such as “P.fluorescens, E. coli, and the like” (Pg. 2 ln. 23). Ramseier teaches “the host cell can be a member of any of the bacterial taxa” (Pg. 16 ln 1). Thus, Ramsier suggests a cell comprising a nucleic acid molecule; and wherein a) said cell is a bacterial cell; b) said cell is a cell of a bacterium recited in Table 1; c) said cell is a cell of a bacterium selected from Escherichia Coli, Alphaproteobacteria, Spirochaete, Purple bacteria, Gammaproteobacteria, deltaproteobacteria and Betaproteobacteria; or d) wherein said cell is a bacterial cell and said bacterium is not a Cyanobacteria or Gram-positive bacteria.
Response to Arguments
Applicants’ arguments filed 05/03/2026 (Pg. 9-12) with respect to claims 1-2,5-6,12-13 and 42-44 have been considered but are not persuasive. To clarify some instances argued in the response filed 05/03/2026 see responses to each argument made by Applicant below:
Applicants’ argument: “In light of this proper reading of this one sentence in Ramseier and in light of the referenced Simmons Yansura, it is clear that Ramseier does not motivate any mutation of regions outside the TIR (translational initiation region). As claim 1 was previously limited to three regions, all of which are outside the TIR, claim 1 is not rendered obvious by Ramseier. There is neither motivation, nor a reasonable expectation of success in modifying non-TIR regions.” (Pg. 10-11).
Response: Applicant’s arguments with respect to claims 1-2,5-6,12-13 and 42-44 have been considered but are not persuasive, because “augments presented by the applicant cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965) and In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984).” (See MPEP 716.01(c)). As stated above in the non-final office action above, briefly, Ramseier teaches a nucleic acid molecules comprising “Modulating translation strength by altering the translation…region” (Pg. 3 ln. 25) which reads on any type of change (e.g. mutation) relative to any position of the coding sequence within a region from upstream or downstream of the TSS causing any type of change in the interaction strength of the nucleic acid molecule to a 16s rRNA. Ramseier teaches a nucleic acid molecules comprising “In addition to altering the RBS sequence for optimizing expression, several additional approaches are also encompassed that can be used to control protein translation levels. For example, using promoters with a range of translation strengths, modulating promoter activity by titrating induction, using plasmids with different copy numbers, improving transcript stability, and manipulating sequences other than the RBS sequence in the translation initiation region” (Pg. 12 ln. 13-18), which reads on wherein said region is a position as recited in claim options a, b, or c. Thus, Ramsier suggests a nucleic acid molecule comprising a coding sequence, wherein said nucleic acid molecule comprises at least one mutation within a region of said molecule, wherein said mutation modulates interaction strength of said nucleic acid molecule to a 16S ribosomal RNA (rRNA); and wherein said region is selected from the group consisting of: a) positions 26 downstream of a translational start site (TSS) of said coding sequence through position -13 upstream of a translational termination site (TTS) of said coding sequence and said mutation modulates interaction strength to an intermediate interaction strength; b) positions -8 through -17 upstream of a TTS of said coding sequence and said mutation increases interaction strength; and c) a position downstream of a TTS of said coding sequence and said mutation increases interaction strength.
The prior art, Ramseier et al., is considered to be analogous to the claimed invention because they are in the same field of altering protein translation. Therefore, the invention as recited in claims 1 and 42-44 is prima facie obvious over the prior art Ramseier et al. The ordinary artisan would have been motivated, based on the teachings of Ramseier stated above in the 35 USC 103 rejection in addition to the suggestion of Ramseier that it will be obvious that certain changes and modifications may be practiced (Pg. 49), to provide a nucleic acid molecule to modulate the translation strength to control protein translation levels by manipulating sequences in and/or out of the translational initiation region. One of ordinary skill in the art would have had a reasonable expectation of success given the obviousness of the claim limitations to modulate the translation initiation region in addition to manipulating sequences other than the RBS sequence in the translation initiation region. One of ordinary skill in the art would have had a reasonable expectation of success given the obviousness of the claims. These claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome according to the limitations of claims 1 and 42-44. Hence, it would have been obvious to have a nucleic acid molecule comprising a coding sequence, wherein said nucleic acid molecule comprises at least one mutation within a region of said molecule, wherein said mutation modulates interaction strength of said nucleic acid molecule to a 16S ribosomal RNA (rRNA) according to the limitations of the instant application claims 1 and 42-44 based on Ramseier et al. (Patent App. Pub. No. WO 2009020899 A1).Thus, Ramseier does suggest or motivate modifying sequence region(s) other than the translation initiation region.
Applicants’ argument: “A general statement regarding making mutations anywhere, would not motivate make mutations in the specific regions recited. Without motivating mutation outside the translation initiation region, without reciting all of the elements of claim 1 and without motivating the specific type of mutation in the specific regions recited, Ramseier in no way renders claim 1 obvious.” (Pg. 11-12).
Response: Applicant’s arguments stated above with respect to claims 1-2,5-6,12-13 and 42-44 have been considered but are not persuasive because of the reasons discussed in the response above.
Applicants’ argument: “Ramseier does not teach each and every aspect of instant claim 1.” (Pg. 11)
Response: Applicant’s arguments with respect to claims 1-2,5-6,12-13 and 42-44 have been considered but are not persuasive. In response to applicant's argument stated above, the claim limitations are made obvious over the teachings of Ramseier. Furthermore, a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. Since teachings of Ramseier would make the structure of claimed invention obvious to the ordinary artisan, the prior art structure is capable of performing the intended use.
Conclusion
No claims are in condition for allowance.
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/KENDRA R VANN-OJUEKAIYE/Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682
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