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 .
DETAILED ACTION
Status of Claims
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office Action has been withdrawn pursuant to 37 CFR 1.114.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 January 29, 2026 has been entered.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1, 3 – 5, 7 – 8, 10, 12, 37, 39 – 40, 43 - 44, 54 –57, and 61 - 69 are currently pending. Claims 1, 40 and 63 are independent claims. Claims 1, 3 – 5, have been amended in the Applicant’s amendment filed 3 July 2025. Claims 5, 41, 42, and 58 - 60 have been canceled, and claims 62 - 69 have been added in the Applicant’s amendment filed December 2, 2025. (Claims 1, 40, and 64 are independent claims).
Applicant's election without traverse of Group I, claims 1 – 12, in response to the election’ restriction filed on 01/13/2023 drawn to a method of expressing a peptide or protein in the cell was previously acknowledged.
The restriction requirement was previously made FINAL in the office action filed on 02/21/2023.
Therefore, claims 1, 3 – 5, 7 – 8, 10, 12, 37, 39 – 40, 43 - 44, 54 –57, and 61 - 69 are under consideration to which the following grounds of rejection are applicable.
Priority
The present application, filed March 11, 2020 claims the benefit of PCT/EP2018/074449, filed September 11, 2018 and foreign priority based on PCT/EP2017/073065, filed on September 13, 2017.
Maintained Objections/Rejections
Claim Rejection - 35 USC § 112(a) Scope of Enablement
The rejection of claims 1, 3 – 5, 7 – 8, 10, 12, 37, 39 – 40, 43 - 44, 54 –57, and 61 - 63 is maintained and claims 64-69 are newly 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
An ex vivo or in vitro method for expressing an RNA encoding a peptide or protein into an immune cell and a fibroblast cell the Toscana virus NSs protein comprising introducing into the human cell an RNA encoding the Toscana virus NSs protein having 100% homology to the amino acid of Seq ID No. 1,
it does not reasonably provide enablement for expressing any RNA functional variant of the Toscana virus non-structural (NSs) protein including variants having 90% sequence identity, wherein any amino acid substitutions relative to Seq ID No: 1 are conservative substitutions (claims 1, 40 and 63), 95% sequence identity, wherein any amino acid substitutions relative to Seq ID No:1 are conservative substitutions (claims 40 and 63) or 98% sequence identity, wherein any amino acid substitutions relative to Seq ID No:1 are conservative substitutions (claims 61-62). Please Note: This rejection has been amended as per the response filed December 2, 2025.
The Specification does not enable any person skill in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. The claims, when given the broadest possible interpretation, encompass a method of expressing (i) a peptide of SEQ ID NO: I in a human cell and not a nucleic acid , e.g, RNA encoding the having 90% sequence identity to Seq ID No: 1, wherein any amino acid substitutions relative to Seq ID No: 1 are conservative substitutions, that when introduced into a human cell enhance stability or expression or both of the RNA encoding a peptide or protein for expression in the human immune cell. Moreover, the Specification does not provide support for method of expressing a peptide or protein in vivo, by introducing an RNA into an immune cell or fibroblast of a human subject other than in vitro or ex vivo introduction of both an RNA encoding the peptide or protein into the human cell and an RNA encoding the amino acid sequence of SEQ ID NO: 1. The Specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the patent coupled with information known in the art without undue experimentation (United States v. Telectronics, Inc., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is required is not based on a single factor but is rather a conclusion reached by weighing many factors (See Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Inter, 1986) and In re Wands, 8USPQ2d 1400 (Fed. Cir. 1988); these factors include the following:
Nature of invention. The invention encompasses a method of expressing a peptide in an immune cell, comprising (i) introducing RNA encoding the peptide into the immune cell, and (ii) providing a Toscana virus NSs protein to the immune cell.
Scope of the invention. The invention encompasses a method of expressing a peptide in an immune cell.
Number of working examples and guidance. In the instant case, Applicant provides no relevant working examples of sequences having 95% or 98% sequence identity to Seq ID No:1 . The Examiner notes that the as-Filed Specification does teach 7 Examples, pertaining to providing the mRNA encoding NSs protein and a mRNA of the protein (such as VEEV trans-replicating and self-replicating RNA) of interest in CD8+ T cell, human peripheral immature dendritic cells, and dendritic cells, but does not teach any examples using a variant of the NSs protein having at least 90 % sequence identity to the amino acid of SEQ ID NO: 1 that when introduced into a human cell enhance stability or expression or both of the RNA encoding a peptide or protein for expression in the human immune cell. Further, there are no examples provided of the NSs protein having any conservative substitutions that when introduced into a human cell enhances stability or expression or both of the RNA encoding a peptide or protein for expression in the human immune cell.
The as-Filed Specification teaches that CD8 positive human T cells were transfeted with the NSs
RNA and the RNA encoding VEEV replicase (Example 6), and that human peripheral dendritic cells were transfected with the mRNA encoding the VEEV replicase and the NSs protein (Example 7). However, these examples do not teach in vivo administration of the RNA encoding the peptide and the NSs protein.
State of the art. Although the field of expressing a peptide in a cell is highly developed, the
method of expressing a peptide using the Toscana virus NSs variant protein is not highly developed. The art must therefore be considered to be poorly developed.
Unpredictability of the art. Before the effective filing date of the claimed invention, it was
known in the art that the inhibition of IFN -β clearly occurred when Toscana virus (TOSV) NSs was expressed from plasmid DNA, but did not as clearly inhibit IFN -β when using authentic TOSV, due to the low expression levels of NSs in authentic TOSV, as evidenced by Ly et al. (Ly HJ, Ikegami T. Rift Valley fever virus NSs protein functions and the similarity to other bunyavirus NSs proteins. Virol J. 2016 Jul 2;13:118. doi: 10.1186/s12985-016-0573-8. PMID: 27368371; PMCID: PMC4930582.) (pg. 8, left column, second paragraph). Ly et al. also teaches that TOSV isolates from the Spanish lineage inhibits IFN-β gene more efficiently than those from the Italian lineage (pg. 8, left column, second paragraph).
Additionally, it was known in the art that NSs is scarcely expressed in HEK293FT cells upon plasmid transfection, and that it is unclear whether NSs has proteolytic activity or if it activates a proteasome-mediated degradation pathway, as evidenced by Gori-Savellini et al. (Gori-Savellini G. et al Toscana virus NSs protein inhibits the induction of type I interferon by interacting with RIG-I. J Virol. 2013 Jun;87(12):6660-7. doi: 10.1128/JVI.03129-12. Epub 2013 Apr 3. PMID: 23552410; PMCID: PMC3676095.) (pg. 6665, left column, first paragraph). Gori-Savellini et al. also teaches that Gori teaches that the NSs plasmid that comprises the viral RNA nucleotide sequence 57 – 1007 nucleotides from GenBank accession no. EU327772 (Plasmids). The nucleotide sequence from 57 – 1007 was converted into to amino acids, which revealed to only have a 95% alignment score with Seq ID No. 1. However, Gori-Savellini et al. does not teach that the nucleotide encoding an amino acid having 90%, 95% or 98% sequence identity to SEO ID NO: 1 when introduced into a human cell enhance stability or expression or both of the RNA encoding a peptide or protein for expression in the human immune cell. As such the integrity of RNA encoding the Toscana virus NSs protein of SEQ ID NO:1 is critical and any variant or fragment of said polypeptide resulting in amino acid changes, deletion, or addition, may alter the conformation of the Toscana virus NSs protein and the corresponding function of enhanced stability or expression of the RNA encoding a peptide in unknown ways.
Additionally, it was known in the art that the C-terminus of TOSV NSs protein inhibits IFN-β system through RIG-I degradation, and that the C-terminal 32 aa sequence of TOSV NSs is involved in protein stability itself, as evidenced by Gori-Savellini (Gori Savellini G. et al. Truncation of the C-terminal region of Toscana Virus NSs protein is critical for interferon-β antagonism and protein stability. Virology. 2015 Dec;486:255-62. doi: 10.1016/j.virol.2015.09.021. Epub 2015 Oct 27. PMID: 26474372) (Abstract). This reference teaches that only the 32 amino acids of C-terminal of the NSs protein is required for the stability of the protein itself. This reference does not teach that what variants of the NSs protein when introduced into a human cell enhances stability or expression or both of the RNA encoding a peptide or protein longer translation of the mRNA for expression in the human immune cell.
Amount of Experimentation Required. Given the unpredictability of the art, the poorly
developed state of the art with regard to TOSV NSs protein function specifically in the IFN-β response, the low expression levels of the NSs protein in cell cultures, and the presence of multiple variants of the Toscana virus with different functions, the skilled artisan would have to conduct undue, and unpredictable experimentation to practice the claimed invention using the Toscana virus, and treat any non-cancerous diseases. Further, due to the lack of specific guidance in the specification for expressing the peptide in the immune cell, and generating/using functional variants of the Toscana virus NSs protein, it would require undue experimentation to practice the breadth of the instant methods as claimed.
Response to Applicants’ Arguments as they apply to 35 USC § 112(a) Rejection
Applicant’s arguments filed December 2, 2025 have been fully considered, but they are not found persuasive. Applicants essentially argue that (a) the claims present a particular amino acid sequence (Seq ID No: 1) and a limited number of possible amino acid substitutions, and the present specification provides guidance to the nature and location of such amino acid substitutions (pg. 8, first and second paragraph).
Regarding (a), Applicant’s argument is not found persuasive. Seq ID No: 1 is comprised of 316 amino acids, and the instantly filed claims are stating that the NSs protein that is administered to enhance stability or expression has at least 90% identity to Seq ID No: 1, and wherein any amino acid substitutions relative to Seq ID No:1 are conservative substitutions. With a 10% variance, a maximum of 32 amino acids is independently varied. There are so many combinations of the NSs protein that can be administered. Even if all the substitutions are “conservative substitutions,” there is no predictability that substituting 32 amino acids (or less than 32 amino acids for that matter) in a given sequence will yield the expected results. Specifically, while the substitutions are occurring on the amino acid level, there is unpredictability in the translation efficiency of the protein and the stability of the secondary structure of the protein, such that the NSs peptide that is expressed may not enhance the stability or expression of the RNA. The Specification has not provided any example of how conservative substitutions alter the function of the Toscana virus nonstructural (NSs) protein having the amino acid sequence of SEQ ID NO: 1 or how to make and use these conservative substitutions so when introduced with an RNA encoding the peptide or protein into the human cell enhances stability of the introduced RNA to enhance translation into the protein of interests. Further, it is unclear which amino acids of the NSs proteins are functional, and are actually involved in enhancing the stability of the RNA. It has not been clarified whether the amino acids of the conservative substitutions are not required for the enhancing the stability and expression for the RNA. For example, patent US 10538572 B2 (published January 21, 2020) teaches that the “polynucleotide encoding the V.sub.α domain is at least 80% identical to the nucleotide sequence of SEQ ID NO 78, 128 or 80” (claim 1). This patent pertains to the CDRS that are separated by framework regions. However, it has been made part of the record that variation in the polynucleotide sequence as compared to a reference sequence does not alter the amino acids sequences of the recited CDRs (pg. 16 of the remarks filed on August 7, 2019). Thus, in this instance, it has been made clear that the variations do not change the amino acid sequence. However, in the instant application, it is still unclear whether the variability in the amino acid sequence of the NSs protein will enhance the expression and stability of the RNA.
The as-Filed Specification also does not teach any examples teaching a sequence of NSs comprising such conservative substitutions. Considering all this, there is an undue burden on the person of ordinary skill in the art to determine the sequence of the NSs protein that will enhance stability and expression of the RNA.
Thus, the scope of enablement rejection requiring the Applicant to specify the types of immune cells that are used in the claims is appropriate.
Claim Rejections - 35 USC § 112(a) - Written Description
The rejection of claims 1, 3 – 5, 7 – 8, 10, 12, 37, 39 – 40, 43 - 44, 54 –57, and 61 - 63 is maintained and claims 64-69 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. Please Note: This rejection has been amended as per the response filed December 2, 2025.
Claims 1, 3 – 5, 7 – 8, 10, 12, 37, 39 – 40, 43 - 44, 54 –57, and 61 - 63 encompasses a method of expressing a peptide in an immune cell, comprising (i) introducing RNA encoding the peptide into the immune cell, and (ii) providing a Toscana virus NSs protein or a functional variant of the Toscana virus NSs protein to the immune cell or fibroblast. Overall, what these statements indicate is that the Applicant must provide adequate description of such core structure and function related to that method such that the Artisan could determine the desired effect. Hence, the analysis below demonstrates that Applicant has not determined the core structure and function for full scope of the claimed method.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail such that the Artisan can reasonably conclude that the inventors had possession of the claimed invention. Such possession may be demonstrated by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and/or formulae that fully set forth the claimed invention. Possession may be shown by an actual reduction to practice, showing that the invention was "ready for patenting", or by describing distinguishing identifying characteristics sufficient to show that Applicant was in possession of the claimed invention (January 5, 2001 Fed. Reg., Vol. 66, No. 4, pp. 1099-11). MPEP § 2163.II.A.3.(b) states, “when filing an amendment an applicant should show support in the original disclosure for new or amended claims” and “[i]f the originally filed disclosure does not provide support for each claim limitation, or if an element which applicant describes as essential or critical is not claimed, a new or amended claim must be rejected under 35 U.S.C. 112, para. 1, as lacking adequate written description”. Moreover, MPEP 2163 states: [A] biomolecule sequence described only by a functional characteristic, without any known or disclosed characteristic, normally is not a sufficient identifying characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence. An invention described solely in terms of a method of making and/or its function may lack written descriptive support where there is no described or art-recognized correlation between the disclosed function and the structure(s) responsible for the function.
In analyzing whether the written description requirement is met for the claimed method, it is first determined whether the examples describe of expressing a peptide in an immune cell, comprising (i) introducing RNA encoding the peptide into the immune cell, and (ii) providing a Toscana virus NSs protein or functional variant of the Toscana virus NSs protein to the immune cell. The instant claims encompass a genus of immune cells and fibroblasts with the contemplated use of introducing RNA encoding a peptide and providing a Toscana virus NSs protein to the immune cell. Applicant does not disclose any relevant examples that teach the structure or the use of the of the Toscana virus NSs with 90% sequence identity comprising conservative substitutions. A structure/function relationship of this variant of the Toscana virus NSs protein in the human cell has not been established.
Moreover, the as-Filed Specification teaches that CD8 positive human T cells were transfeted
with the NSs RNA and the RNA encoding VEEV replicase (Example 6), and that human peripheral dendritic cells were transfected with the mRNA encoding the VEEV replicase and the NSs protein (Example 7). Thus, he Specification does not provide support for method of expressing a peptide or protein in vivo, by introducing an RNA into an immune cell or fibroblast of a human subject other than in vitro or ex vivo introduction of both an RNA encoding the peptide or protein into the human cell and an RNA encoding the amino acid sequence of SEQ ID NO: 1.
The Examiner notes that the instantly recited claims teach that the Toscana
virus NSs protein has at least 90% sequence identity to Seq ID No. 1, wherein any amino acid substitutions relative to Seq ID No: 1 are conservative substitutions. However, the Applicant fails to teach any sequence of the NSs protein that comprises these conservative substitutions.
Before the effective filing date of the claimed invention, it was
known in the art that the inhibition of IFN -β clearly occurred when Toscana virus (TOSV) NSs was expressed from plasmid DNA, but did not as clearly inhibit IFN -β when using authentic TOSV, due to the low expression levels of NSs in authentic TOSV, as evidenced by Ly et al. (Ly HJ, Ikegami T. Rift Valley fever virus NSs protein functions and the similarity to other bunyavirus NSs proteins. Virol J. 2016 Jul 2;13:118. doi: 10.1186/s12985-016-0573-8. PMID: 27368371; PMCID: PMC4930582.) (pg. 8, left column, second paragraph). Ly et al. also teaches that TOSV isolates from the Spanish lineage inhibits IFN-β gene more efficiently than those from the Italian lineage (pg. 8, left column, second paragraph).
Additionally, it was known in the art that NSs is scarcely expressed in HEK293FT cells upon plasmid transfection, and that it is unclear whether NSs has proteolytic activity or if it activates a proteasome-mediated degradation pathway, as evidenced by Gori-Savellini et al. (Gori-Savellini G. et al Toscana virus NSs protein inhibits the induction of type I interferon by interacting with RIG-I. J Virol. 2013 Jun;87(12):6660-7. doi: 10.1128/JVI.03129-12. Epub 2013 Apr 3. PMID: 23552410; PMCID: PMC3676095.) (pg. 6665, left column, first paragraph). Gori-Savellini et al. also teaches that Gori teaches that the NSs plasmid that comprises the viral RNA nucleotide sequence 57 – 1007 nucleotides from GenBank accession no. EU327772 (Plasmids). The nucleotide sequence from 57 – 1007 was converted into to amino acids, which revealed to only have a 95% alignment score with Seq ID No. 1.
Further, there are four known variants of the Toscana virus, wherein the presence of these variants is probably due to the nature of the virus genome and the cycle of the host-vector transmission, as evidenced by Vallassina et al. (Valassina M. et al. Evidence of Toscana virus variants circulating in Tuscany, Italy, during the summers of 1995 to 1997. J Clin Microbiol. 1998 Jul;36(7):2103-4. doi: 10.1128/JCM.36.7.2103-2104.1998. PMID: 9650974; PMCID: PMC104990.) (Abstract, and pg. 2104, right column, first paragraph). These references teach the poorly unpredictability in the art with regard to TOSV NSs protein function specifically in the IFN-β response, the low expression levels of the NSs protein in cell cultures, and the presence of multiple variants of the Toscana virus with different functions.
Thus, the ability to assess a priori whether all activating receptors are compatible with all blocking receptors, or the use of spacer between these receptors is not predictable.
Therefore, the specification does not contain a written description of the invention, and a 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 can make and use the same, nor does it set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention. This limited information is not deemed sufficient to reasonably convey to one skilled in the art that Applicant is in possession of the method of culturing natural killer cells as recited in the instant claims.
Response to Applicants’ Arguments as they apply to 35 USC § 112(a) Rejection
Please see supra for the response.
Conclusion
Claims 1, 3 – 5, 7 – 8, 10, 12, 37, 39 – 40, 43 - 44, 54 –57, and 61 - 63 remain rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to VYOMA SHAILESH THAKKER whose telephone number is (571)272-2954. The examiner can normally be reached M-F 8:30 - 5:30 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Maria Leavitt can be reached on (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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/VYOMA SHUBHAM TIWARI/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
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