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 .
Application Status
This action is written in response to applicant’s correspondence received on 8/26/2024. Claims 1-17 are pending. All pending claims are currently under examination.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO’s electronic filing system (see Section I.1 of the Legal Framework for EFS-Web or Patent Center (https://www.uspto.gov/patents-application- process/filing-online/legal-framework-efs-web), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via EFS-Web or Patent Center as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via EFS-Web or Patent Center as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above. In particular, the sequence incorporation statement entitled “Sequence Listing” in the specification refers to the sequence listing file in terms of “KB,” but must refer to the size of the file in terms of “bytes.” See MPEP 2422.03, section I, “ASCII Text File Submitted VIA EFS-Web.”
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Priority
Acknowledgment is made of applicant's claim for foreign priority based on an application filed in China on 10/09/2021. It is noted, however, that applicant has not filed a certified copy of the CHINA 202111178106.7 application as required by 37 CFR 1.55.
Claim Objections
Claims 15-16 are objected to because of the following informalities:
Regarding claims 15 and 16, these claims recite “a protein, comprising the N protein…the P protein…and the L protein.” Thus claims 15 and 16 recite “a protein,” singular, which comprises three proteins (N,P, and L). Claims 15 and 16 should be amended so that the number of proteins being recited is made more clear and/or whether or not the recited “protein” comprising three proteins is meant to be for instance a fusion protein.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 17 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 17, claim 17 recites “a method for expressing a target molecule in an individual” where the method comprises administering the RNA of claim 1. However, the RNA molecule of claim 1 does not recite a “target molecule” within the RNA of claim 1. It is therefore unclear as to what is meant to be the target protein recited in claim 17. For instance, it is unclear if the “N” protein recited in claim 1 is meant to be the target protein, or if the target protein is meant to be a separate, unrecited molecule in claim 17.
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 1-10 and 15-16 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature without significantly more.
Regarding claim 1, claim 1 recites a self-replicating RNA molecule comprising RNA sequences encoding N, P, and L proteins, where the proteins are suitable for production in an animal cell. Claim 1 is therefore drawn to a composition of matter (Step 1 of the Subject Matter Eligibility Test, MPEP 2106). Regarding the nature of a “self-replication RNA molecule,” the specification defines this term as including an RNA-dependent RNA polymerase which translates the RNA molecule in the cytoplasm of a host cell (paragraph 25). Thus, claim 1 recites a self-replicating RNA molecule which uses host cell machinery to translate the molecule into protein (paragraph 25 of specification). With respect to the N, P, and L, proteins, these are proteins which are naturally encoded by RNA viruses such as Vesicular Stomatitis. For instance, van den Pol (van den Pol AN et al. J Virol. 2013 Jan;87(2):1019-34) teaches that Vesicular Stomatitis Virus (VSV) naturally comprises the N, P, and L genes (Figure 1A, “wildtype” version). Furthermore, as evidenced by Lundstrom (Lundstrom K. Molecules. 2018 Dec 13;23(12):3310) viruses such as VSV are “self-replicating” RNA viruses (Title, Abstract, page 2 third paragraph, page 3 third paragraph). van den Pol teaches that VSV is suitable for production of the N, P, and L proteins in an animal cell (Abstract). Thus, claim 1 is broadly drawn to simply the RNA genome of the VSV virus. Claim 1 therefore recites a product of nature (Step 2A, prong 1). Claim 1 does not recite additional elements which integrate the judicial exception into a practical application (Step 2A, prong 2) or transform the claim into significantly more because the claim does not recite markedly different characteristics compared with the naturally occurring VSV genome (Step 2B). Claim 1 is therefore not subject matter eligible.
Regarding claims 2-4, van den Pol teaches the naturally occurring Vesicular stomatitis virus which reads on claim 1 and is in the Rhabdoviruses family (Abstract, Introduction first paragraph). Claims 2-4 are therefore drawn to the naturally occurring VSV genome and are not subject matter eligible.
Regarding claims 5-8, SEQ ID NOs 1-3 (claims 5-6) comprising the N, P, and L proteins along with the RNA sequences encoding them (SEQ ID NOs 4-6, claims 7-8) are simply the naturally occurring amino acid sequences and RNA sequences of the VSV genome as evidenced by B7UCZ2 (UniProt Accession Number B7UCZ2, uploaded 2009, see for alignment of SEQ ID NOs 1 on page 1), B7UCZ3 (UniProt Accession Number B7UCZ3, uploaded 2009, see for alignment of SEQ ID NO: 2 on page 1), and B7UCZ7 (UniProt Accession Number B7UCZ7, uploaded 2009, see for alignment of SEQ ID NO: 3 on pages 1-5). Furthermore, SEQ ID NOs 4-6 are 100% matches for the naturally occurring coding sequences of the N, P, and L proteins of the VSV virus as evidenced by FJ478454 (NCBI BLAST accession number FJ478454, published 2012, VSV viral genome, pages 1-14 for alignment of SEQ ID NOs 4-6). Note that although FJ478454 references a recombinant form of the virus, the sequences are associated with the publication van den Pol (see page 16 of FJ478454, where FJ478454 references van den Pol as the source of the sequences for FJ478454). As evidenced by van den Pol, van den Pol also teaches that the N, P, and L portions of FJ478454 are comprised in the wildtype or natural VSV genome (Figure 1A). Thus, SEQ ID NOs 1-6 of claims 5-8 are simply naturally occurring genes encoded by the VSV virus along with their naturally occurring gene products/proteins. Claims 5-8 do not recite additional claim limitations, and are therefore drawn to naturally occurring products and sequences of the VSV genome and are not subject matter eligible.
Regarding claim 9, claim 9 recites that the RNA further comprises a target molecule coding region encoding a target molecule. The specification does not specifically define a “target molecule” or “target molecule coding region,” and the claim can therefore broadly be interpreted to encompass any additional coding sequence of the RNA molecule of claim 1. van den Pol teaches that the VSV genome naturally encodes other proteins in its genome (e.g., the M and G regions, Figure 1A of the wildtype). Thus, claim 9 is broadly drawn to the naturally occurring VSV genome without additional structural characteristics. Claim 9 is not subject matter eligible.
Regarding claim 10, claim 10 recites specific intended uses of the target molecules, but does not recite specific target molecules encoded by the RNA molecule. As such, claim 10 is rejected for the reasons outlined for the rejection of claim 9, above, where a given target molecule could broadly be interpreted to be a protein encoded by a naturally occurring VSV viral genome. Claim 10 therefore does not add markedly different characteristics of the naturally occurring VSV viral genome and is not subject matter eligible.
Regarding claim 15, claim 15 recites an RNA-protein complex comprising the nucleic acid of claim 1 and a protein comprising the N, P, and L protein. Claim 15 is broadly interpreted to a complex comprising the components of claim 1, where furthermore Morin (Morin B et al. EMBO J. 2012 Mar 7;31(5):1320-9) teaches that such RNA, N, P, and L complexes form naturally in VSV viral complexes (Abstract). Claim 15 is therefore drawn to naturally occurring RNA-protein complexes and is not subject matter eligible.
Regarding claim 16, claim 16 is most broadly drawn to the same elements as claim 1 where the term “pharmaceutical composition” does not add structural significance to the elements of the claim. Claim 16 is therefore rejected for the same reasons given in the rejection of claim 1 and is not subject matter eligible.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-17 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by van den Pol (van den Pol AN et al. J Virol. 2013 Jan;87(2):1019-34). The rejection is further evidenced by FJ478454 (NCBI BLAST accession number FJ478454, published 2012, VSV viral genome), Lundstrom (Lundstrom K. Molecules. 2018 Dec 13;23(12):3310), and Morin (Morin B et al. EMBO J. 2012 Mar 7;31(5):1320-9).
Regarding claim 1, claim 1 is broadly interpreted to be an RNA molecule capable of self-replication comprising regions encoding the N, P, and L proteins which can be expressed in an animal cell. van den Pol teaches the VSV virus which comprises the N, P, and L proteins encoded within its RNA genome (Figure 1, Introduction 1st paragraph). As evidenced by Lundstrom, VSV is a self-replicating virus (i..e, self-replication RNA, A Title, Abstract, page 2 third paragraph, page 3 third paragraph). van den Pol teaches that the self-replicating VSV suitably expresses the N, P, and L proteins in animal cells (Abstract, Figure 1 and caption of Figure 1).
Regarding claims 2-4, van den Pol teaches that the virus that they used was Vesicular Stomatitis (e.g., Title and throughout, Introduction 1st paragraph)>
Regarding claims 5-8, FJ478454 is sequencing data that is associated with the publication of van den Pol (see page 16 of FJ478454). FJ478454 teaches that instant SEQ ID NOs 4-6, which encode the amino acid sequences of instant SEQ ID NOs 1-3, are a 100% match of the N, P, and L proteins taught by FJ478454 (see alignment pages 1-14 of FJ478454). Thus, van den Pol, by teaching the N, P, and L proteins and also by reference to FJ478454, inherently teach SEQ ID NOs 1-6 (claims 5-8).
Regarding claims 9-11, van den Pol teaches that the VSV genome can comprise target proteins such as fluorescent proteins (Figure 1A, e.g., GFP, claims 9 and 11). van den Pol teaches that the VSV can act as medicaments to target cells such as tumor cells to be used as a tumor vaccine (Abstract, claim 10).
Regarding claims 12-13, van den Pol teaches that the RNA molecule can be encoded in a DNA expression vector (e.g. Figure 1B and page 1019 right column second paragraph).
Regarding claim 14, van den Pol teaches that the recombinant plasmid can be transfected into cells, where the VSV is further recovered from the cells (page 1019, right column second paragraph to page 1020).
Regarding claim 15, as evidenced by Morin, Morin teaches that such viral RNA genomes, N, P, and L complexes form naturally in VSV viral complexes during synthesis within the cell (Abstract). Thus, the recited RNA-protein complex is inherently taught and contained within the teachings of van den Pol, who teaches the viral VSV RNA genome, and each of the N, P, and L proteins (Figure 1A).
Regarding claim 16, as discussed above, van den Pol teaches the RNA of claim 1, where recitation of “pharmaceutical composition” in the claim does not add any structural significance to the claim. van den Pol therefore anticipates claim 16 for the same reasons given in the rejection of claim 1.
Regarding claim 17, van den Pol teaches that VSV vectors are used as therapeutics for the treatment of cancers in humans (Introduction, first paragraph). The practitioner can therefore immediately envision that the VSV would be administered to an individual. Furthermore, van den Pol teaches a method of administering VSV to a mouse (page 1021, final paragraph to page 1022), which can broadly be interpreted to be an individual. Furthermore, van den Pol teaches that a target such as GFP is expressed (Abstract, page 1021 final paragraph to page 1022).
Claim Rejections - 35 USC § 112 - Written Description
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 1-17 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.
MPEP 2163.II.A.3.(a).i) states, “Whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the 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”.
For claims drawn to a genus, MPEP § 2163 states the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Regents of the University of California v. Eli Lilly & Co, 119 F.3d at 1568, 43 USPQ2d at 1406.
Regarding claim 1, claim 1 recites a self-replicating RNA comprising coding sequences which encode N, P, and L proteins, or functional fragments thereof, where the self-replication RNA is suitable for producing the proteins or fragments in an animal cell. Claim 1 is therefore claiming the genera of “N,” “P,” and “L” protein “functional fragments,” where such proteins “fragments” are recited with the functionality of being “N, P, or L” proteins. This claim language is problematic because the specification has not identified suitable “functional fragments” of the N, P, and L proteins, where it is furthermore known in the art that modifications to the N, P, and L proteins can dramatically affect their functionality. For instance, claim 1 broadly encompasses embodiments where the L protein is truncated or severely reduced in size or protein content, where it is unknown if such truncations would yield “functional fragments.” The specification defines “functional fragment” to include such substantial changes as deletions, mutations, substitutions, along the entire length of the full protein (paragraph 30). The Applicant was therefore not in possession of the genus “functional fragments” of the N, P, and L proteins because the specification has not demonstrated guidance sufficient in scope to show possession of such genera.
Regarding the guidance provided in the specification, the Applicant offers Examples 1-8 (pages 58-68). The examples provided are each similar embodiments, where in vitro cell modeling to express target proteins such as GFP are reduced to practice using N, P, and L constructs from different strains of Vesicular Stromatatis (e.g., Indian, New Jersey) where different combinations of N, P, and L from the different strains were demonstrated to express GFP (Examples 1-6), CSF (Example 7), and OVA (Example 8). Example 5 demonstrates that different combinations of NPL proteins from VSV virus and rabies could be used to express GFP in vitro (paragraphs 116-118). With regards to “functional fragments,” the specification does not characterize such fragment functionality. For instance, there are no experiments performed wherein the N protein is truncated to 25% of its size and demonstrated to be a “functional fragment” as presently recited. Furthermore, Examples 1-8 demonstrate that each of N, P, and L are required for proper expression, and therefore shows that these proteins are directly or indirectly functioning together which places greater burden on the Applicant to characterize their functional domains in order to achieve an overall effect of functionality. The Applicant has offered Example 6 where conservative mutations to the N, P, and L proteins were performed. However, Example 6 offers SEQ ID NOs 7, 8, and 12 as examples of mutational analysis, where these sequences have 1, 2, and 3 mutations relative the to wildtype SEQ ID NOs 1-3, respectively. Thus, such limited mutational and structural/functional analysis does not demonstrate broader possession of the genus of “functional fragment” which includes substantial variations to the N, P, and L proteins, which the Applicant has shown to be critical for proper functionality of the experimental systems.
With regards to the state of the art, it is known in the art that the recited proteins have critical enzymatic functional domains which require empirical measurement and experimentation to determine. For instance, Morin (Morin B et al. EMBO J. 2012 Mar 7;31(5):1320-9) teaches that it is known that the L protein comprises catalytically active sites, where mutations in such catalytic domains of L render the protein non-functional for the self-replication of RNA strands of VSV (page 1321 left column, final paragraph). Furthermore, Morin teaches that L, P, and N proteins are interacting with each other to carry out specific replicative functions (page 1323 right column, first paragraph). Morin teaches that:
“Evidence that P directly influences the activities of L in RNA synthesis,
beyond its critical role in bringing L to the template is however lacking. To investigate the effect of P on RNA synthesis initiation by L, we compared initiation of the L–P complex with initiation by L (Figure 5A). Quantitative analysis of the products of the reaction reveals that the L–P complex produces four-fold more RNA than L alone, whereas a P mutant lacking the L binding domain is unable to enhance RNA synthesis (Figure 5A and B). This result demonstrates that P plays more than a structural role in recruiting L to the N-RNA template,” (page 1323, right column, first paragraph).
Thus, Morin teaches that N, P, and L form complexes with binding domains in order to facilitate interactions with each other to affect replicative functions (above). The Applicant has not characterized such binding domains for the N, P, and L proteins, where empirical evidence and experimentation are required in order to determine what truncations, mutations, and deletions of such complex domains could be performed in order to retain “functional fragments” of the N, P, and L proteins.
Furthermore, claim 1 suffers an additional 112(a) written description issue. Claim 1 recites a “self-replicating RNA” that comprises the N, P, and L sequences. Claim 1 therefore broadly encompasses an embodiment of a “self-replicating” RNA molecule which consists only of the N, P, and L sequences. However, it is known in the art that the template of the RNA molecule requires more than the mere presence of the N, P, and L genes in order to be “self-replicating.” For instance, Morin teaches that:
“Crystallographic structures of RdRPs that initiate de-novo in complex with their RNA template reveal an interaction between the 3’ end of the template and the RdRP catalytic site as critical for formation of the initiation complex… Recent work on the NNS RNA virus, respiratory syncytial virus (RSV) shows, however, that initiation can occur even with mutation or deletion of the 3’ terminal nucleotide… We therefore tested the importance of the 3’ terminal nucleotides in control of initiation and found that substitutions at any of the first 6 nt of the RNA affect initiation (Figure 2A). Positions 1 and 2 were most sensitive to substitution, as U1A, U1G, G2C, and G2U ablate the ability of L to initiate RNA synthesis,” (page 1321 right column final paragraph)>
Morin further teaches that:
“Deletion of position 1 (Le19D1) ablates RNA synthesis (Figure 3A and B), further underscoring that the 30 terminal U is essential for the de-novo initiation mechanism,” (page 1322, left column, final paragraph).
Thus, Morin teaches that initiation of synthesis of the RNA strand of VSV is heavily dependent upon a “leader” sequence which is external to the N, P, and L genes at the 3’ end of the RNA in order for initiation of synthesis, “self-replication” to occur (page 1322, left column, final paragraph, Figure 3, page 1323 right column final paragraph, page 1321 left column, second paragraph). Thus, Morin teaches that the actual template of the RNA molecule of a self-replicating RNA strand is critical for initiation of “self-replication,” where additional motifs aside from only the N, P, and L coding regions are known to be required for self-replication initiation. However, the present claims do not recite such leader sequence template motifs which are known requirements for self-replication.
Claims 2-16 depend from claim 1 and do not resolve these 112(a) issues.
Regarding claims 5 and 7, these claims recite SEQ ID numbers with percentage identities for the N, P, and L proteins as low as 75%. As discussed above, the Applicant has not shown possession of such genera of N, P, and L proteins because they have not characterized what domains, mutations, or truncations would render functional fragments of N, P, and L proteins, where it is furthermore known in the art as taught by Morin that such N, P, and L proteins comprise functional domains and also interaction domains with each other. The Applicant has not shown possession of, for instance, a functional N protein encoded by a sequence that is only 75% identical to SEQ ID NO: 1.
Regarding claims 6 and 8, while these claims are drawn to exact sequences, the claims still depend from claim 1 which comprises embodiments including only the N, P, and L proteins without any inclusion of template requirements to render “self-replicating” RNA, as discussed above. As Morin teaches, an RNA molecule consisting only of coding sequences for N, P, and L is not likely to be “self-replicating” because it is lacking critical leader sequences which allow for the molecule to initiate RNA synthesis.
Claim Rejections - 35 USC § 112
Claim 17 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the general administration of an RNA molecule of claim 1 into an individual, does not reasonably provide enablement for the administration of a targeted molecule within an individual. 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.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). Wands states, on page 1404:
Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex parte Forman. They include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of these in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.
Nature of Invention/Breadth of the Claim
Regarding claim 17, claim 17 is drawn to a method of expressing a target molecule in an individual, where the individual is administered to self-replicating RNA of claim 1. Claim 17 therefore broadly recites a “target molecule” which is to be administered in vivo (i.e., to an individual), where a ‘target molecule” to be expressed reasonably includes the delivery to a specific cell type or target within the individual. Although the term “target molecule” is not defined in the specification, this is a reasonable interpretation of the method and its scope, as target molecules are exemplified in claim 10 as being medicaments, tumor vaccines, and pathogen vaccines, which require specific targets and delivery sites. The practitioner is not enabled to use the method as recited in claim 17 because the Applicant has not demonstrated in vivo administration of a target molecule to an individual, where the scope of the claim reasonably includes specific targeting of a molecule to an area or cell-type of the body, where furthermore the Applicant has not demonstrated specific, effective target molecules, either for targeted expression or for targeted modulation, as presently recited.
In addition, claim 17 recites the RNA molecules of claim 1. As discussed in the written description rejection, “functional fragments” of the N, P, and L proteins with the recited functionalities of operating as N, P, and L proteins are not described in the specification. Thus, the complexity of the claimed invention is compounded by the fact that the method recites unpredictable and undefined genera of N, P, and L molecules, where no guidance is provided in the specification with respect to which fragments of N, P, and L proteins might be functional in the recited method. The practitioner is therefore unduly burdened by having to solve experimental questions such as identifying functional fragments without direction or guidance and furthermore being required to develop a targeted delivery system to perform the method as recited (see below).
Guidance in the Specification
Regarding the guidance provided in the specification, the Applicant offers Examples 1-8 (pages 58-68). The examples provided are each similar embodiments, where in vitro cell modeling to express target proteins such as GFP are reduced to practice using N, P, and L constructs from different strains of Vesicular Stromatatis (e.g., Indian, New Jersey) where different combinations of N, P, and L from the different strains were demonstrated to express GFP (Examples 1-6), CSF (Example 7), and OVA (Example 8). Example 5 demonstrates that different combinations of NPL proteins from VSV virus and rabies could be used to express GFP in vitro (paragraphs 116-118). With regards to “functional fragments,” the specification does not characterize such fragment functionality. For instance, there are no experiments performed wherein the N protein is truncated to 25% of its size and demonstrated to be a “functional fragment” as presently recited. Furthermore, Examples 1-8 demonstrate that each of N, P, and L are required for proper expression, and therefore shows that these proteins are directly or indirectly functioning together which places greater burden on the Applicant to characterize their functional domains in order to achieve an overall effect of functionality. The Applicant has offered Example 6 where conservative mutations to the N, P, and L proteins were performed. However, Example 6 offers SEQ ID NOs 7, 8, and 12 as examples of mutational analysis, where these sequences have 1, 2, and 3 mutations relative the to wildtype SEQ ID NOs 1-3, respectively. Thus, such limited mutational and structural/functional analysis does provide a practitioner with sufficient guidance with respect to the “functional fragments” recited in claim 1, and by extension, claim 17.
Additionally, the Examples in the specification offer no in vivo reduction to practice, or guidance surrounding targeted delivery of such VSV expression constructs to target cells, or what targeted molecules should be encoded to obtain a result. The practitioner is therefore experimentally burdened by having to develop a delivery system in order to administer the recited RNA molecules to a target site to deliver the recited payload (i.e., target molecule)>
State of the Art
Regarding the state of the art, it is known in the art that the N, P, and L proteins act as a complex of binding domains with each other and with template RNA (see the discussion of the State of the Art for the written description rejection, above). For the sake of brevity, the state of the art discussion with respect to the “functional fragments” and the unpredictability and lack of characterization of such fragments, e.g., as taught by Morin, in the written description rejection, above, is incorporated herein by reference and applied to the present enablement rejection.
With respect to the targeted delivery of RNA expression constructs such as VSV, it is known in the art that delivery of such target molecules in vivo is complex and unpredictable. For instance, Catacalos-Goad (Catacalos-Goad C et al. Curr Oncol. 2025 Nov 7;32(11):627) is a post-filing publication that focuses on the use of VSV as an oncolytic viral therapy (Title, Abstract, and throughout). Catacalos-Goad teaches that it is known in the art that several challenges exist when administering target molecules using VSV vectors such as the RNA molecules presently claimed. For instance, Catacalos-Goad teaches that:
“Equally unresolved is the strategic identity of VSV as a therapeutic. Should it be
advanced primarily as a lytic monotherapy, optimized for direct tumor cell killing? Or should its greatest value lie in functioning as an adjuvant to immune checkpoint blockade, where its ability to inflame the tumor microenvironment may prove more important than its oncolytic capacity? A third vision sees VSV as a versatile delivery chassis, optimized less for oncolysis per se and more for transporting payloads, cytokines, co-stimulatory ligands, bispecific engagers, or even imaging tools, into tumors. These divergent trajectories reflect different philosophies of what oncolytic virotherapy should achieve and complicate the field’s long-term direction,” (page 25, final paragraph).
Thus, Catacalos-Goad teaches that the status of RNA molecules such as those encoded by VSV and presently recited with respect to their use as delivery vehicles to target cells, specifically tumor cells as exemplified in Catacalos-Goad, is still a burgeoning field where the true direction and application of such expression constructs is yet to be resolved in the field (above).
To further highlight the uncertainty of VSV vectors and their ability to deliver targeted molcules, Catacalos-Goad teaches that:
“Another pressing debate surrounds systemic delivery. It remains unclear whether progressive refinements to the viral backbone, attenuating mutations, gene-order rearrangements, chimeric envelopes, or microRNA-regulated expression, will be sufficient to allow safe intravenous administration. Some groups propose that even the most attenuated VSVs may still require transient immunosuppression to permit effective systemic spread. This strategy reintroduces clinical risks and may blunt the very immune responses that make VSV attractive as cancer immunotherapy,” (page 26, final paragraph).
And further teaches that:
“Looking forward, continued development of VSV-based therapies will likely focus on precision-guided strategies that combine insights from tumor-specific antiviral signaling, immunological profiling, and high-throughput preclinical screening. As the field advances, these efforts are expected to expand the clinical applicability of VSV-based oncolytic virotherapy across a broader spectrum of malignancies and bring the potential for personalized, highly effective viral anti-cancer treatments closer to reality.
The trajectory of VSV-based virotherapy will likely be shaped as much by these
translational and regulatory decisions as by technical innovation itself. The field must confront uncomfortable but essential questions about trade-offs between potency and safety, the desired role of VSV in the therapeutic landscape, and the regulatory models best suited for a modular, rapidly evolving platform. Ultimately, the future of VSV may depend not only on what is scientifically achievable but also on what is judged clinically feasible, ethically acceptable, and societally valuable (page 27, paragraphs 2-3).”
Thus, Catacalos-Goad teaches that targeted delivery of RNA expression constructs such as VSV still suffer known experimental and technical challenges including an unresolved need to find a balance between safety and potency, how to develop “precision-guided strategies,” the intended role of such VSV expression constructs in treatments, as well as unresolved questions surrounding the feasibility of using such constructs, all of which require “technical innovation” in order to achieve translational applicability (above).
Experimental Burden
The practitioner is experimentally burdened in order to practice the presently recited method. Firstly, the practitioner would be required to systematically identify “functional fragments” of N, P, and L proteins, where the specification offers little to no guidance on the required functional and structural domains in order to render functional fragments of these proteins. This constitutes undue experimental burden because the practitioner would be required to identify specific protein interactions, the interactive N, P, and L domains as well as their catalytic domains in combination with which residues or domains could be removed or altered while still retaining functionality. The discovery of such functional fragments would constitute experimental burden, as the practitioner would be required to perform characterization of each protein and its domains.
Furthermore, the use of such RNA molecules as a means to deliver targeted molecules is known in the art to face unresolved challenges in the field. For instance, the practitioner would be burdened not only with needing to identify effective target molecules, but would also be faced with the undue experimental burden of developing a means of delivering such RNA molecules to target cells to render effective results. However, these challenges are a known, unsolved problem in the art as taught by Catacalos-Goad (above). However, the specification has not offered solutions to the known problems of administering such RNA molecules with target molecules, and has not reduced to practice any in vivo experimental data to solve the known challenges in the field.
Conclusion
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/D.C.R./Examiner, Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
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