DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s Response to Election/Restriction Filed, Amendment, and Arguments/Remarks, filed 18 November 2025, have been entered. Claims 1-20 are currently pending. Claims 1, 19, and 20 are independent claims. Applicant’s election without traverse of the invention of Group I, drawn to a nucleic acid composition and a population of sender cells, is acknowledged.
Additionally, applicant’s election of the following species:
Fusogens: e. A viral fusogenic glycoprotein;
Cargo RNAs: a. packing signals: iii. an MS2 phage operator stem-loop, and b. mRNA encoding a payload protein;
RNA exporter proteins: j. SEQ ID NO: 10;
RNA binding domains/proteins: c. MS2 Coat Protein (MCP);
Payload protein capabilities: a. modulating the expression of the one or more endogenous proteins of a receiver cell;
Payload protein activities/identities: a cellular reprogramming factor capable of converting an at least partially differentiated cell to a less differentiated cell: Oct-3; and
Receiver circuit functions: d. configured to reprogram a receiver cell type and/or cell state via expression of transcription factors and/or epigenetic modifiers;
without traverse in a reply filed 18 November 2025 is acknowledged.
Claim 20 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 1-19 are currently pending in the application and under examination to which the following grounds of rejection are applicable. An action on the merits follows.
Priority
The present application claims priority to U.S. Provisional Application Nos. 63/234,087, filed 17 August 2021, and 63/234,085, filed 17 August 2021.
Thus, the earliest possible priority for the instant application is 17 August 2021.
Information Disclosure Statement
The information disclosure statement filed 06 June 2023 has been considered by the Examiner.
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 1-19 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.
Claims 1, 2, 3, 5, 12, 14, 15, 16, 17 and 19 and by dependence, claims 6-10, 11 and 18 are vague and indefinite in the recitation of “…capable of…” , since this phrase refers to a latent ability, and it is unknown whether the ability is expressed or observed in the invention. Note, it has been held that the recitation that an element is “capable of” performing a function is not a positive limitation, but only requires the ability to so perform. It does not constitute a limitation in any patentable sense. In re Hutchinson, 69 USPQ 138. As such, the metes and bounds of the claim cannot be determined.
Claim 3 is vague and indefinite because it recites the phrase "derived from" andthe metes and bounds of how a fusogen can be "derived from" a SNARE protein, dynamin, an FF protein, a FAST protein, a viral fusogenic glycoprotein, and still meet the intended limitation of the claim are not clear. It is not possible to know the metes and bounds of a "derivative" because any given starting material can have many divergent derivatives depending on the process of derivatization. This rejection could be overcome by' substituting "isolated" for "derived" in the claim. As such, the metes and bounds of the claim cannot be determined.
Claim 5 is indefinite in its recitation of “specifically package” . The term " specifically " is not defined by the claim”. The specification does not provide any closed definition as to what is meant by “specifically”. Although it is acknowledged the specification some RNA exporters can package their own RNA e.g., the packing signal(s) comprise an MS2 phage operator stem-loop and the RNA binding protein is MS2 Coat Protein (MCP), where MCP binds RNA tagged with MS2 packaging signal, enabling specific packaging of target RNA (para (0054]) or “MMLV Gag self-assembles to form viral capsid and packages RNA tagged with MMLV packaging signal (Psi) via interaction between MMLV Gag and Ps” (para [0202])or wherein “HIV Gag without nucleocapsid domain fused with leucine zipper dimerization domain from GCN4 (Zip), designated GagZip, which nucleates self-assembly via homodimerization of Zip to form viral capsid. RNA is specifically packaged via interaction of MS2 packaging signal with MCP. (para [0202])”, these are merely exemplary and non-limiting. The metes and bounds of the claims are unclear particular since specifically would vary depending on the recognition of a binding motif within the RNA exporter protein, selected packaging signal and conditions. As such, the metes and bounds of the claims cannot be determined.
Claim 6 recites the term “and/or” in line 4. It is unclear what the metes and bounds of this term, as “and” could be interpreted to include only the packing signal(s) are absent from the cargo RNA molecule(s), or all of the packing signal(s) are absent from the cargo RNA molecule(s) and (ii) the RNA exporter protein does not comprise an RNA binding domain, “or” would imply (i) and (ii) are in the alternative. As such, the metes and bounds of the claims cannot be determined.
Likewise claims 8, line 14; claim 11, line 3; claim 13, line 2; claim 14, lines 2, 3, 8, 10, 14, 19 and 21; claim 15, line 2; claim 16, page 5, line 24, page 7, line 78; claim 18 , lines 7-8, recite the term “and/or”. While this may be a convenient means for Applicant, such legalese renders the claims indefinite because the claimed choices cannot simultaneously be each of the structurally different choices. For example an agonistic antibody of claim 16 cannot be both a PD1 antibody and a non PD1 antibody (claim 16, page 5, line 24). As such, the metes and bounds of the claims cannot be determined.
Claim 8 is vague and indefinite because it recites the phrase "derived from" andthe metes and bounds of how an RNA binding domain can be "derived from" an RNA binding protein, and still meet the intended limitation of the claim are not clear. It is not possible to know the metes and bounds of a "derivative" because any given starting material can have many divergent derivatives depending on the process of derivatization. This rejection could be overcome by' substituting "isolated" for "derived" in the claim. As such, the metes and bounds of the claims cannot be determined.
Claim 15 recites the limitation "the one or more endogenous proteins of a receiver cell" in lines 2-3. There is insufficient antecedent basis for this limitation in the claim. Claim 15 is dependent on claim 12, which is dependent on claim 2, which is dependent on independent claim 1. None of claims 15, 12, 2, nor 1 have any prior recitation of any one or more endogenous proteins of a receiver cell. As such, the metes and bounds of the claim cannot be determined.
Claim 16 has multiple issues of indefiniteness.
Firstly, claim 16 recites several lists which recite “selected from the group comprising” or “selected from the group consisting of”, wherein the list is linked by an “or” linkage, an “and/or” linkage, or no linker (see lines 17-20, 22-24, 41-43, 44-50, 54-63, 75-76, 77-81, 82-83, 84-85), which is indefinite because the metes and bounds of the list to be selected from is unclear.
Secondly, claim 16 recites a list of programmable nucleases in lines 44-50, which comprise a mix of “,” and “;” to separate the list. However, it is unclear how the subgroups separated “,”s between the “;” are related as separate or combined options. For example, the list of “VRER, VQR, EQR SpCas9;” are separated by “,”s between two “;”s but also do not have any “and” which would indicate that they are a joint option or an “or” to indicate that they are sub-options. Additionally, recitation of “dcas9-APOBEC1 fusion, BE3, and dcas9-deaminase fusions;” in lines 47-48, wherein the list separated by “,”s are set-off between items separated by “;” to either side, is indefinite because it is unclear whether they are a single option as a set or whether each fusion is a separate option for a programmable nuclease of the invention. Similarly, recitation of “dcas9-KRAB, dCas9-VP64, dCas9-Tet1, and dcas9-trasncriptional regulator fusions;” is unclear whether the recited options are a single option as a set or whether each fusion is a separate option for a programmable nuclease of the invention.
Thirdly, recitation of “is capable of” in line 87 is definite because it is unclear how a payload protein comprises “is capable of”.
As such, the metes and bounds of the claim cannot be determined.
Note that “selected from the group comprising” has been interpreted to indicate an open group.
Claim Rejections - 35 USC § 112(a)- 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 1-19 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.
Claim 10 recites, “The nucleic acid composition of claim 1, wherein the RNA exporter protein comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to any one of SEQ ID NOS: 1-24”, which SEQ ID NO: 10 as the elected species.
The specification generally teaches, “In some embodiments, the RNA exporter protein comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 98%, 99%, or 100% identical to any one of SEQ ID NOS: 1-24” [0013] and “The RNA exporter protein can comprise an amino acid sequence at least about 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, or a number or a range between any two of these values, identical to any one of SEQ ID NOS: 1-24 (Table 1)“ [0108]. Table 1 indicates that SEQ ID NO: 10 is EPN24-MCP. The specification also teaches the sequence of SEQ ID NO: 11 (EPN24-MCP_I) which has 97.7 % identity to SEQ ID NO: 10. However, the specification does not teach any other sequences which are within the scope of at least 80% sequence identity to SEQ ID NO: 10.
The specification does not disclose which variants of the sequence of SEQ ID NO: 10 would comprise an amino acid sequence which would retain the essential functional properties of the RNA exporter protein nor which variants would disrupt such functions. The specification additionally does not disclose any % identity which would retain the necessary identity and functionality of the RNA exporter protein. As such, the specification fails to provide any specific guidance as to which up to 20% of the sequence of SEQ ID NO: 10 could be changed to allow for a functional RNA exporter protein of the instant invention. Therefore, the description is not sufficient to adequately describe and demonstrate possession of any variants of SEQ ID NO: 10 other than SEQ ID NO: 11, and particularly variants of SEQ ID NO: 10 which comprise up to 20% sequence differences.
The following guidance provided in MPEP 2163 is informative. To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. 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 (see i)(A) above), reduction to drawings (see i)(B) above), 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 i)(C) above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. 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 other words, describing a composition by its function alone typically will not suffice to sufficiently describe the composition. See for example Eli Lilly, 119 F.3 at 1568, 43 USPQ2d at 1406 (Holding that description of a gene’s function will not enable claims to the gene "because it is only an indication of what the gene does, rather than what it is."); see also Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen Inc. v. Chugai Pharm. Co., 927 F.2d 1200, 18 USPQ2d 1016 (Fed. Cir. 1991)). An adequate written description of a chemical invention also requires a precise definition, such as by structure, formula, chemical name, or physical properties, and not merely a wish or plan for obtaining the chemical invention claimed. See, e.g., Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004) (The patent at issue claimed a method of selectively inhibiting PGHS-2 activity by administering a non-steroidal compound that selectively inhibits activity of the PGHS- 2 gene product, however the patent did not disclose any compounds that can be used in the claimed methods. While there was a description of assays for screening compounds to identify those that inhibit the expression or activity of the PGHS-2 gene product, there was no disclosure of which peptides, polynucleotides, and small organic molecules selectively inhibit PGHS-2. The court held that "[w]ithout such disclosure, the claimed methods cannot be said to have been described."). Furthermore, written description issues may also arise if the knowledge and level of skill in the art would not have permitted the ordinary artisan to immediately envisage the claimed product arising from the disclosed process. See, e.g., Fujikawa v. Wattanasin, 93 F.3d 1559, 1571, 39 USPQ2d 1895, 1905 (Fed. Cir. 1996). While it has been held that what is conventional or well known to one of ordinary skill in the art need not be disclosed in detail, for inventions in emerging and unpredictable technologies, or for inventions characterized by factors not reasonably predictable which are known to one of ordinary skill in the art, more evidence is required to show possession.
The specification, as discussed in detail above, provides guidance for only two disclosed species of sequence within the scope of at least 80% sequence identity to SEQ ID NO: 10, which each comprising an EPN24-MCP amino acid sequence, without providing sufficient detailed descriptions of the various variants which would have sufficient structural and functional properties of an RNA exporter protein or which modification within the binding domain will bind the RNA tagged with MS2 packaging signal. As such, the specification fails to provide a description of a representative number of species by actual reduction to practice (see i)(A) above), reduction to drawings (see i)(B) above), 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 any of the claimed genus of variants of SEQ ID NO: 10 comprising up to 20% differences in nucleic acid sequence.
There is no disclosure of which amino acids are in the active site(s), binding pocket(s), or hydrophobic core(s) of the protein. There is no structure/function relationship taught at all for SEQ ID NO: 10. The specification mentions only the full length of two disclosed species of EPN24-MCL which have sequences within 80% identity to SEQ ID NO: 10 (e.g., SEQ ID NOs: 10 and 11). The scope of the claim as written encompasses any variation in the amino acid sequence, which includes variations which change the amino acid sequence at any position to any other amino acid. As such, the claim as written encompasses variations which may change the structure sufficiently to adversely affect the function and/or alter the function of the RNA exporter protein.
Votteler teaches that mutational analysis confirmed that each of the three design elements of an EPN is required for EPN release, such that point mutations designed to disrupt myristoylation or the designed assembly interface were not detectably released and that mutations designed to block ESCRT factor recruitment inhibited EPN release [Votteler et al. 2016, Nature, 540, 292-295, IDS, column 2 ¶ 2, Figure 1, Extended Data Figure 1]. Accordingly, given the dramatic effects single point mutations within the amino acid encoding sequence for the EPN can have on the function of the EPN, sufficient to completely abrogate release, the scope of the claim encompasses variants of the RNA exporter protein sequence which would result in a non- or dys-functional RNA exporter protein. As such, variants of the RNA exporter protein amino acid sequence of up to 20% non-identities relative to the sequence of SEQ ID NO: 10, such that a functional RNA exporter protein is still encoded, were neither conventional nor predictable at the time of filing, and the knowledge and level of skill in the art at the time of filing would not have permitted the ordinary artisan to immediately envisage all the variations of the sequence of SEQ ID NO: 10, up to 20% variant, which would still produce a functional RNA exporter protein from the generic description provided by the specification. In view of these considerations, an ordinarily skilled artisan would not have viewed the teachings of the specification as sufficient to show that the Applicant was in possession of the claimed invention.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-6, 8-9, 11-15, and 17-19 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Zhang [US20200347100A1, filed 16 March 2020, published 05 November 2020], as evidenced by Grahn et al. [2001, RNA, 7, 1616-1627].
Regarding claim 1, Zhang discloses a nucleic acid composition [0010-0011, 0239] comprising a first polynucleotide encoding an RNA exporter protein, wherein the RNA exporter protein comprises and RNA binding domain (e.g., an MS2 coat protein domain) [0006, 0008, Figure 21], a membrane-binding domain (e.g., an epitope tag for expression on the surface of the export compartment) [0009], and an interaction domain capable of nucleating self-assembly (e.g., an export compartment domain that directs self-assembly of the polypeptide into the export compartment) [0005, 0008-0010, Figure 21, 29]; a second polynucleotide encoding one or more cargo RNA molecules [0006, 0008, Figure 21]; and a third polynucleotide encoding a fusogen (e.g., the glycoprotein of vesicular stomatitis virus (VSVG)) [0058, 0106, 0324-0327, Figure 26, 29A, claim 26].
Zhang further discloses wherein a plurality of RNA exporter proteins are capable of self-assembly into lipid-enveloped nanoparticles (LNs) (e.g., nanovesicles/gesicles) secreted from producer/sender cells in which the RNA exporter proteins are expressed, thereby generating a population of LNs comprising the fusogen and exported cargo RNA molecules [0005-0006, 0058, 0106, 0324-0327, Figure 26, 29A-B, 31, claim 1-3, 6, 26].
Regarding claim 2, Zhang teaches wherein the population of LNs/gesicles are capable of fusing with receiver cells, thereby delivering the cargo RNA molecules to said receiver cells [0058, 0155, 0271-0272, 0324-0327, Figure 26, 29A-B, 30, claims 1-3, 6, 26, 35].
Regarding claim 3, Zhang further discloses wherein the fusogen is capable of mediating the fusion of the lipid envelope of the LN/gesicle and a lipid bilayer of a receiver cell [0155, Figure 26, 29B], and wherein the fusogen comprises a viral fusogenic glycoprotein (e.g., VSVG) [0058, 0106, 0324-0327, Figure 26, 29A, claim 26].
Regarding claim 4, Zhang further teaches wherein the cargo RNAs are mRNAs and comprise packing signals (e.g., MS2 sequences, as elected) [0007, 0322, Figure 21, claim 3, 6].
Regarding claim 5, Zhang discloses wherein the RNA binding domain is capable of binding the packing signals, and wherein the cargo RNA molecules is specifically packaged into the LNs via interaction of the packing signals with the RNA binding domain of the RNA exporter protein [0005-0008, Figure 21A-B, claim 6].
Regarding claim 6, Zhang discloses wherein the abundance of cargo RNA molecules exporter to the exterior of a sender cell is at least about 2-fold higher as compared to a sender cell wherein (i) the packing signals are absent from the cargo RNA molecules and (ii) the RNA exporter protein does not comprise an RNA binding domain [0322, Figure 22, 24].
Regarding claim 8, Zhang discloses wherein the RNA binding domain is derived from an MS2 RNA binding protein and the packing signal comprises an MS2 phage RNA sequence [0005-0006], which inherently teaches that the MS2 RNA comprises an MS2 phage operator stem-loop, as taught by Grahn.
Grahn teaches that the coat protein of the MS2 phage interacts specifically with a 19 nt RNA hairpin located at the 5’ end of the viral replicase, wherein the RNA hairpin consists of a 7-bp stem closed by a 4 nt loop (e.g., a stem-loop) [column 1 ¶ 1]. Therefore, Zhang’s teaching of the inclusion of an MS2 RNA which binds to the MS2 RNA binding domain is inherently a teaching that the packing signal comprise an MS2 phage operator stem-loop. “When the structure recited in the reference is substantially identical to that of the claims, claimed properties or functions are presumed to be inherent.” See MPEP 2112.01 or In re Best, 195 USPQ 430, 433 (CCPA 1997).
Regarding claim 9, Zhang discloses wherein the RNA exporter protein comprises at least a portion of a viral coat/capsid protein [0078, 0092].
Regarding claim 11, Zhang teaches the expression of exogenous RNA exporter protein in the sender/producer cells which packages the cargo mRNA into LNs/gesicles which bud off of the producer cells [Figure 29B]. Zhang teaches cargo which is targeted to modify the endogenous transcriptome of a receiver/target cell [Figure 29B, 31]. Zhang does not teach that the expression of the RNA exporter protein in the sender cell alters the endogenous transcriptome, morphology, and/or physiology of the sender cell itself. Thus, absent evidence to the contrary, the nucleic acid composition of Zhang is presumed to meet the limitation recited in claim 11, wherein the expression of the RNA exporter protein in the sender cells does not alter the endogenous transcriptome, morphology, and/or physiology of said sender cells because the structure of the claimed one or more first polynucleotide(s) encoding an RNA exporter protein, one or more second polynucleotide(s) each encoding one or more cargo RNA molecule(s), and one or more third polynucleotide(s) encoding a fusogen and Zhang’s one or more second polynucleotide(s) are the same.
Regarding claim 12, Zhang teaches wherein the cargo RNA is an mRNA which encodes a protein to be expressed in the target cell [0004, 0021, 0026, 0053, 0086, 0132, 0166, Figure 21, 31].
Regarding claims 13-15, Zhang teaches wherein the cargo RNA molecules and/or payload proteins encoded by said cargo RNA molecules constitute two or more components of a receiver circuit (e.g., the cargo RNA molecules encode a CRISPR Cas9 protein and a sgRNA) [0021, 0026, 0187, 0201, 0208]. Zhang also discloses where the receiver circuit is configured to reprogram a receiver cell state via expression of transcription factors and/or epigenetic modifiers (e.g., a dCas9 protein fused to a functional domain, wherein the functional domain is a transcriptional activation domain, a transcriptional repression domain, or a histone modification domain) to modulate the expression of one or more endogenous proteins of the receiver cell [0204-0205].
Zhang further teaches wherein delivery of the exported export compartment/gesicle/LN can be used to induce differentiation of one or more recipient cell populations, including a shift in cell state by triggering the activating and/or silencing of one or more gene products and/or cell pathways, e.g., stem cells induced to differentiate into one or more cell types [0293]. Zhang also teaches wherein delivery of the exported export compartment/gesicle/LN to one or more receiver cell populations may be used to induce a shift in cell state by triggering the activating and/or silencing of one or more cell pathways, such as for reactivating exhausted T cells, inducing a pro-inflammatory state, inducing an anti-inflammatory state, or to treat or ameliorate a disease in a diseased tissue [0295-0296].
Regarding claim 17, Zhang teaches wherein the export compartments/gesicles/LNs are capable of protecting cargo RNA molecules comprises therein from RNase-mediated degradation when contacted with RNase [0055-0056, 0322, Figure 23-24].
Regarding claim 18, Zhang teaches wherein the maximum diameter of the export compartments/gesicles/LNs of the population of export compartments/gesicles/LNs is 500 nm or less, preferably 100 nm or less, and wherein the diameter ranges between 25 nm and 200 nm or 35 nm and 60 nm [0116]. Zhang also teaches particles sizes about 70 nm in diameter [0134, Figure 19-20].
Regarding claim 19, Zhang teaches a population of production/producer/donor/sender cells comprising the nucleic acids as described above for claim 1 and also recited in claim 19 [0004, 0014, 0061-0062, 0147, 0327, Figure 29A-B, claim 35].
Accordingly, by teaching all of the limitations of claims 1-6, 8-9, 11-15, and 17-19 as written, Zhang anticipates the instant invention as claimed.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 2, 4, 7, 10, 12, and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang [US20200347100A1, filed 16 March 2020, published 05 November 2020]; in view of Prel et al. [2015, Molecular Therapy- Methods and Clinical Development, 2, 15039, 1-15]; Grahn et al. [2001, RNA, 7, 1616-1627]; Votteler et al. [2016, Nature, 540, 292-295, IDS]; NCBI [2017, MS2-VP64 [Vector pMM1-40A], GenBank: ASW25882.1, retrieved 17 February 2026 from: <https://www.ncbi.nlm.nih.gov/protein/ASW25882.1?report=genbank&log$=protalign&blast_rank=1&RID=TAHD4D3A014>, published 05 September 2017]; and MacArthur et al. [2012, Stem Cells International, 2012, 564612, 1-9].
Regarding claim 1, Zhang discloses a nucleic acid composition [0010-0011, 0239] comprising a first polynucleotide encoding an RNA exporter protein, wherein the RNA exporter protein comprises and RNA binding domain (e.g., an MS2 coat protein domain) [0006, 0008, Figure 21], a membrane-binding domain (e.g., an epitope tag for expression on the surface of the export compartment) [0009], and an interaction domain capable of nucleating self-assembly (e.g., an export compartment domain that directs self-assembly of the polypeptide into the export compartment) [0005, 0008-0010, Figure 21, 29]; a second polynucleotide encoding one or more cargo RNA molecules [0006, 0008, Figure 21]; and a third polynucleotide encoding a fusogen (e.g., the glycoprotein of vesicular stomatitis virus (VSVG)) [0058, 0106, 0324-0327, Figure 26, 29A, claim 26].
Zhang further discloses wherein a plurality of RNA exporter proteins are capable of self-assembly into lipid-enveloped nanoparticles (LNs) (e.g., nanovesicles/gesicles) secreted from producer/sender cells in which the RNA exporter proteins are expressed, thereby generating a population of LNs comprising the fusogen and exported cargo RNA molecules [0005-0006, 0058, 0106, 0324-0327, Figure 26, 29A-B, 31, claim 1-3, 6, 26].
Regarding claim 2, Zhang teaches wherein the population of LNs/gesicles are capable of fusing with receiver cells, thereby delivering the cargo RNA molecules to said receiver cells [0058, 0155, 0271-0272, 0324-0327, Figure 26, 29A-B, 30, claims 1-3, 6, 26, 35].
Regarding claim 4, Zhang further teaches wherein the cargo RNAs are mRNAs and comprise packing signals (e.g., MS2 sequences, as elected) [0007, 0322, Figure 21, claim 3, 6].
Regarding claim 7, Zhang teaches the limitations of claims 1 and 4. However, Zhang does not teach wherein the packing signal comprise an array of at least about 2 tandem repeats of an aptamer.
Prel teaches the packaging of cargo RNAs into MS2-coat-retrovirus chimeras for better efficiency of delivery to primary cell in vivo, wherein multiple (e.g., 6, 12, or 24) copies of the MS2 stem loop aptamer into the cargo RNAs allowed packaging of significantly more than 2 RNAs per chimeric viral particle and enabled efficient transfer of biologically active RNAs into various cell types [abstract, column 2 ¶ 2, column 15 ¶ 1, Figure 1, 3]. Prel also teaches that an increasing number of MS2 stem loop repeats within the array increased the mobilization efficiency of the particles (e.g., the packaging and delivery of the particles to the target cells) [column 15 ¶ 1- column 16 ¶ 1, Figure 3].
Therefore, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to use an MS2 stem loop aptamer array comprising at least 6, 12, or 24 tandem repeats of the MS2 stem loop aptamer inserted into a cargo RNA to improve packing and delivery efficiency of the cargo RNA.
Regarding claim 10, Zhang teaches the limitations of claim 1. However, Zhang does not teach wherein the RNA exporter protein comprises an amino acid sequence that is at least 80% identical to the elected sequence of SEQ ID NO: 10.
However, Votteler teaches an enveloped protein nanocages (EPNs) (e.g., EPN-24) which self-assemble, direct their own release from human cells inside small vesicles, package cargo from producer cells, and deliver the cargo to target cells (e.g., transferring cargo from one cell to another) [abstract, Figure 4, Extended Data Figure 8]. Votteler teaches that the EPN-24 comprises a PCLδ-PH membrane binding domain, an HIV-1 p6 ESCRT recruitment domain, an I3-01 self-assembling interaction domain, and a myc tag, which together support EPN formation [Figure 4]. Votteler further teaches that the EPN-24 construct yielded robust EPN biogenesis [Extended Data Figure 8]. Votteler further teaches a sequence for EPN-24, wherein the EPN-24 sequence has 100% identity to amino acids 1-396 of instant SEQ ID NO: 10 [Supplementary Table 2]:
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Therefore, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to use EPN-24, comprising a membrane-binding domain and an interaction domain capable of nucleating self-assembling, wherein the EPN-24 sequence has 100% sequence identity to amino acids 1-396 of instant SEQ ID NO: 10, in a cargo exporter protein for delivery of cargo from one cell to another to achieve robust EPN/LN biogenesis.
NCBI teaches a sequence for an MS2 coat protein (MCP) which has 100% sequence identity to amino acids 397-525 of instant SEQ ID NO: 10 (e.g., amino acids 2-130 of the MS2-VP64 sequence):
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which is encoded in a vector and fused to the VP64 transcriptional activation domain [lines 32-35 and 41-43].
Therefore, given the teachings of Zhang to use an MS2 coat protein for targeting RNA exporter proteins to bind cargo RNAs and the teachings of NCBI of a sequence of MS2 coat protein RNA binding domain used to target a fused protein which has 100% sequence identity to amino acids 397-525 of instant SEQ ID NO: 10, an ordinarily skilled artisan would have been motivated to use the MS2 coat protein sequence taught by NCBI, having 100% sequence identity to amino acids 397-525 of instant SEQ ID NO: 10, to target the RNA exporter protein of Zhang with a reasonable expectation of success..
Zhang teaches that the cargo tag can be attached to the exosome carrier (e.g., membrane-binding domain + self-assembling interaction domain) as either an N-terminal tag or a C-terminal tag [Figure 21]. In using the EPN-24 sequence taught by Votteler and the MS2 coat protein sequence taught by NCBI to generate an RNA exporter protein according to Zhang, comprising an exosome carrier plus cargo tag [Figure 21], the ordinarily skilled artisan would merely have to choose between placing the MS2 coat protein (MCP) sequence at the N- or C- termini of the carrier, wherein selecting to place the cargo tag (MCP) sequence at the C-terminal end of the carrier would arrive at a sequence having 100% sequence identity with, and comprising the full sequence according to, SEQ ID NO: 10 of the instant application.
Regarding claim 12, Zhang teaches wherein the cargo RNA is an mRNA which encodes a protein to be expressed in the target cell [0004, 0021, 0026, 0053, 0086, 0132, 0166, Figure 21, 31].
Regarding claim 16, Zhang teaches the limitations of claims 1, 2, and 12., Zhang teaches wherein the payload protein induces differentiation of one or more recipient cell populations [0015, 0293]. Zhang also teaches wherein delivery of the exported export compartment/gesicle/LN to one or more receiver cell populations may be used to induce a shift in cell state [0295-0296].
However, Zhang does not specifically teach wherein the payload protein is a cellular reprogramming factor capable of converting an at least partially differentiated cell to a less differentiated cell, wherein the reprogramming factor is OCT3, as elected.
MacArthur teaches the delivery of RNA encoding OCt3 to reprogram somatic cells (e.g., human fibroblasts) into induced pluripotent stem cells (iPSCs), wherein the generation of iPSCs from somatic cells has enabled the possibility of providing unprecedented access to patient-specific iPSC cells for drug screening, disease modeling, and cell therapy applications [abstract, column 2 ¶ 2, column 6 ¶ 4]. MacArthur also teaches that major obstacles to the use of iPSCs for therapeutic applications are the potential of genomic modifications caused by insertion of viral transgenes in the cellular genome and the requirement to use animal feeder cell layers which hinder the generation of clinical-grade iPSCs [abstract]. MacArthur further teaches that the delivery of RNA encoding Oct3 (e.g., in an RNA Sendai virus vector) allows for both generation of iPSCs without integration of the transgene into the cell’s genome and reprogramming in the absence of feeder cells, thereby facilitating safe downstream applications of iPSC-based cells therapies [abstract].
Therefore, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to deliver an RNA encoding OCT3 to reprogram at least partially differentiated somatic cells (e.g., fibroblasts) into iPSCs to generate clinical grade iPSCs for cell therapy applications with a reasonable expectation of success.
Given the motivation taught by Prel to use an MS2 stem loop aptamer array comprising at least 6, 12, or 24 tandem repeats of the MS2 stem loop aptamer inserted into a cargo RNA to improve packing and delivery efficiency of the cargo RNA; the motivation taught by Votteler use EPN-24, comprising a membrane-binding domain and an interaction domain capable of nucleating self-assembling, wherein the EPN-24 sequence has 100% sequence identity to amino acids 1-396 of instant SEQ ID NO: 10, in a cargo exporter protein for delivery of cargo from one cell to another to achieve robust EPN/LN biogenesis; the teachings of NCBI of a sequence for an MS2 coat protein (MCP) which has 100% sequence identity to amino acids 397-525 of instant SEQ ID NO: 10; and the motivation taught by MacArthur to deliver an RNA encoding OCT3 to reprogram at least partially differentiated somatic cells (e.g., fibroblasts) into iPSCs to generate clinical grade iPSCs for cell therapy applications; it would have been prima facie obvious to an ordinarily skilled artisan to modify the composition and cells of Zhang to comprise an array of MS2 stem loop aptamers comprising at least 6 or 12 tandem repeats as a packing signal in the cargo RNA, to include the EPN24-MCP sequence of SEQ ID NO: 10 in the RNA exporter protein, and to comprise a cargo RNA encoding the reprogramming factor OCT3 with a reasonable expectation of success.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 1-19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-6, 8, 11, 13, 16, 23-24, 28-29, 41, 67, 79, 81, 83, and 102-103 of copending Application No. 18/757,460, hereafter referred to as the ‘460 application, in view of Zhang [US20200347100A1, filed 16 March 2020, published 05 November 2020]; Grahn et al. [2001, RNA, 7, 1616-1627]; Prel et al. [2015, Molecular Therapy- Methods and Clinical Development, 2, 15039, 1-15]; Niwa [2018 Development, 145, dev157420, 1-13]; and MacArthur et al. 2012, Stem Cells International, 2012, 564612, 1-9].
The ‘460 application independent claim 1 recites “A composition comprising a nucleic acid composition comprising one or more first polynucleotide(s) encoding an RNA exporter protein; one or more second polynucleotide(s) each encoding one or more cargo RNA molecule(s); one or more third polynucleotide(s) encoding a fusogen; and one or more fourth polynucleotide(s) encoding an export modulator; wherein the RNA exporter protein comprises: an RNA-binding domain, a membrane-binding domain, and an interaction domain capable of nucleating self-assembly, and wherein a plurality of RNA exporter proteins are capable of self-assembling into lipid-enveloped nanoparticles (LNs) secreted from a sender cell in which the RNA exporter proteins are expressed, thereby generating a population of LNs comprising the fusogen and exported cargo RNA molecule(s).” As such, the ‘460 application independent claim 1 recites a species of instant claim 1 wherein all the limitations of the instant claim 1 are recited, along with an additional recitation of an RNA encoding an export modulator.
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The ’460 application dependent claims 3-4, 16, 23-24, 28-29, 41, 67 and independent claims 102 and 103 recite the additional limitations recited in instant claims 2-5, 8-10, 12, 15-16, and 19, including the elected species of a viral fusogenic glycoprotein, instant SEQ ID NO: 10 (‘460 SEQ ID NO: 10 has 100% identity to instant SEQ ID NO: 10):
, and modulating the expression of one or more endogenous proteins of a receiver cell.
The ’460 application claims do not recite wherein the packing signal is an MS2 phage operator stem-loop, the RNA binding domain is an MS2 coat protein, and wherein the payload protein is Oct-3 and the receiver circuit is configured to reprogram a receiver cell type and/or cell state via expression of transcription factors and/or epigenetic modulators.
The ‘460 application claims recite wherein the RNA molecules comprise packing signals which are bound by the RNA binding domain (claim 16), and wherein the RNA binding domain comprises or is derived from an RNA binding protein, which encompass the instantly claimed packing signal and RNA binding protein combination of an MS2 operator stem-loop and an MS2 coat protein.
Additionally, Zhang teaches a nucleic acid composition [0010-0011, 0239] comprising a first polynucleotide encoding an RNA exporter protein, wherein the RNA exporter protein comprises and RNA binding domain (e.g., an MS2 coat protein domain) [0006, 0008, Figure 21], a membrane-binding domain (e.g., an epitope tag for expression on the surface of the export compartment) [0009], and an interaction domain capable of nucleating self-assembly (e.g., an export compartment domain that directs self-assembly of the polypeptide into the export compartment) [0005, 0008-0010, Figure 21, 29]; a second polynucleotide encoding one or more cargo RNA molecules [0006, 0008, Figure 21]; and a third polynucleotide encoding a fusogen (e.g., the glycoprotein of vesicular stomatitis virus (VSVG)) [0058, 0106, 0324-0327, Figure 26, 29A, claim 26].
Grahn teaches that the coat protein of the MS2 phage interacts specifically with a 19 nt RNA hairpin located at the 5’ end of the viral replicase, wherein the RNA hairpin consists of a 7-bp stem closed by a 4 nt loop (e.g., a stem-loop) [column 1 ¶ 1].
Prel teaches the packaging of cargo RNAs into MS2-coat-retrovirus chimeras for better efficiency of delivery to primary cell in vivo, wherein multiple (e.g., 6, 12, or 24) copies of the MS2 stem loop aptamer into the cargo RNAs allowed packaging of significantly more than 2 RNAs per chimeric viral particle and enabled efficient transfer of biologically active RNAs into various cell types [abstract, column 2 ¶ 2, column 15 ¶ 1, Figure 1, 3]. Prel also teaches that an increasing number of MS2 stem loop repeats within the array increased the mobilization efficiency of the particles (e.g., the packaging and delivery of the particles to the target cells) [column 15 ¶ 1- column 16 ¶ 1, Figure 3]. Therefore, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to use an MS2 stem loop aptamer array comprising at least 6, 12, or 24 tandem repeats of the MS2 stem loop aptamer inserted into a cargo RNA to improve packing and delivery efficiency of the cargo RNA.
As such, the ‘460 application claims encompass and render obvious the species of MS2 stem-loop packing signal pair with an MS2 coat protein RNA binding protein for the capture of the cargo RNA for packing and export.
The ‘460 application claims recite wherein the payload protein is a therapeutic protein or variant thereof, and/or wherein the payload protein comprises one or more receptors and/or a targeting moiety configured to bind a component of a target site of a subject (claim 67), which encompasses an Oct-3 payload protein, which Niwa teaches is a transcription factor which binds to pluripotent stem cell-specific target sites in the genome [column 3 ¶ 1].
MacArthur teaches the delivery of RNA encoding OCt3 to reprogram somatic cells (e.g., human fibroblasts) into induced pluripotent stem cells (iPSCs), wherein the generation of iPSCs from somatic cells has enabled the possibility of providing unprecedented access to patient-specific iPSC cells for drug screening, disease modeling, and cell therapy applications [abstract, column 2 ¶ 2, column 6 ¶ 4]. MacArthur also teaches that major obstacles to the use of iPSCs for therapeutic applications are the potential of genomic modifications caused by insertion of viral transgenes in the cellular genome and the requirement to use animal feeder cell layers which hinder the generation of clinical-grade iPSCs [abstract]. MacArthur further teaches that the delivery of RNA encoding Oct3 (e.g., in an RNA Sendai virus vector) allows for both generation of iPSCs without integration of the transgene into the cell’s genome and reprogramming in the absence of feeder cells, thereby facilitating safe downstream applications of iPSC-based cells therapies [abstract]. Therefore, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to deliver an RNA encoding OCT3 to reprogram at least partially differentiated somatic cells (e.g., fibroblasts) into iPSCs to generate clinical grade iPSCs for cell therapy applications. As such, the ‘460 application claims encompass and render obvious the elected species of Oct-3 payload protein for reprogramming receiver cells.
Accordingly, the ‘460 application claims encompass and render obvious claims 1-19 of the instant application.
This is a provisional nonstatutory double patenting rejection.
Claims 1-19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 and 6-20 of copending Application No. 17/820,235, hereafter referred to as the ‘235 application.
The ‘235 application claims recite “a composition comprising
one or more first polynucleotide(s) encoding an RNA exporter protein,
one or more second polynucleotide(s) each encoding one or more reporter RNA molecule(s), and
one or more third polynucleotide(s) encoding an editor and a targeting molecule,
wherein the editor is a base editor capable of base editing a lineage barcode,
wherein said base editing comprises: adenine (A)-to-guanine (G) base editing and/or cytosine (C)- to-thymine (T) base editing,
wherein the RNA exporter protein comprises:
an RNA-binding domain,
a membrane-binding domain, and
an interaction domain capable of nucleating self-assembly, and
wherein a plurality of RNA exporter proteins are capable of self-assembling into lipid-enveloped nanoparticles (LNs) secreted from a reporter cell in which the RNA exporter proteins are expressed, thereby generating a population of LNs comprising exported reporter RNA molecule(s).”
Note that the broadest independent claim (claim 1) of the ‘235 application recites all the limitations of instant independent claim 1. Further, the ‘235 application claim 1 specifically recites a species of the instant application claims in that the cargo RNAs claimed in the ‘235 application (e.g., RNA encoding a base editor and a targeting molecule) are a species of the cargo RNA(s) recited in instant independent claim 1. Further, the species of cargo RNAs encoding a base editor and a targeting molecule are specifically recited in instant dependent claim 16.
Accordingly, the ‘235 claims anticipate, encompass, and render obvious claims 1-19 of the instant application.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claim is allowed.
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DR. KATIE L. PENNINGTON
Examiner
Art Unit 1634
/KATIE L PENNINGTON/Examiner, Art Unit 1634
/MARIA G LEAVITT/ Supervisory Patent Examiner, Art Unit 1634