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 .
Priority
Applicant’s claim to priority from International Application no. PCT/US2021/052315 filed 09/29/2021 and from Provisional Application No. 63/084,027 filed 09/28/2020 is hereby acknowledged.
Election/Restrictions
Applicant’s election without traverse of Invention Group II (claims 38-45) drawn to a method of modifying a target molecule in a cell, and Species Group B (claim 43; RNA) in the reply filed on 04/29/2026 is acknowledged.
Claims 32-37 and 46-51 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 04/29/2026.
Application Status
Claims 1-31 are cancelled. Claims 32-51 are currently pending. Claims 32-37 and 46-51 are withdrawn after election of invention Group II. Therefore, claims 38-45 are considered in this office action.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on 07/21/2023 and 12/19/2024 are hereby acknowledged. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Drawings
The drawings are objected to for the following reasons:
37 CFR 1.84 (u)(1) states “View numbers must be preceded by the abbreviation "FIG."”
In the current case, the view numbers for Figures 1-5 are preceded by the word "Figure" instead of the abbreviation "FIG.", such as FIG. 1A, FIG. 1B, etc.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Interpretation
The following is a quotation of 35 U.S.C. 112(f):
(f) Element in Claim for a Combination. – An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The following is a quotation of pre-AIA 35 U.S.C. 112, sixth paragraph:
An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art. The broadest reasonable interpretation of a claim element (also commonly referred to as a claim limitation) is limited by the description in the specification when 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is invoked.
As explained in MPEP § 2181, subsection I, claim limitations that meet the following three-prong test will be interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph:
(A) the claim limitation uses the term “means” or “step” or a term used as a substitute for “means” that is a generic placeholder (also called a nonce term or a non-structural term having no specific structural meaning) for performing the claimed function;
(B) the term “means” or “step” or the generic placeholder is modified by functional language, typically, but not always linked by the transition word “for” (e.g., “means for”) or another linking word or phrase, such as “configured to” or “so that”; and
(C) the term “means” or “step” or the generic placeholder is not modified by sufficient structure, material, or acts for performing the claimed function.
Use of the word “means” (or “step”) in a claim with functional language creates a rebuttable presumption that the claim limitation is to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites sufficient structure, material, or acts to entirely perform the recited function.
Absence of the word “means” (or “step”) in a claim creates a rebuttable presumption that the claim limitation is not to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is not interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites function without reciting sufficient structure, material or acts to entirely perform the recited function.
Claim limitations in this application that use the word “means” (or “step”) are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action. Conversely, claim limitations in this application that do not use the word “means” (or “step”) are not being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action.
This application includes one or more claim limitations that do not use the word “means,” but are nonetheless being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, because the claim limitation(s) uses a generic placeholder that is coupled with functional language without reciting sufficient structure to perform the recited function and the generic placeholder is not preceded by a structural modifier. Such claim limitation(s) is/are: “wherein the one or more intronic domains comprise one or more RNA-binding protein sites configured to promote tissue-specific splicing patterns” in claim 38.
Because this claim limitation is being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, it is being interpreted to cover the corresponding structure described in the specification as performing the claimed function, and equivalents thereof.
If applicant does not intend to have this/these limitation(s) interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, applicant may: (1) amend the claim limitation(s) to avoid it/them being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph (e.g., by reciting sufficient structure to perform the claimed function); or (2) present a sufficient showing that the claim limitation(s) recite(s) sufficient structure to perform the claimed function so as to avoid it/them being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 38-45 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claim comprises limitations that invoke 35 U.S.C. 112(f), but the specification does not link structure to function. There is no sequence described as being part of the one or more domains, nor a consensus sequence with enumeration in residues. Thus, the specification does not disclose adequate structure to perform the claimed functions.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 38-45 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 38’s limitation " wherein the one or more intronic domains comprise one or
more RNA-binding protein sites configured to promote tissue-specific splicing patterns" invoke 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. However, the written description fails to disclose the corresponding structure, material, or acts for performing the entire claimed function and to clearly link the structure, material, or acts to the function. Therefore, the claim is indefinite and is rejected under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph.
Applicant may:
Amend the claim so that the claim limitation will no longer be
interpreted as a limitation under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph;
Amend the written description of the specification such that it expressly
recites what structure, material, or acts perform the entire claimed function, without introducing any new matter (35 U.S.C. 132(a)); or
Amend the written description of the specification such that it clearly
links the structure, material, or acts disclosed therein to the function recited in the claim, without introducing any new matter (35 U.S.C. 132(a)).
If applicant is of the opinion that the written description of the specification
already implicitly or inherently discloses the corresponding structure, material, or acts and clearly links them to the function so that one of ordinary skill in the art would recognize what structure, material, or acts perform the claimed function, applicant should clarify the record by either:
Amending the written description of the specification such that it
expressly recites the corresponding structure, material, or acts for performing the claimed function and clearly links or associates the structure, material, or acts to the claimed function, without introducing any new matter (35 U.S.C. 132(a)); or
Stating on the record what the corresponding structure, material, or
acts, which are implicitly or inherently set forth in the written description of the specification, perform the claimed function.
For more information, see 37 CFR l.75(d) and MPEP §§ 608.0l(o) and 2181.
Claim 38 is also rejected for reciting the terms: “primarily in a specific tissue or cell type”. It is unclear what is the “specific tissue” or “specific cell type” claimed. The use of the term “primarily” also renders the metes and bounds of the claim indefinite.
Claims 39-45 are dependent upon claim 38, therefore they are rejected as well.
Claims 39-41 and 45 are also 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 39, it recites the terms “preferentially targeted by RNA-binding proteins carrying disease-associated mutations”. It is unclear what would constitute a preferred targeted sequence.
Regarding claims 40 and 41, they recite “ comprises a 3’ untranslated region” or “comprises a 5’ untranslated region” , “that improves the trans-splicing efficiency of the trans-splicing nucleic acid to the target RNA”. It is unclear what the reference is, to compare to and obtain an improvement of the trans-splicing efficiency.
Regarding claim 45, it recites “wherein the therapeutic sequence is not inserted into a target RNA in a second tissue or a second cell type”. It is not clear what constitute a first and a second tissue, or a first and second cell type.
Claim Rejections - 35 USC § 112(a)
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 38-45 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
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 Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
Nature of the Invention:
Claim 38 recites “A method for modifying a target RNA molecule in a cell, the method comprising administering a trans-splicing nucleic acid to the cell, wherein the trans-splicing nucleic acid comprises (a) one or more replacement domains that encode a therapeutic sequence; (b) one or more intronic domains, wherein the one or more intronic domains promote ribonucleic acid (RNA) splicing of the replacement domain primarily in a specific tissue or cell type, and wherein the one or more intronic domains comprise one or more RNA-binding protein sites configured to promote tissue-specific splicing patterns; and ( c) one or more anti sense domains that promote binding to the target RNA molecule.”
It is therefore expected in the instant application a disclosure of a method using an agent or a composition with a mix of agents, that promotes trans-splicing of a target RNA molecule; a specific composition for administering the agent to a subject’s tissue (any tissue), or a cell in vivo or in vitro.
It is expected in the disclosure the “naming” of such agents involved in specific targeting with a specific RNA target, and specific domain and enunciation of specific residues or a generic formula/consensus for such domain. It is expected the naming of a specific therapeutic sequence and its target, as well as the naming of the specific tissue or cell. It is expected an enumeration of specific residue or generic pattern of residues, for the “replacement domains”, “intronic domains”, “RNA-binding protein sites”, and “antisense domains”.
Claim 39 recites “RNA-binding proteins carrying disease-associated mutations”.
Claims 40 and 41 are drawn to 3’ or 5’ untranslated region capable of improving the trans-splicing efficiency.
Claim 42 also recites “ The method of claim 38, further comprising providing an RNA-binding protein that strengthens the interaction among the trans-splicing nucleic acid and the target RNA molecule”.
Claim 45 is drawn to a “therapeutic sequence that is not inserted into a target RNA in a second tissue or a second cell type”.
It is therefore expected to find in the disclosure the description of a specific composition as an example, in a preferred embodiment, including an agent, a nucleic acid agent, having the capability of provoking the trans-splicing of a specific target RNA , and a nucleic acid encoding for the RNA-binding protein, with or without disease-causing mutation, or a composition comprising a specific nucleic acid and a specific RNA-binding protein.
It is expected in this disclosure a reduction to practice with examples of compositions acceptable for the method in cells, or subjects’ samples before and after treatment with examples of agents, with measures of claimed target RNA.
It is expected in the disclosure an example of construct with effective 3’ or 5’ untranslated region, as well as an enunciation in residues or a generic formula.
It is also expected within the disclosure a connection in an example, a reduction to practice, between a specifically targeted tissue and the trans-splicing activity of the claimed nucleic acid molecule, and the amount of therapeutic protein produced. It is expected an example showing the absence of trans-splicing in a non-specifically targeted cell or tissue.
Claim 43 is drawn to a trans-splicing nucleic acid, and recites acceptable alternatives, such as RNA, DNA, DNA/RNA hybrid, nucleic acid analog, a chemically-modified nucleic acid, or a chimera composed of two or more nucleic acids or nucleic acid analogs. It is therefore expected an example and reduction into practice of a DNA molecule capable of inducing trans-splicing, or an RNA, or an hybrid. It is also expected in the disclosure a list of acceptable chemically-modifications and patterns of such modifications, and a specific example of modified nucleic acid molecules.
The State of the Art:
Hong (Hong, E.M. et al. “Therapeutic applications of trans-splicing”. British
Medical Bulletin, Vol. 136 (2020), pp: 4-20) teaches instances where “trans-splicing” was used in Table 1 (page 8). Table 1 summarizes the applications of RNA trans-splicing up to 2020, with references to repairing mutations in cancer and genetic diseases, to inducing cell death in in vitro or in vivo models, to generating therapeutic proteins and molecular imaging (page 9). For gene therapy, repair of mutated proteins using trans-splicing has been performed on p16, p53, CD22, CFTR, Dystrophin, COL7A1, COL17A1, Keratin 14, FVIII, Huntingtin, LMNA genes to name a few.
Doi (Doi, A. et al. “RNA exon editing: splicing the way to treat human diseases”. Molecular Therapy: Nucleic Acids, Vol. 35 (2024); https://doi.org/10.1016/j.omtn.2024.102311.) teaches that advances in synthetic biology, with a deeper understanding of mechanisms controlling RNA splicing have triggered a re-emergence of trans-splicing and the development of new RNA exon editing molecules for treating human diseases (see title and abstract).
Bubenik (Bubenik, J.L. et al. “Therapeutic targeting of RNA for neurological and neuromuscular disease.” Genes & Development, Vol. 38 (2026), pp: 698-717) teaches adaptation of RNA targeting therapeutics to treat neurological and neuromuscular diseases (see title and abstract; Table 1). Bubenik teaches that trans-splicing targeting coding exon for repair is delivered via viral vectors (see Table 1).
Wu (Wu, J. et al. “Engineering targeted gene delivery systems for primary hereditary skeletal myopathies: current strategies and future perspectives.” Biomedicines, Vol. 13 (2025), p: 1994) teaches that it is the innovations in Adeno-associated virus (AAV) vectors such as capsid modification (chemical conjugation, rational design, directed evolution), self-complementary genomes, and tissue-specific promoters, that enhance muscle tropism, while mitigating immunogenicity and off-target effects (see abstract).
Therefore, a nucleic acid molecule targeting muscle tissue or cell, is likely a nucleic acid comprising an AAV or other viral vector, with tissue-specific promoters, independently of the portion of nucleic acid that is targeting the endogenous RNA to be modified/repaired.
Indeed, before the advent of adapted AAV with tissue tropism, Lorain (Lorain, S. et al. “Exon exchange approach to repair Duchenne Dystrophin transcripts”. PLoS ONE, Vol. 5, No. 5 (2010), p: e10894) taught trans-splicing using a plasmid comprising a CMV promoter.
In 2014, just four years later, Koo (Koo, T. et al. “Triple Trans-splicing adeno-associated virus vectors capable of transferring the coding sequence for full-length dystrophin protein into dystrophic mice”. Human Gene Therapy, Vol. 25 (2014), pp: 98-108) taught the use of multiple recombinant AAVs vectors allowing for a higher payload packaging capacity, capable of an efficient widespread transgene expression in skeletal muscle after systemic delivery. Koo also taught a triple-AAV trans-splicing vector system (see abstract).
However, Ke ( Ke, S. et al. “Context-dependent splicing regulation. Exon definition, co-occurring motif pairs and tissue specificity”. RNA Biology, Vol. 8, No. 3 (2011), pp: 384-388) teaches about tissue-specificity resulting from intronic motifs (see title and abstract). Ke teaches that splicing regulation occurs via specific motifs, and is coordinated by trans elements, i.e., splicing factors resulting in tissue-specific alternative splicing (see abstract).
Ke teaches that splicing regulatory elements are often found to act in a context-dependent mode, with combinatorial effects of two or more splicing regulatory elements (see page 385, right column, “Cis-context effect exemplified by co-occurring motifs pairs” section, lines 1-3). For example, the binding of same hnRNPs at the two ends of a long intron can promote splicing by interacting with each other to bring the two splice sites closer together. Motifs co-occurring at intro ends revealed by a computational search were shown to enhance intron removal (see page 386, left column, first paragraph).
Ke teaches that in Trans-context, splicing regulatory factor are key to tissue specificity (page 386, middle column, “Trans-context effect exemplified by splicing regulatory factor tissue specificity” section). For example, the presence of Nova in brain tissue, Fox in muscle and brain triggers tissue-specific alternative splicing (see page 386, right column, lines 1-10).
Indeed, Minovitsky (Minovitsky, S. et al. “The splicing regulatory element, UGCAUG, is phylogenetically and spatially conserved in introns that flank tissue-specific exons” Nucleic Acids Research, Vol. 33, No. 2 (2005), pp: 714-724), teaches that there is a specific motif, UGCAUG, triggering alternative splicing, and that this sequence is phylogenetically and spatially conserved in introns that flank brain-enriched alternative exons from fish to human (see abstract). Minovitsky also teaches that proteins related to Fox1 splicing factor may play a critical role in mediating this specificity (abstract). Minovitsky also teaches that “GGG” triplets are lacking in the proximal downstream intron of brain-enriched pre-mRNA (see page 718, right column, “Deficiency of G-triplets in the proximal downstream intron of brain-enriched datasets” section). Minovitsky concludes stating that a variety of splicing co-factors must cooperate with Fox proteins to activate splicing switches for highly selective groups of exons at the appropriate time and place during development. Such co-factors may include members of the SR and hnRNP families, factors related to NOVA-1 or CUG-binding proteins of the CELF family, or proteins yet to be characterized (see page 722, right column, second paragraph).
Ule (Ule, J. et al. “Nova regulates brain-specific splicing to shape synapse”. Nature Genetics, Vol. 37, No. 8 (2005), pp: 844-852) teaches that Nova is regulating alternative splicing of proteins involved in an interaction module in the synapse (see title, abstract, and “Discussion” section, page 851, left column, “In summary” paragraph).
In summary, it seems that mostly, constructing an expression cassette comprising a tissue-specific promoter to direct tissue-specificity is common practice. However, one with ordinary skills in the art could optimize the gene delivery further by introducing intronic motifs, such as those recognized by Nova when the brain or nerve tissues are targeted. However, the construct may not be the same according to the tissue targeted, the motifs may vary according to trans-splicing factors available. Perhaps further optimization would be overexpressing these tissue-specific trans-splicing factors to ensure the preferential splicing and expression of a therapeutic sequence.
Given the challenges in the art, and the different possibilities, it is even more critical to list all the components and sequences involved. The abstract from Hong states “Areas of controversy: off-target effects can lead to therapeutically undesirable consequences. In vivo efficacy is typically low, and delivery issues remain a challenge”. Hong also states in “Growing points” section, “However, much more research needs to be done before developing towards preclinical studies”. Hong also recognizes that developing research is needed for trans-splicing efficacy and specificity, by rational design, screening, and in view of competitive inhibition of endogenous cis-splicing.
What the Specification does teach:
In the “Summary” section, Applicant states that the “disclosure provides a composition comprising a nucleic acid sequence encoding a trans-splicing RNA molecule comprising (a) at least one domain that promotes trans-splicing in a tissue-restricted manner ("lntronic Domain"), (b) at least one binding domain ("Antisense Domain") that consists of a sequence complementary to a pre-mRNA present in
a human cells ("Target RNA"), and (c) one coding domain that is inserted into the Target RNA via trans-splicing ("Replacement Domain").”
The Specification lists genes known to cause disease in the brain, liver, heart and/or muscle ( see 6-14, pages 2-9 ).
The Specification lists genes that are RNA-binding proteins that promote trans-splicing in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more tissues (see 11, 13, 19, page 8).
The Specification lists genes that can cause disease, for which an antisense domain is complementary (see 6, 8, 10, 14, pages 2-5).
The Specification states existence of 3’ or 5’ untranslated region that increases the stability of trans-splicing generally (see 20 and 21, pages 8-9).
The Specification lists genes comprising intronic domains that promote trans-splicing (see 7, page 2).
The Specification states generally that the intronic domains promote trans-splicing of the trans-splicing nucleic acid in a spatially-restricted manner so that trans-splicing occurs primarily in one tissue selected from the group consisting of: muscle cells, cardiac muscle cells, neurons, kidney cells, liver cells, epithelial cells, striatal tissue, basal ganglia tissue, substantia nigra tissue, lung tissue, spinal cord tissue, cranial nerve tissue, optic nerve tissue, oligodendrocytes, astrocytes, ependymal cells, microglia, airway tissue, inner eye tissue, retinal tissue, cerebellar tissue, pineal gland, thymus gland, pituitary gland, thyroid gland, adrenal gland, apocrine gland, holocrine gland, merocrine gland, serous gland, mucous gland, sebaceous gland, naive T cells, effector T cells, helper T cells, memory T cells, regulatory T cells, gamma-delta T cells, natural killer cells, B cells, dendrocytes and macrophages (see 22, page 9).
The Specification also state generally that in some embodiments, the lntronic Domains broadly promote trans-splicing in many tissues but do not promote trans-splicing in a tissue selected from the following group consisting of: skeletal muscle cells, cardiac muscle cells, neurons, kidney cells, liver cells, epithelial cells, striatal tissue, basal ganglia tissue, substantia nigra tissue, lung tissue, spinal cord tissue, cranial nerve tissue, optic nerve tissue, oligodendrocytes, astrocytes, ependymal cells, microglia, airway tissue, inner eye tissue, retinal tissue, cerebellar tissue, pineal gland, thymus gland, pituitary gland, thyroid gland, adrenal gland, apocrine gland, holocrine gland, merocrine gland, serous gland, mucous gland, sebaceous gland, naive T cells, effector T cells, helper T cells, memory T cells, regulatory T cells, gamma-delta T cells, natural killer cells, B cells, dendrocytes and macrophages. In some embodiments, the lntronic Domains do not promote trans-splicing in 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or more tissues but promote trans-splicing in other cell types or tissues.
The Specification gives a list of vectors that can be used (see 29-30, 36, and 1286-1287; pages 11, 14 and 459) and a list of non-viral gene delivery systems (see 31 and 1289-1294; pages 11 and 461), also a list of regulatory elements, i.e., promoters to choose from (33 and 1295, pages 12 and 461).
The Specification lists sequences of genes with SEQ ID NOs from 1 to 492 to be used as alternative choices/possibilities of intronic domains in a nucleic acid for trans-splicing targeting the brain. This represents a list of 492 different genes sequences, that seems to be obtained from a brain tissue library.
SEQ ID NOs 493 to 798 are alternative sequences for intronic domains in a nucleic acid for trans-splicing targeting the liver. This is a list of 305 genes and therefore 305 possibilities.
SEQ ID NOs 799 to 1104 are alternative sequences for intronic domains in a nucleic acid for trans-splicing targeting the heart. This is a list of 305 genes with as many possibilities.
SEQ ID NOs 1105 to 1220 are alternative sequences for intronic domains in a nucleic acid for trans-splicing targeting the muscle. This is a list of 115 genes, and 115 possibilities.
The Specification lists replacement domains from a long list of genes associated with diseases, and states “Compositions comprising replacement domains disclosed herein include any strategies where replacement or insertion of RNA sequences could be an effective therapy” (see 1278, pages 457-458). The disclosure also teaches that the replacement domain can comprise a non-human viral sequences that increases protein production (see 1280, page 458).
The Specification teaches generically about antisense domains, being complementary to a pathogenic RNA molecule that is the target of trans-splicing (see 1281-1284; pages 458-459).
Finally, the Specification teaches a list of diseases that could be treated with the method of trans-splicing (see 1317-1329; pages 466-474). The example embodiments are a list of genes for which the sequences, intronic domain, replacement domain and antisense domain, could be used (see page 476-483). Examples (pages 483-485) are summarized by Drawings that are illustrations of signal pathways and possible constructs to design, and mostly teach general concepts (see pages 15-16).
- What the Specification does not teach:
The Specification does not describe a specific construct comprising a single intronic sequence, a single replacement sequence and an antisense sequence from specific genes together. There is no data with one construct targeting one gene in one tissue. There is no evidence that the intronic sequence/domain would work when combined with a specific gene in a specific construct comprising a vector, a regulatory elements, a 3’ end region and a 5’ end region and a specific antisense sequence and replacement sequence; and there is no evidence that such construct will not work in a specific tissue that is not targeted for gene delivery.
Basically, Applicant is giving a list of alternatives and possibilities, and more or less, invites one with ordinary skills in the art, to go and try make them work.
Conclusion:
There is a complete lack of written description for the claimed nucleic acid.
Taking into consideration the factors outlined above, including the nature of the
invention, the state of the art, the guidance provided by the applicant and the specific example, it is the conclusion that Applicant does not possess the invention. There is no specific written example within the Specification that would lead one with ordinary skills in the art to a different conclusion.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim 38, 40-41 and 43-45 are rejected under 35 §U.S.C. 103 as being unpatentable over Shababi (Shababi, M. et al. “Optimization of SMN Trans-splicing through the analysis of SMN introns”. Journal of Molecular Neuroscience, Vol 46 (2012), pp: 459-469), in view of Garcia (Garcia, L. et al. WO 2011/042556 A1; published April 14, 2011; cited on IDS filed 12/19/2024), Modafferi (Modafferi, E.F. et al. “A complex intronic splicing enhancer from the c-src pre-mRNA activates inclusion of a heterologous exon”. Molecular and Cellular Biology, Vol. 17, No. 11 (1997), pp: 6537-6545) and Minovitsky (Minovitsky, S. et al. “The splicing regulatory element, UGCAUG, is phylogenetically and spatially conserved in introns that flank tissue-specific alternative exons”. Nucleic Acids Research, Vol. 33, No. 2 (2005), pp: 714-724).
Regarding claim 38, Shababi teaches a method for modifying a target RNA molecule in a cell, the method comprising administering a trans-splicing nucleic acid to the cell (see title and abstract).
Shababi teaches optimizing the trans-splicing of SMN pre-mNA to increase full-length protein, since SMN2 generates a transcript lacking exon 7 that gives rise to an unstable truncated SMN protein unable to rescue the loss of SMN1 responsible for Spinal muscular atrophy (SMA) (abstract).
Shababi teaches using SMN1 exon 7 as a replacement , i.e., “replacement domain” in SMN2 pre-mRNA (see abstract). Shababi teaches that all introns within SMN2 pre-mRNA except for intron 1 are tractable introns and replacing exons 2b-7 is achievable in this type of cellular model (see page 462, right column, first paragraph, and Figure 1). Therefore, Shababi teaches more than one “replacement domains” to encode a therapeutical sequence.
Shababi teaches that adding an antisense to Int3 trans-splicing RNA improves the efficacy of Trans-splicing (see page 464, left column, “Addition of an antisense to Int3 tsRNA improves the efficacy of Trans-splicing” section).
Shababi also teaches that adding one more antisense to intronic sequence int4, int411 , to the construct enhances trans-splicing efficiency of Int3 construct (see Figure 5a and 5c; page 464, right column, lines 29-32 and page 465, right column, first paragraph). Shababi teaches that blocking endogenous cis-splicing increases the efficiency of trans-splicing via blocking the cis-splicing sites using antisense sequences (see page 468, left column, second paragraph).
Shababi teaches one or more introns as binding domains/antisense domains and a 3’UTR (see Figures 1 and 5); see Figure 5a below:
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Shababi states “the intron (int)3 construct is capable of increasing the level of SMN protein in disease-relevant tissue such as the brain and spinal cord following intracerebroventricular (ICV) injection of plasmid DNA into SMNΔ7 mice. Collectively, these results demonstrate that trans-splicing can be optimized by examining various intron-exon junctures and that optimization can lead to efficient trans-splicing in vivo.”(page 460, right column, second paragraph’s last 8 lines).
However, Shababi does not teach whether the intronic domains comprise one or more RNA-binding protein sites configured to promote tissue-specific splicing patterns.
However, Garcia teaches a neuromuscular disorder Duchenne Muscular Dystrophy, for which pre-trans-splicing molecules (PTMs) are designed targeting the DMD (dystrophin) pre-mRNA (see title and abstract; see page 1, lines 1-17).
Garcia teaches the use of intronic splice enhancer sequences on exon replacement efficiency (see page 6, lines 5-14). Garcia teaches the G-rich intronic splice enhancer from the human GH-1 gene and/or the DISE (downstream intronic splice enhancer) sequence from rat FGFR2 gene can be used as splicing enhancers (see page 13, lines 17-22).
Garcia teaches that specific intronic splicing enhancers can be designed upstream and downstream of the exon(s) sequences for replacement (see page 31, lines 18-31; “Optimization of ExChange efficacy by adding up intronic splice enhancers” section).
Modafferi teaches that an intronic splicing enhancer from the c-src pre-mRNA activates inclusion of a heterologous exon (see title and abstract).
Modafferi teaches that the intronic splicing enhancer is made of multiple smaller elements that must act in combination, and one of these elements is identified as the sequence UGCAUG (see abstract). Constructing minigene cassettes for splicing assays and performing site-directed mutagenesis, Modafferi teaches heterologous exon inclusion. And using constructs including 3 copies of UGCAUG sequence, Modafferi teaches a more effective in neuronal LA-N-5 cells (see Figure 6, clone 4-108), therefore, Modafferi teaches including synthetic intronic enhancer sequences to induce tissue-specific splicing, in this case, neuronal cell-specificity, of heterologous exons .
Minovitsky teaches that the sequence UGCAUG is phylogenetically and spatially conserved in introns that flank tissue-specific alternative exons (see title and abstract). Minovitsky teaches that this sequence is present in introns that flank brain-enriched alternative exons from fish to human (see abstract).
Minovitsky teaches that this sequence UGCAUG is preferably preceded by a pyrimidine nucleotide (see page 717, right column, lines 7-11). Minovitsky teaches that zebrafish Fox-1 preferably binds to a pentamer GCAUG, and thus, the hexamer UGCAUG is likely to be bound with Fox proteins that cooperate with splicing co-factors such as the SR and hnRNP families, factors related to NOVA-1 or CUG-binding protein of the CELF family, i.e., RNA-binding proteins (see page 722, right column, second paragraph’s last 13 lines).
Therefore, it would have been obvious to one with ordinary skills in the art, before the effective filing date of the claimed invention, to have modified the pre-trans-splicing molecule ( PTM) taught by Shababi, and included one or more intronic enhancer sequences within the PTM, upstream and downstream of an exon or replacement sequence, as taught by Garcia and Modafferi. One with ordinary skills in the art motivated in obtaining a tissue-specific splicing of the PTM, and especially in nerve tissue, could have performed this modification using a intronic enhancer sequence, i.e., an intronic domain, comprising three UGCAUG sequence as taught by Modafferi and Minovitsky, with a reasonable expectation of success, and would arrived at the claimed invention.
Regarding claims 40 and 41, Shababi teaches a 3’UTR sequence and a 5’ UTR composed of a polypyrimidine tract, a branch point and a 3’ splice site that is recognized by the spliceosome complex and mediates the splicing reaction (see page 460, left paragraph, third paragraph).
Garcia teaches that specific intronic splicing enhancers can be designed upstream and downstream of the exon(s) sequences for replacement (see page 31, lines 18-31; “Optimization of ExChange efficacy by adding up intronic splice enhancers” section; see Figure 3). Garcia teaches that the replacing exon/domain is flanked by artificial intronic sequences with a strong acceptor and donor splice sites (i.e., untranslated regions) (see page 28, lines 12-19). Garcia also teaches the artificial intron includes a spacer sequence, a strong conserved yeast branch point sequence, a polypyrimidine tract, and a canonical 3’ acceptor splice site, as does Shababi (see page 28, lines 28-31). The obviousness of the combination of references is described above.
Regarding claim 43, Shababi teaches that the trans-splicing nucleic acid comprises RNA (see figure 1). The obviousness of the combination of references is described above.
Regarding claim 44, Shababi teaches inserting the therapeutic sequence into the target RNA, i.e., a functional SMN2 exon 7 (see Abstract and Figure 1). The obviousness of the combination of references is described above.
Regarding claim 45, Modafferi teaches that inserting a triple UGCAUG element into the PTM (clone 4-108) induces 48.6+/- 4.2 % exon inclusion in neuronal cells, while the percentage of exon inclusion within HEK293 cells, i.e., non-neuronal cells, is 2.5 +/- 1.8%. There is an improvement in splicing efficiency that is tissue-specific in one type of cells, over the second type of cells.
Therefore, it would be obvious to one with ordinary skills in the art, before the effective filing date of the claimed invention, to have modified the PTM construct according to Shababi modified by Modafferi, and optimized the construct further, adding more elements and other tissue-specific regulatory elements. One with ordinary skills in the art, motivated in obtaining stringent tissue specificity could have performed this modification with a reasonable expectation of success, in view of the references Shababi, Garcia, Modafferi and Minovitsky, and would arrived at the claimed invention.
Claim 42 is rejected under 35 §U.S.C. 103 as being unpatentable over Shababi (Shababi, M. et al. “Optimization of SMN Trans-splicing through the analysis of SMN introns”. Journal of Molecular Neuroscience, Vol 46 (2012), pp: 459-469), in view of Garcia (Garcia, L. et al. WO 2011/042556 A1; published April 14, 2011; cited on IDS filed 12/19/2024), Modafferi (Modafferi, E.F. et al. “A complex intronic splicing enhancer from the c-src pre-mRNA activates inclusion of a heterologous exon”. Molecular and Cellular Biology, Vol. 17, No. 11 (1997), pp: 6537-6545) and Minovitsky (Minovitsky, S. et al. “The splicing regulatory element, UGCAUG, is phylogenetically and spatially conserved in introns that flank tissue-specific alternative exons”. Nucleic Acids Research, Vol. 33, No. 2 (2005), pp: 714-724), as applied to claim 38 above, and in further view of Zhang (Zhang, C. et al. “Defining the regulatory network of the tissue-specific splicing factors Fox-1 and Fox-2”. Genes & Development, Vol. 22 (2008), pp: 2550-2563) and Auweter (Auweter, S.D. et al. “Molecular basis of RNA recognition by the human alternative splicing factor Fox-1”. The EMBO Journal, Vol. 25 (2006), pp: 163-173).
The rejection of claim 38 is described above. The combination of references Shababi, Garcia, Modafferi, and Minovitsky renders elements of claim 38 obvious.
However, the combination of references does not render obvious the fact that the intronic domains comprise one or more sequences that are preferentially targeted by RNA-binding proteins carrying disease-associated mutations.
Regarding claim 42, Zhang teaches that splicing factors Fox-1 and Fox-2 binds to RNA elements UGCAUG (see abstract), and are exclusively or preferentially expressed in the brain, heart, and skeletal muscle. Zhang further teaches that mutation or abnormal expression of Fox-1 has been found in patients with several genetic diseases, including epilepsy, mental retardation, autism and heart disease (see page 2551, left column, lines 52-58).
Zhang teaches overexpression of Fox-1/2 in cells that upregulates the splicing of target mRNA and increases the exon inclusion in cassette with conserved downstream intronic sites in Hela cells (see Figure 4, and page 2555, left column, second paragraph).
Auweter teaches the structure of Fox-1 RNA binding domain (RBD) in complex with UGCAUGU element, and shows an unusual molecular mechanism of sequence-specific RNA recognition by Fox-1, with an exceptional high affinity for the defined but short sequence element (see abstract).
Therefore, according to the teachings of Zhang and Auweter, the RNA-binding protein Fox-1 can bind with high affinity and when overexpressed, efficiently include targeted sequence/exon flanked with the targeted element UGCAUGU in a cassette.
It would have been obvious to one with ordinary skills in the art, before the effective filing date of the claimed invention, to have modified the composition in the method of trans-splicing taught by Shababi, Garcia, Modafferi, and Minovitsky, and added an expression cassette to overexpress Fox-1/2 proteins as taught by Zhang. One with ordinary skills in the art, motivated in increasing the efficiency of the method of trans-splicing taught by Shababi modified by Garcia, Modafferi, and Minovitsky, could have performed this modification to the composition comprising a trans-splicing nucleic acid and added a nucleic acid encoding for Fox-1/2 with a reasonable expectation of success, as taught by Zhang, and expect a strengthening of RNA binding, as taught by Auweter and an increase in trans-splicing efficiency after overexpression as taught by Zhang. One with ordinary skills in the art could have performed these modifications before the effective filing date and arrived at the claimed invention.
Double Patenting
The non-statutory 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 non-statutory 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 non-statutory 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 non-statutory 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.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim 38 is provisionally rejected on the ground of non-statutory double patenting as being unpatentable over claims 1 and 19 of co-pending Application No. 18/485,535 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because:
Regarding claim 38, co-pending app.’535 ‘s claim 19 is drawn to “A method for treating a disease comprising administering to a patient in need of a therapeutically effective amount of the composition according to claim 1”.
Claim 1 of co-pending app.’535 is drawn to “A composition comprising a trans-splicing nucleic acid, comprising:(a) one or more replacement domains that encode a therapeutic sequence operably linked to; (b) one or more intronic domains that promote RNA splicing of the one or more replacement domains, wherein the one or more intronic domains each comprises a trans-splicing enhancer sequence; and (c) one or more antisense domains that promote binding to a target RNA molecule.
This is a provisional non-statutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claim is allowed.
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/A.D./Examiner, Art Unit 1636
/NANCY J LEITH/Primary Examiner, Art Unit 1636
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