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 PCT/US2021/049889 filed 09/10/2021 and Provisional Applications 63/230,381 filed 08/06/2021, 63/214,747 filed 06/24/2021 and 63/077,141 filed 09/11/2020 is hereby acknowledged.
Election/Restrictions
Applicant’s election without traverse of Invention Group I (Claims 1-4, 17-18, 23-26, 34-36, 43-44, 47-49 and 51-54), drawn to a delivery vehicle, a composition, and a pharmaceutical composition, for inhibiting expression of a gene expressed in skeletal muscle cells comprising an RNAi agent, a targeting ligand and a PK/PD modulator, in the reply filed on 01/27/2026 is acknowledged.
Applicant’s election of Species (as described below) in the reply filed on 01/27/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Election of Species was made as follow:
In Species Group A: (claims 4 and 17-18) a targeting ligand with L-arginine optionally having N-terminal cap that is with a general formula 1 (claim 17):
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In Species Group B: (claims 23-26, 34-36, 43-44, and 47) a PK/PD modulator is
with a Formula (Ic), wherein at least one of X or Y is Lipid 3 and
LP29b.
Claims 18, 25, 34-35, 55-56 and 66 are withdrawn from further consideration
pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Species and Invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 01/27/2026.
Application Status
This Application is a CON of PCT/US2021/049889 filed 09/10/2021.
Amendments to claims filed 01/27/2026 are hereby acknowledged.
Claims 1, 25, 47 and 56 are currently amended.
Claims 5-16, 19-22, 27-33, 37-42, 45-46, 50 and 57-65 are cancelled.
Claim 67 is newly added. Therefore, claims 1-4, 17-18, 23-26, 34-36, 43-44, 47-49, 51-56 and 66-67 are pending.
Claims 18, 25, 34-35, 55-56 and 66 are withdrawn.
Therefore, claims 1-4, 17, 23-24, 26, 36, 43-44, 47-49, 51-54 and 67 are under consideration in this office action.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on 11/06/2024 (2) and 01/27/2026 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 filed 03/03/2023 are hereby acknowledged and are acceptable.
Claim Objections
Claim 1 is objected to because of the following informalities: A semi-colon is missing after the terms “skeletal muscle cells” in the limitation (i). Appropriate correction is required.
Claim 4 is objected to because of sequence non-compliance, claiming a sequence that has at least 4 identifiable amino acids without providing a sequence ID number in the Specification.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - Sequences appearing in the specification are not identified by sequence identifiers (i.e., “SEQ ID NO:X” or the like) (see claim 4 and [0083]) in accordance with 37 CFR 1.831(c).
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. §112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. §112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-4, 17, 23-24, 26, 36, 43-44, 47-49, 51-54 and 67 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 1 recites “A delivery vehicle for inhibiting expression of a gene expressed
In skeletal muscle cells comprising:
(a) an RNAi agent comprising:
(i) an antisense strand comprising 17-49 nucleotides wherein at least 15
nucleotides are complementary to the mRNA sequence of a gene that is expressed in
skeletal muscle cells
(ii) a sense strand that is 16-49 nucleotides in length that is at least
Partially complementary to the antisense strand;
(b) a targeting ligand with affinity for a receptor present on the surface of a
Skeletal muscle cell, wherein the targeting ligand is a polypeptide; and
( c) a PK/PD modulator;
wherein the RNAi agent is linked to the targeting ligand and to the PK/PD modulator
via a linker.”
It is therefore expected in the instant application a disclosure of different types of genes, genes involved in different signal pathways, involved in the biology of a skeletal muscle cell, since there is no specificity claimed.
It is also expected in the disclosure, a reduction into practice involving different types of RNA interference agents, i.e., DNA molecules or RNA molecules such as microRNA, shRNA, siRNA, dsRNA, ribozymes and gapmers.
It is expected in the disclosure, a reduction into practice of different types of targeting ligands and their receptors, e.g., polypeptides from hormones and their receptors, polypeptides from antibodies and their targeted proteins, small molecules ligands and their receptors/sensors.
It is also expected that any gene expressed in a skeletal muscle cells using the claimed delivery vehicle, comprising any nucleic acid comprising 17-49 nucleotides on the antisense strand and 16-49 nucleotides on the sense strand, and linked via a linker to a targeting ligand with affinity for a receptor present on the cell surface and a PK/PD modulator, can be inhibited as claimed.
The State of the Art:
Regarding the genes
Kouadjo (Kouadjo, K.E. et al.” Housekeeping and tissue-specific genes in mouse tissues”, Vol. 8 (2007), p:127) teaches that house-keeping genes are also expressed in the skeletal muscle cell (see Table 1). Kouadjo also shows that some transcripts are exclusive to the skin, liver, adipose tissue, lung, bone and skeletal muscle (see Table 4).
Therefore, a house-keeping gene can be expressed and be necessary for a skeletal muscle cell physiology.
Sebastian (Sebastian, S. et al. “Tissue-specific splicing of a ubiquitously expressed transcription factor is essential for muscle differentiation”. Genes & Development, Vol. 27 (2013), pp: 1247-1259) teaches that some ubiquitously expressed genes, such as Mef2D can produce splicing isoforms that are tissue-specific and have tissue-specific function (see title and abstract).
Therefore, some genes that are not tissue-specific, can produce a tissue-specific isoform necessary in a skeletal muscle physiology.
Coulon (Coulon, V. et al. “A muscle-specific promoter directs Pitx3 gene expression in skeletal muscle cells”. The Journal of Biological Chemistry, Vol. 282, No. 45 (2007), pp: 33192-33200) teaches that ubiquitously expressed genes, such as Pitx3 can be differentially regulated depending on its promoter (see title).
Therefore, some genes are ubiquitous, but their tissue-specific expression is conferred by a specific promoter/regulatory region.
Regarding the targeting ligands and receptors
Azhar (Azhar, M. et al. “Cellular Receptors and Cell signaling”. Cell Signaling, 1st Edition. CRC Press (2025), pp: 46-63) reviews the different types of receptors, and specifically receptors at the cell surface involved in different signaling pathways (see Figure 3.1, page 56). Azhar teaches that there are at least five broad signaling pathways: JAK/STAT pathway, cAMP pathway, Ras/raf/MAPK pathway, Pi3k/Akt pathway and PLC pathway (see Figure 3.1). Azhar reviews the different receptors and their ligands involved with specific pathways, with their associated diseases and treatment strategies (see Table 3.1, page 59).
Therefore, there is a large amount of receptors and ligands that are encompassed in the claimed limitations in claim 1.
What the Specification does and does not teach:
The disclosure teaches chemical structures for targeting ligands and especially [Symbol font/0x61]vβ6 integrin receptor peptides linked to a pharmacokinetic and/or pharmacodynamic modulators such as polyethylene glycol (see [0100]).
The disclosure is not focused on siRNAs, shRNAs, gapmers, nor ribozymes.
The disclosure does not teach many examples of genes expressed in a skeletal muscle cells.
The first mention of a specific nucleic acid is in Example 7 (see [0794]) and siRNA against MSTN are mentioned in Tables 25-25, 31-67, 69 and 71-73. The disclosure seems to be focused on MSTN (myostatin), while claiming any gene expressed in a skeletal muscle cell.
The disclosure is also focused on peptide targeting the [Symbol font/0x61]vβ6 integrin receptor, not any other type of cell surface receptor.
Conclusion:
As far as the cell surface receptor is concerned, claims 2 and 3 remedy the
deficiency of claim 1. However, as far as the genes and signal pathways representatives are concerned, claims 2 and 3 do not remedy the Written Description’s deficiencies of claim 1. Claims 4, 17, 23-24, 26, 36, 43-44, 47-49, 51-54 and 67 do not remedy any of the deficiencies of claim 1 under the Written Description’s rejection as well.
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 as broadly claimed. There is no specific written example within the Specification that would lead one with ordinary skills in the art to a different conclusion.
Therefore, claims 1-4, 17, 23-24, 26, 36, 43-44, 47-49, 51-54 and 67 are rejected.
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.
Claims 1, 23-24, 48, 51-54 and 67 are rejected under 35 U.S.C. §102(a)(2) as being anticipated by Subramanian (Subramanian, R.R. et al. US 11,911,484 B2 dated February 27, 2024, benefitting from priority of PCT/US2019/044987 filed August 2, 2019 and of Provisional Applications Nos. 62/859,672 filed June 10, 2019, 62/858,888 filed June 7, 2019, 62/855,761 filed May 31, 2019, 62/779,161 filed December 13, 2018, and 62/713,914 filed August 2, 2018).
Claim 1 recites “A delivery vehicle for inhibiting expression of a gene expressed
In skeletal muscle cells comprising:
(a) an RNAi agent comprising:
(i) an antisense strand comprising 17-49 nucleotides wherein at least 15
nucleotides are complementary to the mRNA sequence of a gene that is expressed in
skeletal muscle cells
(ii) a sense strand that is 16-49 nucleotides in length that is at least
Partially complementary to the antisense strand;
(b) a targeting ligand with affinity for a receptor present on the surface of a
Skeletal muscle cell, wherein the targeting ligand is a polypeptide; and
( c) a PK/PD modulator;
wherein the RNAi agent is linked to the targeting ligand and to the PK/PD modulator
via a linker.”
Regarding claim 1, Subramanian teaches muscle-targeting complexes, i.e., delivery vehicles, for treating myotonic dystrophy (see title). Subramanian teaches that these complexes comprise a muscle-targeting agent covalently linked to a molecular payload, said muscle-targeting agent being capable of binding to an internalizing cell surface receptor on muscle cells, and said molecular payload that is an oligonucleotide or an antisense or RNAi oligonucleotide, capable of inhibiting expression or activity of a DMPK (Myotonic Dystrophy Protein Kinase ; column 10, lines 56-59) allele comprising a disease-associated-repeat (see abstract).
Subramanian teaches that the oligonucleotide can hybridize to a DMPK mRNA transcript , i.e., is complementary to the DMPK mRNA (see column 3, lines 31-46). Subramanian teaches that the oligonucleotide can be 15, 16, 17 or 18 nucleotides in length and comprises a region of complementarity that is fully complementary, along a length of at least 14 contiguous nucleotides to a coding region of a DMPK sequence (see column 295, claim 1), meaning that 14 nucleotides is the minimum.
Subramanian teaches that the oligonucleotide is a double-stranded oligonucleotide of 19 to 25 nucleotides in length (see column 4, lines 8-12). Subramanian also teaches that the overall length of the siRNA molecules can vary from about 14 to about 100 nucleotides depending on the type of siRNA molecule being designed. Generally about 14 and about 50 of these nucleotides are complementary to the RNA target sequences (see columns 56 (lines 66-67) and 57 (lines 1-4).
Subramanian teaches that the targeting agent comprises a polypeptide that is an antibody , or chimeric antibody, in the form of a ScFv, Fab fragment, Fab’ fragment, F(ab’)2 fragment, or Fv fragment (see column 3, lines 3-9).
Subramanian teaches that the cell surface receptor is a transferrin receptor (see column 3, lines 1-3).
Subramanian teaches that the muscle-targeting agent can comprise linkers composed of repeating units of polyethylene glycol (PEG) (see column 57, lines 49-56; column 65, lines 8-16; column 66, lines 9-15; column 296, claim 6). Subramanian teaches one or more PEG units (see column 296, claim 6).
In instant Application, a PK/PD modulator is described as comprising at least one polyethylene glycol (PEG) unit in some embodiments; in other embodiments, it comprises at least 10 PEG units (see [0022]).
Therefore, a linker that comprises repeating units of PEG is also a PK/PD modulator. Subramanian teaches a PK/PD modulator.
Regarding claim 2, Subramanian teaches that the antibody can be targeted against, and specifically bind an integrin receptor, e.g., integrin alpha 7 beta 1 and CD29 (see column 37, lines 50-67).
Regarding claims 23 and 24, Subramanian teaches one or more PEG units (see column 296, claim 6).
Regarding claim 48, Subramanian teaches a muscle-targeting complex, i.e., a delivery vehicle and an RNAi agent inhibiting expression of the mRNA of a human gene in a skeletal muscle cell (see title and abstract; see column 5, lines 14-16).
Regarding claim 51, Subramanian teaches a composition comprising the muscle-targeting complex, i.e., the delivery vehicle (see column 74, lines 5-14, lines 46-64).
Regarding claim 52, Subramanian teaches a pharmaceutical composition comprising the composition and a pharmaceutical excipient (see column 73, lines 30-49; column 75, lines 1-12).
Regarding claims 53 and 54, Subramanian teaches a pharmaceutical composition wherein the excipient is “Water-for-Injection” or a saline solution (see column 75, lines 1-12).
Regarding claim 67, Subramanian teaches that the oligonucleotide comprises at least one nucleotide modified at the 2’ position of the sugar; in some embodiments RNA modifications include abasic residues or an inverted base at the 3’ end of the RNA ( see column 52, lines 32-38).
As the statement is generic, Examiner interprets this modification as possible as a combination and on either the sense strand or antisense strand of a double-stranded oligonucleotide.
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 non-obviousness.
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.
Claims 3-4, 17, 26, 36, 43-44, 47 and 49 are rejected under 35 U.S.C. §103 as being unpatentable over Subramanian (Subramanian, R.R. et al. US 11,911,484 B2 dated February 27, 2024, benefitting from priority of PCT/US2019/044987 filed August 2, 2019 and of Provisional Applications Nos. 62/859,672 filed June 10, 2019, 62/858,888 filed June 7, 2019, 62/855,761 filed May 31, 2019, 62/779,161 filed December 13, 2018, and 62/713,914 filed August 2, 2018), as applied to claim 1 above and in further view of Ducceschi (Ducceschi, M. et al. “Post-transcriptional regulation of ITGB6 protein levels in damaged skeletal muscle” Journal of Molecular Histology, Vol. 45 (2014), pp: 329-336), Liu (Liu, H. et al. “Molecular imaging of integrin [Symbol font/0x61]vβ6 expression in living subjects”. Am. J. Nucl. Med. Mol. Imaging., Vol. 4, No. 4 (2014), pp: 333-345), Almeida (Almeida, A. et al. WO 2018/085415 A1, published May 11, 2018) and Li (Li, Z. et al. WO 2020/146521 A2 published July 16, 2020, benefitting from priority from US Provisional Applications Nos: 62/790,360 filed January 9, 2019, 62/827,564 filed April 01, 2019 and 62/839,381 filed April 26, 2019).
It is noted that claim 1 is anticipated by Subramanian.
Indeed, regarding claim 1, Subramanian teaches muscle-targeting complexes, i.e., delivery vehicles, for treating myotonic dystrophy (see title). Subramanian teaches that these complexes comprise a muscle-targeting agent covalently linked to a molecular payload, said muscle-targeting agent being capable of binding to an internalizing cell surface receptor on muscle cells, and said molecular payload that is an oligonucleotide or an antisense or RNAi oligonucleotide, capable of inhibiting expression or activity of a DMPK (Myotonic Dystrophy Protein Kinase ; column 10, lines 56-59) allele comprising a disease-associated-repeat (see abstract).
Subramanian teaches that the oligonucleotide can hybridize to a DMPK mRNA transcript , i.e., is complementary to the DMPK mRNA (see column 3, lines 31-46). Subramanian teaches that the oligonucleotide can be 15, 16, 17 or 18 nucleotides in length and comprises a region of complementarity that is fully complementary, along a length of at least 14 contiguous nucleotides to a coding region of a DMPK sequence (see column 295, claim 1), meaning that 14 nucleotides is the minimum.
Subramanian teaches that the oligonucleotide is a double-stranded oligonucleotide of 19 to 25 nucleotides in length (see column 4, lines 8-12). Subramanian also teaches that the overall length of the siRNA molecules can vary from about 14 to about 100 nucleotides depending on the type of siRNA molecule being designed. Generally about 14 and about 50 of these nucleotides are complementary to the RNA target sequences (see columns 56 (lines 66-67) and 57 (lines 1-4).
Subramanian teaches that the targeting agent comprises a polypeptide that is an antibody , or chimeric antibody, in the form of a ScFv, Fab fragment, Fab’ fragment, F(ab’)2 fragment, or Fv fragment (see column 3, lines 3-9).
Subramanian teaches that the cell surface receptor is a transferrin receptor (see column 3, lines 1-3).
Subramanian teaches that the muscle-targeting agent can comprise linkers composed of repeating units of polyethylene glycol (PEG) (see column 57, lines 49-56; column 65, lines 8-16; column 66, lines 9-15; column 296, claim 6). Subramanian teaches one or more PEG units (see column 296, claim 6).
In instant Application, a PK/PD modulator is described as comprising at least one polyethylene glycol (PEG) unit in some embodiments; in other embodiments, it comprises at least 10 PEG units (see [0022]).
Therefore, a linker that comprises repeating units of PEG is also a PK/PD modulator. Subramanian teaches a PK/PD modulator.
However, Subramanian does not teach a targeting ligand that has affinity for an [Symbol font/0x61]vβ6 integrin receptor (claim 3), nor a targeting ligand that is a polypeptide with the formula (P): Xaa1G’DLXaa2Xaa3L-Xaa4Xaa5L--
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25
14
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, wherein Xaa1 is L-arginine, and wherein “
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25
14
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“ indicates a point of connection to the RNAi agent (claim 4).
Although Subramanian does not teach the elements from claims 3 and 4, Ducceschi teaches that Integrin beta 6 (ITGB6) protein level is upregulated in damaged skeletal muscle (see title). Ducceschi teaches that the [Symbol font/0x61]Vβ6 integrin has been considered as an epithelia restricted integrin receptor, as it has only been found on the surface of particular epithelial cells (see page 330, left column, second paragraph).
Ducceschi also teaches that the ITGB6 receptor mRNA is expressed in skeletal muscle, however its protein is not detected until after injury to the muscle (see page 330, left column, third paragraph; see pages 334-335, Figure 4).
Ducceschi teaches increase of ITGB6 expression in muscles of Dystrophin mutant mdx mouse, a genetic model of Duchenne Muscular Dystrophy, in which the muscle tissue is subject to continuous rounds of injury and repair due to the loss of Dystrophin and the resulting susceptibility of the muscle to mechanical damage (see Figure 5).
Therefore, Ducceschi’s teachings suggest that ITGB6 protein is expressed only in pathological conditions and in regenerative processes (see Figures 4 and 5). This suggests that ITGB6 is suitable as a marker or a target for cell specificity and pathological condition specificity.
Liu teaches the use of [Symbol font/0x61]Vβ6 integrin as a tool, a target, for molecular imaging in living subjects (see title). Liu teaches that 8 out of 24 integrins recognize native ligands through the Arg-Gly-Asp (RGD) triple peptide motif (see page 333, right column, lines 9-14). Liu also teaches that [Symbol font/0x61]Vβ6 integrin is a subtype that is exclusively expressed on epithelial cells, combining the β6 subunit with the [Symbol font/0x61]V to generate a single heterodimer, and that this subtype is usually expressed at low undetectable levels in normal adult tissues but can be highly upregulated during pathological and physiological processes such as wound healing, fibrosis, inflammation and cancer (page 334, last paragraph of left column and first paragraph of right column). Liu further teaches that [Symbol font/0x61]Vβ6 integrin has become a promising target for disease diagnosis and therapy (same page and paragraphs).
Liu also teaches that several [Symbol font/0x61]Vβ6 integrin-targeting peptides have been developed such as A20FMDV2 (NAVPNLRGDLQVLAQ-KVART). Liu further teaches that the motif RGDLXXL (X indicates a nonspecific amino acid sequence) has been found to be a key motif for [Symbol font/0x61]Vβ6 integrin specific binding. Liu teaches that a modified peptide A20FMDV2 conjugated with PEG spacers used as radiotracers significantly improved tumor retention without affecting the high specificity for [Symbol font/0x61]Vβ6 integrin binding ( see page 336, right column, second paragraph, lines 24-28 and page 337, left column, lines 1-3).
Liu also teaches a motif corresponding to RGDLXXLXXL in Table 2 (lines 11, ref# 69 and 19, ref# 75). Liu teaches that a two copies of chelator-modified peptide sequence RGDLATLRQL showed three-times level of tumor uptake (see page 337, right column, second paragraph).
It would have been obvious to one of ordinary skills in the art, before the effective filing date of the claimed invention to have substituted the antibody or antibody fragment taught by Subramanian in the muscle-targeting complex, with an [Symbol font/0x61]Vβ6 integrin specific binding polypeptide, as suggested by the teachings of Ducceschi, and comprising two RGDLXXLXXL motifs as taught by Liu. One with ordinary skills in the art, motivated in specifically targeting injured muscle cells in pathological conditions such as a muscular dystrophy, and obtaining a specific and high uptake into the targeted cells, could have performed this modification with a reasonable expectation of success and arrived at the claimed invention.
Regarding claim 49, Subramanian teaches a muscle-targeting complex, i.e., a delivery vehicle, that is formulated in a saline buffer, or wherein the pharmaceutically acceptable salt is a sodium salt, such as sodium citrate or sodium phosphate (see column 73, lines 30-41; and column 75, lines 6-12). Subramanian teaches that the complexes are formulated with an excipient that confers to the composition improved stability and/or therapeutic enhancement of the active ingredient, and that such excipient can be a buffering agent (column 73, lines 30-41).
The obviousness of the combination of references, Subramanian, Ducceschi and Liu is described above. Since Subramanian teaches the elements of claim 49, the combination of references also renders the elements of claim 49 obvious.
Indeed, it would have been obvious to one of ordinary skills in the art, before the effective filing date of the claimed invention to have combined the muscle-targeting complexes as taught by Subramanian modified by Ducceschi and Liu with a pharmaceutically acceptable sodium salt as excipient in the formulation as taught by Subramanian. One with ordinary skills in the art, motivated in formulating a solution with improved solubility and/or therapeutic enhancement of the active ingredient, could have performed this modification with a reasonable expectation of success and arrived at the claimed invention.
Regarding claim 17, the combination of Subramanian, Ducceschi and Liu does not teach the elements of claim 17, i.e., the formula:
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Or a pharmaceutically acceptable salt thereof, wherein
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indicates a point of connection to the remainder of the delivery vehicle.
However, Almeida teaches a structure that comprises the elements claimed in claim 17. Almeida is drawn to [Symbol font/0x61]Vβ6 integrin ligands and their uses (see title). Almeida teaches integrin ligands that confers serum stability to siRNA payload and affinity for the cell surface receptor (see abstract).
Almeida teaches a structure similar to the one claimed in instant claim 17, shown above, in Figure 7:
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Almeida also teaches a structure that is the structure claimed in instant claim 17, as it also contains some elements of the remainder of the vehicle, in Figure 9:
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Figure 9 is the only clear drawing featuring an oligonucleotide RNAi agent attached to an RGD peptide. Almeida describes the structure in Figure 9 as “an example of an [Symbol font/0x61]Vβ6 integrin ligand that includes CH3CO as an amine-terminal cap, a PEG20, and a FCitFP linking group. Further shown in the structure is a 20 kilodalton (KDa) PEG moiety, and the structure is shown linked to an oligomeric compound such as an RNAi agent” (see page 25, lines 12-15).
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 substituted the muscle-targeting RGD polypeptide in the complex/delivery vehicle as taught by Subramanian modified by Ducceschi and Liu, with the [Symbol font/0x61]Vβ6 integrin ligand as taught by Figure 9 of Almeida. One with ordinary skills in the art, motivated in evaluating and comparing the serum stability of multiple [Symbol font/0x61]Vβ6 integrin ligand in complex with the RNAi agent, could have performed this modification with a reasonable expectation of success and arrived at the claimed invention.
Regarding claim 26, Subramanian teaches that the muscle-targeting agent may comprise, or consist of, a nucleic acid, a peptide, a lipid or a sugar moiety (see column 16, lines 6-9). Subramanian also teaches the use of a L-Valine-L-citrulline linker molecule to link the anti-transferrin receptor antibody (see column 76, lines 58-67 and column 77, lines 1-12). See structure below and columns 67-68:
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Subramanian modified by Ducceschi and Liu does not teach a multibranched molecules also comprising at least 5 PEG units on each arm as well as a lipid molecule and an [Symbol font/0x61]Vβ6 integrin ligand.
The combination of Subramanian, Ducceschi, and Liu does not teach a PK/PD modulator of Formula (I) as shown below:
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Or a pharmaceutically acceptable salt thereof, wherein LA is a bond or a bivalent moiety connecting Z to the RNAi agent; Z is CH, phenyl, or N; L1 and L2 are each independently linkers comprising at least about 5 PEG units; X and Y are each independently lipids comprising from about 10 to about 50 carbon atoms; and
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indicates a point of connection to the RNAi agent.
However, Almeida teaches a complex in Figure 9 that combined the RNAi agent with an [Symbol font/0x61]Vβ6 integrin ligand linked to the agent via a spacer and 20 units of PEG on one branch, and having a second branch with additional PEG units.
Therefore, Almeida teaches the possibility of linking multiple an [Symbol font/0x61]Vβ6 integrin ligand to an RNAi agent. Almeida also shows in Figure 10 a multibranched combination of 5 PEG units on each branch linked to an [Symbol font/0x61]Vβ6 integrin ligand. See below:
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Almeida does not teach a 2-arms branched molecule, nor lipids on each arm.
However, Li does teach a PK/PD modulator molecule with a structure of the Formula (I) (see page 109, and structure shown below):
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In this molecule taught by Li, Z is a phenyl, LA is a bivalent moiety, with L1 and L2 each comprising 10 PEG units and a C18 lipid.
In KSR Int 'l v. Teleflex, the Supreme Court, indicated that “The principles underlying [earlier] cases are instructive when the question is whether a patent claiming the combination of elements of prior art is obvious. When a work is available in one field of endeavor, design incentives and other market forces can prompt variations of it, either in the same field or a different one. If a person of ordinary skill can implement a predictable variation, § 103 likely bars its patentability”. KSR Int'l v. Teleflex lnc., 127 S. Ct. 1727, 1740 (2007).
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 muscle-targeting RGD polypeptide in the complex/delivery vehicle as taught by Subramanian modified by Ducceschi and Liu, into a two arms branched molecule comprising each a PK/PD modulator linked to additional lipidic structure and the [Symbol font/0x61]Vβ6 integrin ligand as taught by Almeida modified by Li. One with ordinary skills in the art, motivated in evaluating the efficiency of delivery at the targeted site using multiple targeting peptides capable of being internalized at the cell membrane facilitated by lipidic structures could have constructed this 2-arm branched molecule with two [Symbol font/0x61]Vβ6 integrin ligands linked to the RNAi agent. One with ordinary skills in the art could have performed this modification with a reasonable expectation of success since the coupling methods are taught by Subramanian, Almeida and Li, and would arrived at the claimed invention.
Regarding claims 36 and 43-44, Li teaches that in some embodiments, PK enhancers may include molecules that are fatty acids, lipids, albumin-binders, antibody-binders, polyesters, polyacrylates, poly-amino acids, and linear or branched polyethylene glycol (PEG) moieties having about 20-1000 ethylene oxide (CH2-CH2-O) units (see [0183]). Li teaches that a PK enhancer can include a compound having the structure of the following formula:
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wherein Y is optionally substituted saturated or unsaturated aliphatic chain, and n is an integer from 5-25 (see [0184]).
Li also teaches a PK/PD modulator with a structure similar to Formula (Ic), wherein Z = N, and X and Y are C18 lipids. See page 109 (Table 6, [0187]) and below:
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The structure taught by Li has only 4PEG units on each arm.
However, Almeida teaches a structure with 5 PEG units on each arm.
It would have been obvious to one with ordinary skills in the art, before the effective filing date of the claimed invention to have tried to use different numbers of PEG units as taught by Almeida and Li, and modified the muscle-targeting delivery vehicle complex taught by Subramanian modified by Ducceschi and Liu. One with ordinary skills in the art motivated in evaluating the efficiency and stability of systems with different numbers of PEG units could have made this modification with a reasonable expectation of success, since Almeida teaches a 3-arm branched molecule comprising 5 PEG units and Li teaches a 2-arm branched molecule with 4 PEG units and a C18 lipid on both branches, and would arrived at the claimed invention.
Regarding claim 47, the combination of Subramanian, Ducceschi and Liu does not render obvious elements of claim 47, i.e., a structure such as LP29b or a pharmaceutically acceptable salt of a LP29b PK/PD modulator , wherein each
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indicates a point of connection to the RNAi agent, and wherein the point of connection comprises a linker, as shown below:
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However, Li teaches that in some embodiments, PK enhancers may include molecules that are fatty acids, lipids, albumin-binders, antibody-binders, polyesters, polyacrylates, poly-amino acids, and linear or branched polyethylene glycol (PEG) moieties having about 20-1000 ethylene oxide (CH2-CH2-O) units (see [0183]). Li teaches that a PK enhancer can include a compound having the structure of the following formula:
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wherein Y is optionally substituted saturated or unsaturated aliphatic chain, and n is an integer from 5-25 (see [0184]).
Li also teaches the structure below (see page 109, Table 6, [0187]):
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As shown in the highlighted box, the structure in the box is similar to part of LP29b that is connected to the RNAi agent via a linker.
Li teaches that PK enhancers may include a maleimide moiety and be reacted with an RNAi agent comprising a disulfide linkage to form an RNAi agent comprising a PK enhancer as shown below (see page 112, [0189]):
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“Wherein PK comprises a PK enhancer, RNA comprises an RNAi agent, and R may be any suitable group known in the art” ([0189]). Li teaches the modified maleimide group attached to a connection point on page 327, second structure, as shown below:
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Therefore, since Li teaches compounds that can comprise 20 to 1000 units of PEG as PK/PD modulator, and enhancers that can be fatty acids or lipids comprising an aliphatic chain with 5 to 25 repeats, Li teaches compounds with structures that include the structure of LP29b which comprises additional 47 PEG units in each arm as well as aliphatic chains with 7 repeats in both arms.
In KSR Int 'l v. Teleflex, the Supreme Court, indicated that “The principles underlying [earlier] cases are instructive when the question is whether a patent claiming the combination of elements of prior art is obvious. When a work is available in one field of endeavor, design incentives and other market forces can prompt variations of it, either in the same field or a different one. If a person of ordinary skill can implement a predictable variation, § 103 likely bars its patentability”. KSR Int'l v. Teleflex lnc., 127 S. Ct. 1727, 1740 (2007).
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 tried to use different numbers of PEG units and different lipids as taught by Almeida and Li, and modified the muscle-targeting delivery vehicle complex taught by Subramanian modified by Ducceschi and Liu. One with ordinary skills in the art motivated in evaluating the efficiency and stability of systems comparatively, with different numbers of PEG units and different lipids, could have made these modifications with a reasonable expectation of success, since Almeida teaches 3-arm branched molecules comprising multiple PEG units and Li teaches possible embodiments with 20-1000 PEG units and lipids with aliphatic chains with 5-25 repeats, and would arrived at the claimed invention.
.
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.
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.
Claims 1-4, 47, 48, 49, and 51-52 are rejected on the ground of non-statutory double patenting as being unpatentable over claims 1, 4, 7, 11-18 of U.S. Patent No. 11,845,937 B2. Although the claims at issue are not identical, they are not patentably distinct from each other because:
Regarding instant claims 1-4, USPat.’937’s claims 1 and 4 are drawn to an RNAi agent species that is encompassed by instant claims 1-4.
Regarding instant claim 47, USPAT.’937’s claim 7 is drawn to a RNAi agent wherein the PK/PD modulator is LP29b.
Regarding instant claim 48, USPAT.’937’s claims 12-18 are drawn to the use of an RNAi agent that inhibits expression of a mRNA of a human gene in a skeletal muscle.
Regarding instant claims 49, 51 and 52, USPAT.’937’s claims 9-11 are drawn to a pharmaceutically acceptable salt of a RNAi agent, a sodium salt, and wherein the composition comprising the RNAi agent further comprises a pharmaceutically acceptable excipient.
Claims 1-3, 23-24, 26, 36, 43-44, 47-48, 51 and 52 are provisionally rejected on the ground of non-statutory double patenting as being unpatentable over claims 1-3, 10, 13, 19, 24-30 of co-pending Application No. 18/181,335 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because:
Regarding instant claim 1, co-pending app.’335’s claim 1 is are also drawn to “A delivery platform for inhibiting expression of a gene expressed in skeletal muscle cells comprising:(a) An RNAi agent comprising: (i) An antisense strand comprising 17-49 nucleotides wherein at least 15 nucleotides are complementary to the mRNA sequence of a gene that is expressed in skeletal muscle cells (ii) A sense strand that is 16-49 nucleotides in length that is at least partially complementary to the antisense strand; (b) A targeting ligand with affinity for a receptor present on the surface of a skeletal muscle cell; and (c) A PK/PD modulator; wherein the RNAi agent is covalently linked to the targeting ligand and to the PK/PD modulator”.
Regarding instant claim 2, co-pending app. ‘335’s claim 2 is also drawn to “The delivery platform of claim 1, wherein the targeting ligand has affinity for an integrin receptor”.
Regarding instant claim 3, co-pending app.’335’s claim 3 is also drawn to “the delivery platform of any one of claim 1, wherein the targeting ligand has affinity for the [Symbol font/0x61]vβ6 integrin receptor”.
Regarding instant claims 23 and 24, co-pending app.’335’s claim 10 is drawn to the same elements, i.e., “wherein the PK/PD modulator comprises at least one polyethylene glycol (PEG) unit”.
Regarding instant claims 26 and 36, co-pending app.’335’s claim 13 is drawn to the same formula then in claim 26, which also encompasses structure in instant claim 36.
Regarding instant claims 43 and 44, co-pending app.’335’s claims 19, 24, 25 and 26 are drawn to the same structures shown in the table of instant claims 43 and 44.
Regarding instant claim 47, co-pending app.’335’s claim 27 is drawn to the same elements shown in the table of instant claim 47.
Regarding instant claim 48, co-pending app.335’s claim 28 is also drawn to a delivery vehicle, or platform, “wherein the RNAi agent inhibits expression of the mRNA of a human gene in a skeletal muscle cell”.
Regarding instant claim 51, co-pending app.335’s claim 29 is also drawn to a composition comprising the delivery vehicle or platform.
Regarding instant claim 52, co-pending app.335’s claim 30 is also drawn to a pharmaceutical composition comprising the composition and a pharmaceutical excipient.
This is a provisional nonstatutory double patenting rejection.
Claims 1-4, 47, 48, 49, and 51-52 are provisionally rejected on the ground of non-statutory double patenting as being unpatentable over claims 1, 5, 11, 15, 16, 20, 31, 38, 40, 41, 57, 60 and 61 of co-pending Application No. 18/181,311 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because:
Regarding instant claims 1-4, copending App.’311’s claims 1, 5, 11 and 15-16 are drawn to an RNAi agent species that is encompassed by instant claims 1-4.
Regarding instant claim 47, copending App.’311’s claims 20, 31, 57, 60 and 61 are drawn to a RNAi agent wherein the PK/PD modulator is LP29b.
Regarding instant claim 48, copending App.’311’s claims 41 is drawn to the use of an RNAi agent that inhibits expression of a mRNA of a human gene in a skeletal muscle.
Regarding instant claims 49, 51 and 52, copending App.’311’s claims 38 and 40 are drawn to a pharmaceutically acceptable salt of a RNAi agent, a sodium salt, and wherein the composition comprising the RNAi agent further comprises a pharmaceutically acceptable excipient.
This is a provisional nonstatutory double patenting rejection.
Claims 47, 48, 49, and 51-52 are provisionally rejected on the ground of non-statutory double patenting as being unpatentable over claims 25-27, 112-114, 133 and 135-136 of co-pending Application No. 18/178,242 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because:
Regarding instant claim 47, copending App.’242’s claims 25, 26 and 133 are drawn to a RNAi agent wherein the PK/PD modulator is LP29b.
Regarding instant claim 48, copending App.’242’s claims 113 and 114 are drawn to the use of an RNAi agent that inhibits expression of a mRNA of a human gene in a skeletal muscle.
Regarding instant claims 49, 51 and 52, copending App.’242’s claims 27, 112 and 135-136 are drawn to a pharmaceutically acceptable salt of a RNAi agent, a sodium salt, and wherein the composition comprising the RNAi agent further comprises a pharmaceutically acceptable excipient.
This is a provisional nonstatutory double patenting rejection.
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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