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 .
Claim Status
Claims 1-26 were pending in the present application. By virtue of a First Preliminary Amendment, filed by Applicant on 24 January 2023, claims 1-3, 5-9, 11-13, 15, 17, 21, 23, 24, and 26 were amended, and claims 14, 16, 18-20, and 22 were cancelled. Therefore, claims 1-13, 15, 17, 21, and 23-26 are pending and currently under examination.
Priority
Acknowledgment is made of applicant's claim for priority based on a parent application
filed on 23 July 2020.
The instant application filed on 20 January 2023 is a 371 of PCT/US2021/41008 filed
09 July 2021, which is a provisional of the following applications: 63/143,833 (filed 30 January 2021) and 63/055,759 (filed 23 July 2020) and which finds full support for the instant claims. Therefore, the effective filing date of the instant application is 23 July 2020 (the date 63/055,759 was filed).
Information Disclosure Statement (IDS)
The IDS (1) filed on 21 April 2023 has been considered by the examiner. A signed copy is enclosed.
Applicant is reminded of their duty to disclose to the Office all information known to the
person to be material to patentability as defined in 37 CFR 1.56. As stated therein, “[e]ach
individual associated with the filing and prosecution of a patent application has a duty of candor
and good faith in dealing with the Office, which includes a duty to disclose to the Office all
information known to that individual to be material to patentability as defined in this section.”
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 1, 3-5, 7-13, 15, 17, 21, and 23-26 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 claims under rejection are directed to a complex comprising an anti-transferrin receptor (TfR) antibody covalently linked to a molecular payload configured to modulated expression or activity of a pro-atrophy disease gene. The anti-TfR antibody comprises “a heavy chain variable region (VH) comprising an amino acid sequence at least 95% identical to SEQ ID NO: 77; and/or a light chain variable region (VL) comprising an amino acid sequence at least 95% identical to SEQ ID NO: 78” (instant claim 1, emphasis added).
The claims at issue are reciting a genus of antibody variants comprising a heavy chain variable region (VH) comprising an amino acid sequence at least 95% identical to SEQ ID NO: 77; and/or a light chain variable region (VL) comprising an amino acid sequence at least 95% identical to SEQ ID NO: 78. As required by instant claim 1, these variants must retain the property of being an anti-TfR antibody.
To satisfy the written description aspect of 35 U.S.C. 112(a) for a claimed genus of
molecules, it must be clear that: (A) the identifying characteristics of the claimed molecules have
been disclosed, e.g., 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; or (B) a representative number of species
within the genus must be disclosed. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
From the Applicant’s disclosure, it appears SEQ ID NOs: 77 and 78 form the 5H12 VH5 (C33Y*)/Vκ3 antibody (see Specification pages 50-52, Table 4) which in itself is a variant of the disclosed 5H12 antibody represented by SEQ ID NOs: 61 (VH) and 62 (VL) (see Specification pages 31-33, Table 2). The specification states the percentage of possible variation for SEQ ID NOs: 77 and 78 ([000135]), but does not disclose specifically where this variation occurs in order to retain anti-TfR properties. Though Applicant identifies the CDR regions, the art suggests that together with the CDR loops, the relative VH-VL interdomain orientation plays an important role in determining the shape of the antigen binding site where even slight mutations in the framework regions, particularly the VH-VL interface, can result in structural changes of the binding site and hence can influence antigen recognition.1 Therefore, Applicants have not disclosed the identifying characteristics of the claimed molecules.
Regarding disclosure of a representative number of species within the genus: a review of the specification shows that Applicant has disclosed two additional variants of the 5H12 antibody, 5H12 VH5 (C33D*)/Vκ4 and 5H12 VH5 (C33Y*)/Vκ5, discussed below:
5H12 VH5 (C33D*)/Vκ4: represented by SEQ ID NO: 79 (VH) and SEQ ID NO: 80 (VL)
SEQ ID NO: 79 contains a single mismatch when compared to SEQ ID NO: 77 (98.5% similar):
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730
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SEQ ID NO: 80 contains a single mismatch when compared to SEQ ID NO: 78 (98.5% similar):
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734
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5H12 VH5 (C33Y*)/Vκ5: represented by SEQ ID NO: 77 (VH) and SEQ ID NO: 80 (VL)
SEQ ID NO: 77 is the same in both 5H12 VH5 (C33Y*)/Vκ3 and 5H12 VH5 (C33Y*)/Vκ5.
SEQ ID NO: 80 contains a single mismatch when compared to SEQ ID NO: 78 (98.5% similar):
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734
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Neither of the variants disclosed by the Applicant contain a 95% variation to the VH or VL. In fact, really only one variation of SEQ ID NO: 77 and one variation of SEQ ID NO: 78 were provided (SEQ ID NOs: 79 and 80). There is no disclosure of other acceptable variants of SEQ ID NOs: 77 or 78. This is problematic for the following reasons: a single example of a VH and VL variant is insufficient disclosure given all that is encompassed by the broad breadth of ‘at least 95% identical’ to SEQ ID NOs: 77 and/or 78 while still maintaining anti-TfR properties. Therefore, Applicant has not disclosed a representative number of species, as would be required to support the written description requirement and to show possession of the entire genus.
In fact, prior art teaches against a 5% variation in SEQ ID NOs: 77 and/or 78 while still maintaining anti-TfR properties. Loew2 discloses antibody molecules that bind to TCR Vβ regions and comprise one or more nucleic acid molecule encoding an exogenous cellular receptor (abstract). Loew further discloses SEQ ID NO: 132 (VL), which binds to human TCR Vβ 27, which is 95.2% identical to instant SEQ ID NO: 78. Therefore, SEQ ID NO: 132 of Loew meets the limitations of instant claim 1 regarding percent identity, but fails to meet the properties also stated by instant claim 1 in terms of TfR binding.
Thus, one of ordinary skill in the art, in looking to the instant specification, would not be
able to determine that Applicants were in possession of the invention, as claimed, at the time the
invention was made. Accordingly, claim 1 is considered to lack sufficient written
description and are properly rejected under 35 USC 112(a). Claims 3-5, 7-13, 15, 17, 21, and 23-26 are rejected by virtue of their dependency on claim 1.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 26 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 26 recites “the muscle disease is a disease listed in Table 1.” Incorporation by reference to a table is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a table into a claim. See MPEP 2173.05(s). Muscle diseases are easily and concisely articulated in claim language and therefore, the information of Table 1 does not warrant reference to a table in the claim.
This claim is further rejected because Table 1 does not actually reference muscle diseases ([00079]). The title of Table 1 is “List of pro-atrophy gene examples” and references gene symbols, the GenBank Accession number, and related publications. It is unclear whether the muscle diseases of claim 26 encompasses every single disease associated with the pro-atrophy genes listed in Table 1.
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.
Co-pending application No. 18/017,167
Claims 1-9, 21, and 24-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 8-10, 12-15, 18 and 26 of copending Application No. 18/017,167 (reference application ‘167).
Although the claims at issue are not identical, they are not patentably distinct from each other because they are each directed to overlapping embodiments: a complex comprising an anti-TfR antibody covalently linked to a molecular payload to treat a muscular disease.
Claim 1 of ‘167 further requires the anti-TfR antibody comprises a VH comprising an amino acid sequence at least 95% identical to SEQ ID NO: 77; and/or a VL comprising an amino acid sequence at least 95% identical to SEQ ID NO: 78 (instant claim 1). SEQ ID NOs: 77 and 78 of ‘170 are identical to SEQ ID NOs: 77 and 78 of the instant application as shown below:
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269
727
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(SEQ ID NO: 77)
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(SEQ ID NO: 78)
Claim 2 of ‘167 indicates the anti-TfR antibody comprises a VH comprising SEQ ID NO: 77 and a VL comprising SEQ ID NO: 78 (instant claim 2).
Claims 3 and 4 of ‘167 pertain to the antibody type (instant claims 3 and 4).
Claims 5 and 6 of ‘167 are drawn to the heavy and light chains of the antibody, represented by SEQ ID NOs: 102 and 93 respectively, which are identical to the heavy and light chains of the instant application as disclosed in instant claims 5 and 6 and as shown below:
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737
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(SEQ ID NO: 102)
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723
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(SEQ ID NO: 93)
Claim 8 of ‘167 pertains to the antibody binding site on the transferrin receptor (instant claim 7).
Claim 9 of ‘167 pertains to the antibody cross-reactivity with extracellular epitopes (instant claim 8).
Claims 10 and 12 of ‘167 pertains to the molecular payload is an oligonucleotide (instant claims 1, 9, and 10).
Claims 13-15 of ‘167 pertains to the antibody linked to molecular payload via cleavable linker (instant claim 21).
Claim 18 of ‘167 pertains to a method of delivering a molecular payload to a cell (instant claims 24 and 25).
Claims 25 and 26 of ‘167 pertains to a method of treating a muscle disease (instant claim 26).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 10, 12, 13, and 15 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 8-10, 12-15, 18 and 26 of copending Application No. 18/017,167 in further view of Lee (“RNAse H-mediated degradation of toxic RNA is myotonic dystrophy type 1,” published: 13 March 2012).
While ‘167 claims overlapping embodiments of the instant claims, a complex comprising an anti-TfR antibody covalently linked to a molecular payload to treat a muscular disease, ‘167 does not explicitly claim the limitations of instant claims 10, 12, 13, and 15.
Lee teaches the use of antisense oligonucleotides (ASOs) as a therapeutic approach to target the pathogenic RNA in myotonic dystrophy type 1 (DM1) (abstract).
Regarding instant claim 10, Lee teaches the predominant cause of DM1, a pro-atrophy muscle disease, pathogenesis is the gain-of-function of mutant DMPK mRNA, which contains long CUG repeats that accumulate in the nuclei as RNA foci (p. 4221).
Regarding instant claim 12, Lee teaches the ASOs further contain a center gap region with 7-10 nucleotides containing RNase H-compatible phosphorothioate (PS) DNA (p. 4221).
Regarding instant claims 13 and 15, Lee teaches the stability and efficiency of the ASO gapmers can be enhanced by substituting DNA with modified nucleotides with increased affinity for RNA and resistance to nucleases, including locked nucleic acids (LNA) or 2ˈ-O-Methoxyethyl (MOE) nucleic acids (abstract and p. 4221).
Lee teaches the use of ASOs as a therapeutic approach to target the pathogenic RNA in DM1. Therefore, ‘167 in view of Lee makes prima facie obvious the instant claims because one of ordinary skill in the art would have the breadth of knowledge to formulate the complex of ‘167 to target a pro-atrophy muscle disease where the oligonucleotide contains the limitations of instant claims 10, 12, 13, and 15. One would predict success in doing so because Lee teaches success using such ASOs to treat DM1, which is a pro-atrophy muscle disease.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 11 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 8-10, 12-15, 18 and 26 of copending Application No. 18/017,167 in further view of Sandri (“Foxo Transcription Factors Induce the Atrophy-Related Ubiquitin Ligase Atrogin-1 and Cause Skeletal Muscle Atrophy,” published 30 April 2004).
While ‘167 claims overlapping embodiments of the instant claims, a complex comprising an anti-TfR antibody covalently linked to a molecular payload to treat a muscular disease, ‘167 does not explicitly claim the limitations of instant claim 11.
Sandri teaches Foxo transcription factors that induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy (title).
Regarding instant claim 11, Sandri teaches the ubiquitin ligase, atrogin-1 (MAFbx), is dramatically induced and causes rapid atrophy (p. 1). Sandri shows that inhibiting MAFbx (also known as FBXO32) expression, is an attractive approach to combat muscle wasting because atrogin-1 is the protein induced most dramatically during atrophy (p. 1). Sandri further teaches the Forkhead box O (Foxo) transcription factors are contained within mammalian cells (p. 2) and function through activation of the ubiquitin-proteasome pathway which leads to protein degradation and ultimately muscle atrophy (p. 1).
Sandri teaches FBXO32 is involved in muscle atrophy and treatment of muscle atrophy could involve inhibiting its expression. Therefore, ‘167 in view of Sandri makes prima facie obvious the instant claims because one of ordinary skill in the art would have the breadth of knowledge to formulate the complex of ‘167 to reduce the expression or activity of the targeted muscle gene to treat muscle atrophy with the limitations of claim 11. One would predict success in doing so because Sandri teaches FBXO32 encodes a non-secreted product that functions within the muscle cell and is responsible for muscle atrophy.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 17 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 8-10, 12-15, 18 and 26 of copending Application No. 18/017,167 in further view of Bisset (“Therapeutic impact of systemic AAV-mediated RNA interference in a mouse model of myotonic dystrophy” published: 16 June 2015).
While ‘167 claims overlapping embodiments of the instant claims, a complex comprising an anti-TfR antibody covalently linked to a molecular payload to treat a muscular disease, ‘167 does not explicitly claim the limitations of instant claim 17.
Bisset teaches RNA interference (RNAi) offers a promising therapeutic approach for dominant genetic disorders that involve gain-of-function mechanisms (abstract). Specifically, Bisset teaches DM1, a muscle atrophy disease, is a candidate disease for RNAi therapy and RNAi has the potential to provide a long-term therapy for DM1 and other dominant muscular dystrophies (abstract). Bisset further teaches experimental RNAi treatment of HASLR mice significantly reduced disease pathology in muscles and reduced CUG repeat mRNA (abstract and p. 4972).
Bisset teaches the use of RNAi as a therapeutic approach to target mutant mRNA in DM1. Therefore, ‘167 in view of Bisset makes prima facie obvious the instant claims because one of ordinary skill in the art would have the breadth of knowledge to formulate the complex of ‘167 to target DM1 where the oligonucleotide contains the limitations of instant claim 17. One would predict success in doing so because Bisset teaches success using RNAi to treat DM1.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 23 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 8-10, 12-15, 18 and 26 of copending Application No. 18/017,167 in further view of Brun (“Chapter 10: Protocols for Lysine Conjugation” published: 01 July 2013).
While ‘167 claims overlapping embodiments of the instant claims, a complex comprising an anti-TfR antibody covalently linked to a molecular payload to treat a muscular disease, ‘167 does not explicitly claim the limitations of instant claim 23.
Brun teaches protocols for lysine conjugation in antibody-drug conjugates (title). Specifically, Brun teaches the most widely used chemical methodology for the conjugation of drugs to monoclonal antibodies involves either lysine or cysteine residues (abstract, p. 173). In addition, Brun teaches lysine residues exposed at the surface of antibodies are used as sites for drug conjugations as their side-chain amino groups are good nucleophiles (p. 173). Finally, Brun teaches an immunoglobulin contains approximately 80-100 lysine residues and most of them are sufficiently exposed or accessible to be reactive (p. 173).
Brun teaches widely used methods in molecular biology to form antibody-drug conjugates through either the lysine or cysteine residues of antibodies. Therefore, ‘167 in view of Brun makes prima facie obvious the instant claims because one of ordinary skill in the art would have the breadth of knowledge to formulate the complex of ‘167 using widely practiced protocols in the art which contain the limitations of instant claim 23. One would predict success in doing so because Brun teaches such methods are widely accepted and used in the field.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Co-pending application No. 18/017,170
Claims 1-9, 12, 13, 15, 21, and 24-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8, 10, 14-17, 22, and 23 of copending Application No. 18/017,170 (reference application ‘170).
Although the claims at issue are not identical, they are not patentably distinct from each other because they are each directed to overlapping embodiments: a complex comprising an anti-TfR antibody covalently linked to a molecular payload configured for reducing expression or activity of a muscle disease gene.
Claim 1 of ‘170 further requires the anti-TfR antibody comprises a VH comprising an amino acid sequence at least 95% identical to SEQ ID NO: 77; and/or a VL comprising an amino acid sequence at least 95% identical to SEQ ID NO: 78 (instant claim 1). SEQ ID NOs: 77 and 78 of ‘170 are identical to SEQ ID NOs: 77 and 78 of the instant application as shown below:
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(SEQ ID NO: 77)
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(SEQ ID NO: 78)
Claim 2 of ‘170 indicates the anti-TfR antibody comprises a VH comprising SEQ ID NO: 77 and a VL comprising SEQ ID NO: 78 (instant claim 2).
Claims 3 and 4 of ‘170 pertain to the antibody type (instant claims 3 and 4).
Claims 5 and 6 of ‘170 are drawn to the heavy and light chains of the antibody, represented by SEQ ID NOs: 102 and 93 respectively, which are identical to the heavy and light chains of the instant application as disclosed in instant claims 5 and 6 and as shown below:
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(SEQ ID NO: 102)
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731
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(SEQ ID NO: 93)
Claim 7 of ‘170 pertains to the antibody binding site on the transferrin receptor (instant claim 7).
Claim 8 of ‘170 pertains to the antibody cross-reactivity with extracellular epitopes (instant claim 8).
Claim 10 of ‘170 pertains to the molecular payload of the complex is an oligonucleotide (instant claim 9).
Claim 14 of ‘170 pertains to the oligonucleotide mediating RNAse H-mediated cleavage of a DMPK mRNA transcript (instant claim 15).
Claim 15 of ‘170 pertains to the oligonucleotide molecular payload containing a modified nucleoside (instant claim 13).
Claim 16 of ‘170 pertains to the oligonucleotide comprising at least one modified internucleoside linkage (instant claim 12).
Claim 17 of ‘170 pertains to the complex of claim 1 where the antibody is covalently linked to the molecular payload via a cleavable linker or where the antibody is covalently linked to the molecular payload via conjugation to lysine residue or cysteine residue of the antibody (instant claim 21).
Claim 22 of ‘170 pertains to a method of reducing expression in a cell (instant claims 24 and 25).
Claim 23 of ‘170 pertains to a method of treating a subject having a muscle disease (instant claim 26).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 10 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8, 10, 14-17, 22, and 23 of copending Application No. 18/017,170 in further view of Lee (“RNAse H-mediated degradation of toxic RNA is myotonic dystrophy type 1,” published: 13 March 2012).
While ‘170 claims overlapping embodiments of the instant claims, a complex comprising an anti-TfR antibody covalently linked to a molecular payload to treat a muscular disease, ‘170 does not explicitly claim the limitations of instant claim 10.
Lee teaches the use of antisense oligonucleotides (ASOs) as a therapeutic approach to target the pathogenic RNA in myotonic dystrophy type 1 (DM1) (abstract).
Regarding instant claim 10, Lee teaches the predominant cause of DM1 pathogenesis is the gain-of-function of mutant DMPK mRNA, which contains long CUG repeats that accumulate in the nuclei as RNA foci (p. 4221).
Lee teaches the use of ASOs as a therapeutic approach to target the pathogenic RNA in DM1. Therefore, ‘170 in view of Lee makes prima facie obvious the instant claims because one of ordinary skill in the art would have the breadth of knowledge to formulate the complex of ‘170 to target a pro-atrophy muscle disease where the oligonucleotide contains the limitations of instant claim 10. One would predict success in doing so because Lee teaches success using such ASOs to treat DM1, which is a pro-atrophy muscle disease.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 11 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8, 10, 14-17, 22, and 23 of copending Application No. 18/017,170 in further view of Sandri (“Foxo Transcription Factors Induce the Atrophy-Related Ubiquitin Ligase Atrogin-1 and Cause Skeletal Muscle Atrophy,” published 30 April 2004).
While ‘170 claims overlapping embodiments of the instant claims, a complex comprising an anti-TfR antibody covalently linked to a molecular payload to treat a muscular disease, ‘170 does not explicitly claim the limitations of instant claim 11.
Sandri teaches Foxo transcription factors that induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy (title).
Regarding instant claim 11, Sandri teaches the ubiquitin ligase, atrogin-1 (MAFbx), is dramatically induced and causes rapid atrophy (p. 1). Sandri shows that inhibiting MAFbx (also known as FBXO32) expression, is an attractive approach to combat muscle wasting because atrogin-1 is the protein induced most dramatically during atrophy (p. 1). Sandri further teaches the Forkhead box O (Foxo) transcription factors are contained within mammalian cells (p. 2) and function through activation of the ubiquitin-proteasome pathway which leads to protein degradation and ultimately muscle atrophy (p. 1).
Sandri teaches FBXO32 is involved in muscle atrophy and treatment of muscle atrophy could involve inhibiting its expression. Therefore, ‘170 in view of Sandri makes prima facie obvious the instant claims because one of ordinary skill in the art would have the breadth of knowledge to formulate the complex of ‘170 to reduce the expression or activity of the targeted muscle gene to treat muscle atrophy with the limitations of claim 11. One would predict success in doing so because Sandri teaches FBXO32 encodes a non-secreted product that functions within the muscle cell and is responsible for muscle atrophy.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 17 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8, 10, 14-17, 22, and 23 of copending Application No. 18/017,170 in further view of Bisset (“Therapeutic impact of systemic AAV-mediated RNA interference in a mouse model of myotonic dystrophy” published: 16 June 2015).
While ‘170 claims overlapping embodiments of the instant claims, a complex comprising an anti-TfR antibody covalently linked to a molecular payload to treat a muscular disease, ‘170 does not explicitly claim the limitations of instant claim 17.
Bisset teaches RNA interference (RNAi) offers a promising therapeutic approach for dominant genetic disorders that involve gain-of-function mechanisms (abstract). Specifically, Bisset teaches DM1, a muscle atrophy disease, is a candidate disease for RNAi therapy and RNAi has the potential to provide a long-term therapy for DM1 and other dominant muscular dystrophies (abstract). Bisset further teaches experimental RNAi treatment of HASLR mice significantly reduced disease pathology in muscles and reduced CUG repeat mRNA (abstract and p. 4972).
Bisset teaches the use of RNAi as a therapeutic approach to target mutant mRNA in DM1. Therefore, ‘170 in view of Bisset makes prima facie obvious the instant claims because one of ordinary skill in the art would have the breadth of knowledge to formulate the complex of ‘170 to target DM1 where the oligonucleotide contains the limitations of instant claim 17. One would predict success in doing so because Bisset teaches success using RNAi to treat DM1.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 23 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8, 10, 14-17, 22, and 23 of copending Application No. 18/017,170 in further view of Brun (“Chapter 10: Protocols for Lysine Conjugation” published: 01 July 2013).
While ‘170 claims overlapping embodiments of the instant claims, a complex comprising an anti-TfR antibody covalently linked to a molecular payload to treat a muscular disease, ‘170 does not explicitly claim the limitations of instant claim 23.
Brun teaches protocols for lysine conjugation in antibody-drug conjugates (title). Specifically, Brun teaches the most widely used chemical methodology for the conjugation of drugs to monoclonal antibodies involves either lysine or cysteine residues (abstract, p. 173). In addition, Brun teaches lysine residues exposed at the surface of antibodies are used as sites for drug conjugations as their side-chain amino groups are good nucleophiles (p. 173). Finally, Brun teaches an immunoglobulin contains approximately 80-100 lysine residues and most of them are sufficiently exposed or accessible to be reactive (p. 173).
Brun teaches widely used methods in molecular biology to form antibody-drug conjugates through either the lysine or cysteine residues of antibodies. Therefore, ‘170 in view of Brun makes prima facie obvious the instant claims because one of ordinary skill in the art would have the breadth of knowledge to formulate the complex of ‘170 using widely practiced protocols in the art which contain the limitations of instant claim 23. One would predict success in doing so because Brun teaches such methods are widely accepted and used in the field.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Co-pending application No. 18/017,173
Claims 1-9, 12, 13, 21, and 23-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8, 10, 17, 21, 23, 26, and 27 of copending Application No. 18/017,173 (reference application ‘173).
Although the claims at issue are not identical, they are not patentably distinct from each other because they are each directed to overlapping embodiments: a complex comprising an anti-TfR antibody covalently linked to a molecular payload configured for reducing expression or activity of a muscle disease gene.
Claim 1 of ‘173 further requires the anti-TfR antibody comprises a VH comprising an amino acid sequence at least 95% identical to SEQ ID NO: 77; and/or a VL comprising an amino acid sequence at least 95% identical to SEQ ID NO: 78 (instant claim 1). SEQ ID NOs: 77 and 78 of ‘173 are identical to SEQ ID NOs: 77 and 78 of the instant application as shown below:
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290
724
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(SEQ ID NO: 77)
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267
729
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(SEQ ID NO: 78).
Claim 2 of ‘173 indicates the anti-TfR antibody comprises a VH comprising SEQ ID NO: 77 and a VL comprising SEQ ID NO: 78 (instant claim 2).
Claims 3 and 4 of ‘173 pertain to the antibody type (instant claims 3 and 4).
Claims 5 and 6 of ‘173 are drawn to the heavy and light chains of the antibody, represented by SEQ ID NOs: 102 and 93 respectively, which are identical to the heavy and light chains of the instant application as disclosed in instant claims 5 and 6 and as shown below:
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422
735
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(SEQ ID NO: 102)
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427
728
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(SEQ ID NO: 93)
Claim 7 of ‘173 pertains to the antibody binding site on the transferrin receptor (instant claim 7).
Claim 8 of ‘173 pertains to the antibody cross-reactivity with extracellular epitopes (instant claim 8).
Claim 10 of ‘173 pertains to the molecular payload of the complex is an oligonucleotide (instant claim 9).
Claim 17 of ‘173 pertains to the oligonucleotide molecular payload containing a modified nucleoside (instant claim 13) and at least one modified internucleoside linkage (instant claim 12).
Claim 21 of ‘173 pertains to the complex of claim 1 where the antibody is covalently linked to the molecular payload via a cleavable linker (instant claim 21).
Claim 23 of ‘173 pertains to the antibody covalently linked to the molecular payload via conjugation to lysine residue or cysteine residue of the antibody (instant claim 23).
Claim 26 of ‘173 pertains to a method of reducing expression in a cell (instant claim 24 and 25).
Claim 27 of ‘173 pertains to a method of treating a subject having a muscle disease (instant claim 28).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 10 and 15 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8, 10, 17, 21, 23, 26, and 27 of copending Application No. 18/017,173 in further view of Lee (“RNAse H-mediated degradation of toxic RNA is myotonic dystrophy type 1,” published: 13 March 2012).
While ‘173 claims overlapping embodiments of the instant claims, a complex comprising an anti-TfR antibody covalently linked to a molecular payload to treat a muscular disease, ‘173 does not explicitly claim the limitations of instant claims 10 and 15.
Lee teaches the use of antisense oligonucleotides (ASOs) as a therapeutic approach to target the pathogenic RNA in myotonic dystrophy type 1 (DM1) (abstract).
Regarding instant claim 10, Lee teaches the predominant cause of DM1, a pro-atrophy muscle disease, pathogenesis is the gain-of-function of mutant DMPK mRNA, which contains long CUG repeats that accumulate in the nuclei as RNA foci (p. 4221).
Regarding instant claim 15, Lee teaches the stability and efficiency of the ASO gapmers can be enhanced by substituting DNA with modified nucleotides with increased affinity for RNA and resistance to nucleases, including locked nucleic acids (LNA) or 2ˈ-O-Methoxyethyl (MOE) nucleic acids (abstract and p. 4221).
Lee teaches the use of ASOs as a therapeutic approach to target the pathogenic RNA in DM1. Therefore, ‘173 in view of Lee makes prima facie obvious the instant claims because one of ordinary skill in the art would have the breadth of knowledge to formulate the complex of ‘173 to target a pro-atrophy muscle disease where the oligonucleotide contains the limitations of instant claims 10 and 15. One would predict success in doing so because Lee teaches success using such ASOs to treat DM1, which is a pro-atrophy muscle disease.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 11 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8, 10, 17, 21, 23, 26, and 27 of copending Application No. 18/017,173 in further view of Sandri (“Foxo Transcription Factors Induce the Atrophy-Related Ubiquitin Ligase Atrogin-1 and Cause Skeletal Muscle Atrophy,” published 30 April 2004).
While ‘173 claims overlapping embodiments of the instant claims, a complex comprising an anti-TfR antibody covalently linked to a molecular payload to treat a muscular disease, ‘173 does not explicitly claim the limitations of instant claim 11.
Sandri teaches Foxo transcription factors that induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy (title).
Regarding instant claim 11, Sandri teaches the ubiquitin ligase, atrogin-1 (MAFbx), is dramatically induced and causes rapid atrophy (p. 1). Sandri shows that inhibiting MAFbx (also known as FBXO32) expression, is an attractive approach to combat muscle wasting because atrogin-1 is the protein induced most dramatically during atrophy (p. 1). Sandri further teaches the Forkhead box O (Foxo) transcription factors are contained within mammalian cells (p. 2) and function through activation of the ubiquitin-proteasome pathway which leads to protein degradation and ultimately muscle atrophy (p. 1).
Sandri teaches FBXO32 is involved in muscle atrophy and treatment of muscle atrophy could involve inhibiting its expression. Therefore, ‘173 in view of Sandri makes prima facie obvious the instant claims because one of ordinary skill in the art would have the breadth of knowledge to formulate the complex of ‘173 to reduce the expression or activity of the targeted muscle gene to treat muscle atrophy with the limitations of claim 11. One would predict success in doing so because Sandri teaches FBXO32 encodes a non-secreted product that functions within the muscle cell and is responsible for muscle atrophy.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 17 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8, 10, 17, 21, 23, 26, and 27 of copending Application No. 18/017,173 in further view of Bisset (“Therapeutic impact of systemic AAV-mediated RNA interference in a mouse model of myotonic dystrophy” published: 16 June 2015).
While ‘173 claims overlapping embodiments of the instant claims, a complex comprising an anti-TfR antibody covalently linked to a molecular payload to treat a muscular disease, ‘173 does not explicitly claim the limitations of instant claim 17.
Bisset teaches RNA interference (RNAi) offers a promising therapeutic approach for dominant genetic disorders that involve gain-of-function mechanisms (abstract). Specifically, Bisset teaches DM1, a muscle atrophy disease, is a candidate disease for RNAi therapy and RNAi has the potential to provide a long-term therapy for DM1 and other dominant muscular dystrophies (abstract). Bisset further teaches experimental RNAi treatment of HASLR mice significantly reduced disease pathology in muscles and reduced CUG repeat mRNA (abstract and p. 4972).
Bisset teaches the use of RNAi as a therapeutic approach to target mutant mRNA in DM1. Therefore, ‘173 in view of Bisset makes prima facie obvious the instant claims because one of ordinary skill in the art would have the breadth of knowledge to formulate the complex of ‘173 to target DM1 where the oligonucleotide contains the limitations of instant claim 17. One would predict success in doing so because Bisset teaches success using RNAi to treat DM1.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Co-pending application No. 18/017,179
Claims 1-9, 12, 21, and 24-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6-8, 23, 24, 27, and 28 of copending Application No. 18/017,179 (reference application ‘179).
Although the claims at issue are not identical, they are not patentably distinct from each other because they are each directed to overlapping embodiments: a complex comprising an anti-TfR antibody covalently linked to a molecular payload configured for reducing expression or activity of a muscle disease gene.
Claim 1 of ‘179 further requires the anti-TfR antibody comprises a VH comprising an amino acid sequence at least 95% identical to SEQ ID NO: 77; and/or a VL comprising an amino acid sequence at least 95% identical to SEQ ID NO: 78 (instant claim 1). SEQ ID NOs: 77 and 78 of ‘179 are identical to SEQ ID NOs: 77 and 78 of the instant application as shown below:
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282
743
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(SEQ ID NO: 77)
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280
731
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(SEQ ID NO: 78).
Claim 2 of ‘179 indicates the anti-TfR antibody comprises a VH comprising SEQ ID NO: 77 and a VL comprising SEQ ID NO: 78 (instant claim 2). Since the antibody of ‘179 and the currently claimed antibody are identical, the limitations pertaining to the antibody as recited in instant claim 8 is inherent to the structure and thus, also included as being anticipated by ‘179. See MPEP 2112 (III).
Claims 3 and 4 of ‘179 pertain to the antibody type (instant claims 3 and 4).
Claim 6 of ‘179 are drawn to the heavy and light chains of the antibody, represented by SEQ ID NOs: 102 and 93 respectively, which are identical to the heavy and light chains of the instant application as disclosed in instant claims 5 and 6 and as shown below:
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426
734
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(SEQ ID NO: 102)
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423
730
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(SEQ ID NO: 93)
Claim 7 of ‘179 pertains to the antibody binding site on the transferrin receptor (instant claim 7).
Claim 8 of ‘179 pertains to the molecular payload of the complex is an oligonucleotide (instant claim 9).
Claim 23 of ‘179 pertains to the oligonucleotide-antibody complex where the oligonucleotide is modified (instant claim 12).
Claim 24 of ‘179 pertains to the complex of claim 1 where the antibody is covalently linked to the molecular payload via a cleavable linker (instant claim 21).
Claim 27 of ‘179 pertains to a method of reducing expression in a cell (instant claims 24 and 25).
Claim 28 of ‘179 pertains to a method of treating a subject having a muscle disease (instant claim 26).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 10, 13, and 15 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6-8, 23, 24, 27, and 28 of copending Application No. 18/017,179 in further view of Lee (“RNAse H-mediated degradation of toxic RNA is myotonic dystrophy type 1,” published: 13 March 2012).
While ‘179 claims overlapping embodiments of the instant claims, a complex comprising an anti-TfR antibody covalently linked to a molecular payload to treat a muscular disease, ‘179 does not explicitly claim the limitations of instant claims 10, 13, and 15.
Lee teaches the use of antisense oligonucleotides (ASOs) as a therapeutic approach to target the pathogenic RNA in myotonic dystrophy type 1 (DM1) (abstract).
Regarding instant claim 10, Lee teaches the predominant cause of DM1, a pro-atrophy muscle disease, pathogenesis is the gain-of-function of mutant DMPK mRNA, which contains long CUG repeats that accumulate in the nuclei as RNA foci (p. 4221).
Regarding instant claims 13 and 15, Lee teaches the stability and efficiency of the ASO gapmers can be enhanced by substituting DNA with modified nucleotides with increased affinity for RNA and resistance to nucleases, including locked nucleic acids (LNA) or 2ˈ-O-Methoxyethyl (MOE) nucleic acids (abstract and p. 4221).
Lee teaches the use of ASOs as a therapeutic approach to target the pathogenic RNA in DM1. Therefore, ‘179 in view of Lee makes prima facie obvious the instant claims because one of ordinary skill in the art would have the breadth of knowledge to formulate the complex of ‘179 to target a pro-atrophy muscle disease where the oligonucleotide contains the limitations of instant claims 10, 13, and 15. One would predict success in doing so because Lee teaches success using such ASOs to treat DM1, which is a pro-atrophy muscle disease.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 11 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6-8, 23, 24, 27, and 28 of copending Application No. 18/017,179 in further view of Sandri (“Foxo Transcription Factors Induce the Atrophy-Related Ubiquitin Ligase Atrogin-1 and Cause Skeletal Muscle Atrophy,” published 30 April 2004).
While ‘179 claims overlapping embodiments of the instant claims, a complex comprising an anti-TfR antibody covalently linked to a molecular payload to treat a muscular disease, ‘179 does not explicitly claim the limitations of instant claim 11.
Sandri teaches Foxo transcription factors that induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy (title).
Regarding instant claim 11, Sandri teaches the ubiquitin ligase, atrogin-1 (MAFbx), is dramatically induced and causes rapid atrophy (p. 1). Sandri shows that inhibiting MAFbx (also known as FBXO32) expression, is an attractive approach to combat muscle wasting because atrogin-1 is the protein induced most dramatically during atrophy (p. 1). Sandri further teaches the Forkhead box O (Foxo) transcription factors are contained within mammalian cells (p. 2) and function through activation of the ubiquitin-proteasome pathway which leads to protein degradation and ultimately muscle atrophy (p. 1).
Sandri teaches FBXO32 is involved in muscle atrophy and treatment of muscle atrophy could involve inhibiting its expression. Therefore, ‘179 in view of Sandri makes prima facie obvious the instant claims because one of ordinary skill in the art would have the breadth of knowledge to formulate the complex of ‘179 to reduce the expression or activity of the targeted muscle gene to treat muscle atrophy with the limitations of claim 11. One would predict success in doing so because Sandri teaches FBXO32 encodes a non-secreted product that functions within the muscle cell and is responsible for muscle atrophy.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 17 is provisionally rejected on the ground