Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Application Status
Claims 18-33 are pending and examined on the merits herein.
Information Disclosure Statement
The references cited on the information disclosure statements were considered and have been made of record to the extent that each was provided.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code on page 141. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Interpretation
Claim 18 is drawn to a method of treatment comprising administering an effective amount of an antibody; wherein that amount does not elevate expression of an inflammatory marker this limitation is not an active method step and does not require active measurement of the marker during or after the course of treatment, as such it is interpreted as an intended result and not a required limitation.
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 18-31 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. This is a written description rejection.
The teachings of the specification and the claimed invention:
Claim 18 is directed to a method of treating an inflammatory fibrotic disease in a subject comprising administering to the subject an antibody or antigen binding fragment thereof that specifically binds to LTBP1-proTGFbeta complex and/or a LTBP3-proTGFbeta complex but does not bind GARP-proTGFbeta complex in an amount effective to treat the inflammatory fibrotic disease.
The claim is therefore drawn to a genus of antibodies or antigen binding fragments that bind to LTBP1 and/or LTBP3 but not GARP complexed to pro TGFbeta.
Claims 19-28 depend from claim 18 without rectifying the issue and are therefore included in this rejection.
Claims 29-31 are drawn to the antibody or fragment binding to a specific epitope within the prodomain of the complex, and further interaction with specific residues.
The instant specification does define the structural features of the paratope-epitope binding and the residues therein that facilitate binding of an antibody to LTBP1 and/or LTBP3 but not GARP in a pro TGF beta complex for the specific clone Ab42. Claims 18-31 do not define the CDRs comprising the binding paratope of the antibody. The instant specification discloses inhibitory antibodies that specifically target only the LTBP-associated large latent complexes of proTGFβ1, sparing immune cell-associated proTGFβ1 (para 10).
The instant specification further discloses more potent TGFβ1 inhibitors that selectively bind to and inhibit LTBP-presented large latent complexes (LLCs); in incorporated reference WO 2020/160291 (IDS entered 04/23/2024). The incorporated reference demonstrates that the antibody clone binds to both LTBP1 and LTBP3 but not GARP pro-TGFβcomplexes (fig 24 and instant fig 2). This disclosed antibody is identical to the clone claimed in instant claims 32-33.
The instant specification further discloses that epitope mapping by H/DX-MS identified the segment of the antigen that is important in Ab42 binding which was later confirmed by x-ray crystallography which identified the epitope for Ab42 within the alpha-1 helix region of the prodomain and the finger-1 domain of the growth factor domain (para 172).
The disclosed antibody clone is not representative of the claimed genus of antibodies. This is because when antibodies are raised to an antigen each monoclonal antibody raised comes from one unique cell with unique CDRs which are responsible for antibody binding, such that the structure of CDRs for one antibody cannot be considered representative of other antibodies with different CDRs that bind the same antigen or even substantially the same epitope. Notably, the epitope structure that one antibody binds on an antigen, do not inform the skilled artisan as to what other antibodies would bind the same or substantially the same structure.
Claim analysis:
As detailed below, one skilled in the art would be unable to envision the entire genus of antibodies that would bind to LTBP1-proTGFbeta complex and/or a LTBP3-proTGFbeta complex but not bind GARP-proTGFbeta complex.
The state of the art as it applies to the claimed invention:
Antibody binding to the same antigen, or even the same epitope on that antigen, can be accomplished with an impressively wide variety of antibody structures, even when the antibodies are limited to those from a particular source (Gershoni et al., Biodrugs (2007), 21 (3): 145-156; page 146, section 1.1). The skilled artisan therefore understood that antibodies from a variety of different sources may bind the same antigen and even mediate the same functional effects, but differ widely in the details of the structure of their antigen-binding sites, particularly in the amino acid sequence.
Further, it is not possible to predict the amino acid sequence when an epitope is recited, because there are many different epitope arrangements, such as linear and discontinuous epitopes that is dictated by the unique interaction between an antibody and its cognate epitope (Blythe et al. Protein Science (2005), 14:246–248; page 246). 3D structural analyses of antibody-epitope binding highlights the deficiency in the ability to predict the structural features of an antibody when the epitope is disclosed (Schreiber et al. J Comput Chem (2005), 26(9):879-87; page 879).
Ladner (Biotechnology and Genetic Engineering Reviews (2007), 24(1): 1-30) teaches that competitive binding assays demonstrate that two antibodies bind to overlapping or non-overlapping epitopes but not the same epitope (page 3; paragraph 3), so for accurate epitope mapping techniques that can be used are large energy transfer between labeled antibody to an antigen, antigen fragment binding, competitive peptide and antigen binding to antibody, antigen or antibody mutation, antigen-antibody complex analysis by NMR, determination of the 3D crystal structure of the antigen-antibody complex or electron microscopy (pages 5-7).
There are antibodies that bind to LTBP1 or LTBP3 known in the prior art. Schurpf (WO 2020/160291 A2; published 08/06/2020; IDS entered 04/23/2024) teaches an isolated antibody that specifically binds a human LTBP1 -proTGFb complex and/or a human LTBP3-proTGF complex, and does not bind a human GARP-proTGF complex (claim 1) for the treatment of a fibrotic condition in a human subject (claim 41) with identical sequences to the instantly claimed antibody. Hori (Kidney International, Vol. 53 (1998), pp. 1616–1625; PTO-892) teaches an LTBP-1 antibody (Ab39) that inhibited fibronectin and collagen I expression in a dose dependent manner in mesangial cells suggesting that the LTBP-ECM interaction may be a pivotal step in TGF-b action and ECM accumulation, providing a new therapeutic strategy against progression of glomerulosclerosis and other fibrotic diseases (abstract), there was no data provided about binding to LTBP-3 or GARP. Li (Expert Opinion on Therapeutic Patents, 31:8, 723-743; PTO-892) teaches a review of therapeutics targeting TGF beta signaling including TGF-β antibodies, TGF-β ligand traps, and inhibitors of TGF-β receptor kinases and that since the approval of pirfenidone, targeting TGF-β signaling has been anticipated as an effective therapy for fibrosis (abstract). Li further teaches the monoclonal antibodies AB2 and AB3 specifically bind to the pro-TGF-β complex and effectively inhibit activation of TGF-β, showing a therapeutic effect in a renal fibrosis model and further that monoclonal IgG antibody targeting LTBP1-proTGF1 complex was prepared, which significantly inhibited activation of the LTBP1-proTGF1 and LTBP3-proTGF1 signaling pathways (section 2.3, page 732). Li further teaches a recombinant chimeric monoclonal antibody derived from a rabbit monoclonal antibody targeting human and mouse latent TGF-β1 bound to cell surface latent TGF-β1 and inhibit the enzyme catalyzed cleavage of inactive complexes and release of TGF-β(section 2.3, page 732).
Accordingly, one skilled in the art would be unable to predict or envision a genus of antibodies that bind to LTBP1-proTGFbeta complex and/or a LTBP3-proTGFbeta complex but not GARP-proTGFbeta complex. Since the disclosure fails to describe a sufficient number of species to describe the claimed genus, it is submitted that the written description requirement of 35 U.S.C. 112(a) has not been met.
Claim Rejections - 35 USC § 102
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 18, 20-25, 27-28, and 33 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Schurpf (WO 2019/023661 A1; PTO-892).
Regarding claim 18, Schurpf teaches an antibody, or antigen-binding fragment thereof, for use in a method for treating a fibrotic disorder in a subject, wherein the antibody, or antigen-binding fragment thereof, specifically binds a human LTBP1- proTGF i complex and/or a human LTBP3-proTGF i complex, and does not bind a human GARP- proTGF i complex; wherein the antibody, or antigen-binding fragment thereof, is an isoform-specific TGF i inhibitor; and, wherein: a) the fibrotic disorder comprises chronic inflammation (claim 1)
Regarding claims 20-21, 23, 27, Schurpf teaches wherein the fibrotic disorder is an organ fibrosis (claim 2); wherein the organ fibrosis is selected from the group consisting of: kidney fibrosis, liver fibrosis, lung fibrosis, cardiac fibrosis, pancreatic fibrosis, skin fibrosis, scleroderma, muscle fibrosis, uterine fibrosis and endometriosis (claim 3)
Regarding claim 22, Schurpf teaches wherein the subject has chronic kidney disease (CKD) (claim 8).
Regarding claim 24-25, Schurpf teaches wherein the fibrotic disorder comprising chronic inflammation is a muscular dystrophy, multiple sclerosis (MS), or Cystic Fibrosis (CF) (claim 4); wherein the muscular dystrophy is Duchenne muscular dystrophy (DMD) (claim 5).
Regarding claim 28, Schurpf teaches wherein the subject has nonalcoholic steatohepatitis (NASH) (claim 9).
Regarding claim 33, Schurpf teaches wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region having an amino acid sequence that is at least 90% identical to SEQ ID NO: 7 or SEQ ID NO: 88 (claim 14); wherein the antibody, or antigen-binding fragment thereof, comprises a light chain variable region having an amino acid sequence that is at least 90% identical to SEQ ID NO: 8 or SEQ ID NO:89 (claim 15). SEQ ID NO: 88 has 90.7% sequence identity to the instant claimed SEQ ID NO: 7. SEQ ID NO: 319 has 97.6% sequence identity to the instant claimed SEQ ID NO: 8.
Claims 18-25 and 27-33 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Schurpf (Herein referred to as “Jackson” for clarity of the record; WO 2020/160291 A2; published 08/06/2020; IDS entered 04/23/2024).
The applied reference has a common inventor and assignee with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). This rejection under 35 U.S.C. 102(a)(2) might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B) if the same invention is not being claimed; or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed in the reference and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement.
Regarding claim 18, Jackson teaches an isolated antibody that specifically binds a human LTBP1 -proTGFb complex and/or a human LTBP3-proTGF complex, and does not bind a human GARP-proTGF complex (claim 1), a pharmaceutical composition comprising the antibody of any one of the preceding claims and a pharmaceutically acceptable excipient (claim 37), the composition of any one of claims 37-40 for use in a method for the treatment of a fibrotic condition in a human subject, wherein the treatment comprises administration of the composition to the subject in an amount effective to treat the fibrotic disorder (claim 41). Regarding the recitation that administration does not elevate expression of an inflammatory marker, this is not an active method step.
Regarding claim 19, Jackson teaches selection of a TGF inhibitor for therapeutic use includes an assessment of the ability for the TGF inhibitor to trigger cytokine release from cytokine-producing cells in which inflammatory cytokines: IL-2, TNFa, IFNy, IL-Ib, CCL2 (MCP-1), and IL-6 may be assayed and should not exceed 2 fold activation over the negative control (para 487).
Regarding claims 20-21, 23, and 27, Jackson teaches wherein the organ fibrosis is selected from the group consisting of: kidney fibrosis, liver fibrosis, lung fibrosis, cardiac fibrosis, pancreatic fibrosis, skin fibrosis, scleroderma, muscle fibrosis, uterine fibrosis and endometriosis (claim 44); wherein the lung fibrosis is idiopathic pulmonary fibrosis (IPF) (claim 45).
Regarding claim 22, Jackson teaches wherein the subject has chronic kidney disease (CKD).
Regarding claims 24-25, Jackson teaches the fibrotic disorder comprising chronic inflammation is a muscular dystrophy and in a further embodiment, the muscular dystrophy is Duchenne muscular dystrophy (DMD) (para 0556).
Regarding claim 28, Jackson teaches wherein the liver fibrosis is associated with nonalcoholic steatohepatitis (NASH) (claim 47).
Regarding claims 29-33, Jackson teaches an antibody, or antigen-binding fragment thereof, which selectively binds to human LTBP1- TGF i complex and human LTBP3-TGF i complex and competes or cross-competes with an antibody having a heavy chain variable region sequence as set forth in SEQ ID NO: 318 and light chain variable region sequence as set forth in SEQ ID NO: 319 (claim 24). SEQ ID NO: 318 has 100% sequence identity to the instant claimed SEQ ID NO: 1-3 and 7. SEQ ID NO: 319 has 100% sequence identity to the instant claimed SEQ ID NO: 4-6 and 8. Regarding claims 29-31, it naturally flows that an antibody comprising an identical VH and VL sequence will bind to the antigen at the same epitope.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim 26 is rejected under 35 U.S.C. 103 as being unpatentable over Schurpf (WO 2019/023661 A1; PTO-892) as applied to claims 18, 20-25, 27-28, and 33 above, and further in view of Muntoni (Nat Rev Drug Discov 10, 621–637 (2011); PTO-892).
The teachings of Schurpf regarding claims 18, 20-25, 27-28, and 33 are detailed above.
Schurpf does not teach that the DMD is treated with gene therapy or RNA-based therapy.
Muntoni teaches that in the case of Duchenne muscular dystrophy (DMD), exon-skipping therapies to restore a viable open reading frame in the DMD gene using antisense oligonucleotides, which are designed to target RNA and modulate pre-mRNA splicing to restore functional protein isoforms (abstract). Muntoni further teaches that redirecting pre-mRNA splicing of dystrophin offers several advantages over other therapeutic strategies including restoration of the ORF to prevent nonsense mediated mRNA decay and accumulation of the functional protein (page 622, last para). Muntoni further teaches that there are proof of concept preclinical studies as well as two recent systemic delivery clinical trials have reported that treatment is well tolerated and encouraging data on the restoration of dystrophin protein expression (page 628-630, table 2). Muntoni further teaches that muscle inflammation was also considerably reduced in a dose-dependent manner (page 629, col 1, para 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to add an RNA based therapy for DMD as taught by Muntoni to the method of treating DMD with an LBTP1-proTGFbeta antibody as taught by Schurpf. The ordinary artisan would have been motivated to do so because Muntoni teaches restoration of protein expression as well as protein accumulation using antisense oligonucleotides to restore functional protein isoforms by modulation of pre-mRNA. Muntoni further teaches that the RNA based treatments are well tolerated and demonstrate restoration of dystrophin expression with reduction in muscle inflammation. The ordinary artisan has a reasonable expectation of success to treat DMD with an RNA based therapy in addition to an antibody targeting LTBP-1 and/or LTBP-3 proTGFbeta complex.
Claim 26 is rejected under 35 U.S.C. 103 as being unpatentable over Schurpf (Herein referred to as “Jackson” for clarity of the record; WO 2020/160291 A2; published 08/06/2020; IDS entered 04/23/2024) as applied to claims 18-25 and 27-33 above, and further in view of Muntoni (Nat Rev Drug Discov 10, 621–637 (2011); PTO-892).
The applied reference has a common applicant and inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
The teachings of Jackson regarding claims 18-25 and 27-33 are detailed above.
Jackson does not teach that the DMD is treated with gene therapy or RNA-based therapy.
Muntoni teaches that in the case of Duchenne muscular dystrophy (DMD), exon-skipping therapies to restore a viable open reading frame in the DMD gene using antisense oligonucleotides, which are designed to target RNA and modulate pre-mRNA splicing to restore functional protein isoforms (abstract). Muntoni further teaches that redirecting pre-mRNA splicing of dystrophin offers several advantages over other therapeutic strategies including restoration of the ORF to prevent nonsense mediated mRNA decay and accumulation of the functional protein (page 622, last para). Muntoni further teaches that there are proof of concept preclinical studies as well as two recent systemic delivery clinical trials have reported that treatment is well tolerated and encouraging data on the restoration of dystrophin protein expression (page 628-630, table 2). Muntoni further teaches that muscle inflammation was also considerably reduced in a dose-dependent manner (page 629, col 1, para 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to add an RNA based therapy for DMD as taught by Muntoni to the method of treating DMD with an LBTP1-proTGFbeta antibody as taught by Jackson. The ordinary artisan would have been motivated to do so because Muntoni teaches restoration of protein expression as well as protein accumulation using antisense oligonucleotides to restore functional protein isoforms by modulation of pre-mRNA. Muntoni further teaches that the RNA based treatments are well tolerated and demonstrate restoration of dystrophin expression with reduction in muscle inflammation. The ordinary artisan has a reasonable expectation of success to treat DMD with an RNA based therapy in addition to an antibody targeting LTBP-1 and/or LTBP-3 proTGFbeta complex.
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 18 and 20-33 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10, 12-14, and 20 of U.S. Patent No. 12,173,059 B2. Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding claims 18 and 32-33, the patented claims teach a method of inhibiting transforming growth factor β1 (TGFβ1) signaling in a subject, the method comprising administering to the subject an antibody, or an antigen-binding fragment thereof, that specifically binds a human latent transforming growth factor beta binding protein 1 (LTBP1)-proTGFβ1 complex or a human latent transforming growth factor beta binding protein 3 (LTBP3)-proTGFβ1 complex, comprising a heavy chain variable domain and a light chain variable domain (claim 1); wherein the heavy chain variable domain comprises an amino acid sequence set forth as SEQ ID NO: 318 and the light chain variable domain comprises an amino acid sequence set forth as SEQ ID NO: 319 (claim 2-3 and 20); wherein the subject has a fibrotic condition (claim 4); wherein the fibrotic condition is a fibrotic disorder comprising chronic inflammation (claim 7). SEQ ID NO: 318 has 100% sequence identity to the instant claimed SEQ ID NO: 1-3 and 7. SEQ ID NO: 319 has 100% sequence identity to the instant claimed SEQ ID NO: 4-6 and 8.
Regarding claims 20-21, 23, and 27, the patented claims teach wherein the organ fibrosis is selected from the group consisting of kidney fibrosis, liver fibrosis, lung fibrosis, cardiac fibrosis, pancreatic fibrosis, skin fibrosis, muscle fibrosis, and uterine fibroids (claims 5-6).
Regarding claim 22, the patented claims teach wherein the fibrotic condition is Alport syndrome (claim 10).
Regarding claims 24-25, the patented claims teach wherein the fibrotic disorder comprising chronic inflammation is muscular dystrophy, multiple sclerosis, or cystic fibrosis (claim 8); wherein the muscular dystrophy is Duchenne muscular dystrophy (DMD) (claim 9).
Regarding claim 28, the patented claims teach wherein the NAFLD is non-alcoholic fatty liver (NAFL) or non-alcoholic steatohepatitis (NASH) (claims 12-14).
Regarding claims 29-31, it naturally flows that an antibody comprising an identical VH and VL sequence will bind to the antigen at the same epitope.
Claims 18, 24-25, and 32-33 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 11-13, 16-17, 21-23, 25-26, 28, 30, 36-37, 41, and 44 of copending Application No. 18/941,156 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding claim 18, the copending claims teach an antibody, or antigen-binding fragment thereof, which specifically binds human LTBP1-TGFB1 complex and human LTBP3 -TGFB1 complex (claims 11-13, 16-17, 21, 23, 26, 28, 30, 36), which does not show detectable binding to a human GARP-proTGFB1 complex (claim 25), a pharmaceutical composition comprising the antibody of claim 11 and a pharmaceutically acceptable excipient (claim 37), a method for the treatment of a fibrotic condition in a human subject, wherein the treatment comprises administration of the composition of claim 37 to the subject in an amount effective to treat the fibrotic disorder (claims 37 and 41).
Regarding claims 24-25, the copending claims teach wherein the fibrotic disorder is a muscle fibrosis, optionally wherein the muscle fibrosis is a muscular dystrophy,
further optionally wherein the muscular dystrophy is Duchenne muscular dystrophy
(DMD) (claim 44).
Regarding claims 32-33, the copending claims teach wherein the antibody comprises: a heavy chain variable region having an amino acid sequence that is at least 90% identical to SEQ ID NO: 318; and a light chain variable region having an amino acid sequence that is at least 90% identical to SEQ ID NO: 319 (claims 11 and 22). SEQ ID NO: 318 has 100% sequence identity to the instant claimed SEQ ID NO: 1-3 and 7. SEQ ID NO: 319 has 100% sequence identity to the instant claimed SEQ ID NO: 4-6 and 8.
Regarding claim 33, the copending claims teach wherein the antibody comprises:
a heavy chain variable region having an amino acid sequence that is at least 90% identical to SEQ ID NO: 88; and a light chain variable region having an amino acid sequence that is at least 90% identical to SEQ ID NO: 89 (claims 1 and 5). SEQ ID NO: 88 has 90.7% sequence identity to the instant claimed SEQ ID NO: 7. SEQ ID NO: 319 has 97.6% sequence identity to the instant claimed SEQ ID NO: 8.
Claims 18, 20-21, 23-25, 27, and 29 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 19-23, 25-27, 31-32, and 34-35 of copending Application No. 19/700,698 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding claim 18, the copending claims teach a method for treating a disease associated with TGFB1 dysregulation in a subject, the method comprising a step of administering to the subject a therapeutically effective amount of a composition comprising an isoform-specific inhibitor of TGFB1 and a pharmaceutically acceptable excipient, wherein the inhibitor targets both ECM-associated TGFB1 and immune cell-associated TGFB1 but does not target TGFB2 or TGFB3 in vivo, and, wherein the disease is characterized by dysregulation or impairment at least two of the following attributes:
a) regulatory T cells (Treg);
b) effector T cell (Teff) proliferation or function;
c) myeloid cell proliferation or differentiation;
d) monocyte recruitment or differentiation;
e) macrophage function;
f) epithelial-to-mesenchymal transition (EMT) and/or endothelial-to-mesenchymal transition (EndMT);
g) gene expression in one or more of marker genes selected from the group consisting of: PAl-1, ACTA2, CCL2, Col1 a1, Col3a1, FN-1, CTGF, and TGFB1;
h) ECM components or function; and,
fibroblast activation/differentiation (claim 1);
wherein the ECM-associated TGFB1 is LTBP1-presented TGFB1 and/or LTBP3-presented TGFB1 (claim 2); wherein the disease involves a proliferative component and/or a fibrotic component (claim 3); wherein the disease is a fibrotic disorder (claims 19-21); wherein the fibrotic disorder comprises chronic inflammation (claim 25); wherein the inhibitor is a monoclonal antibody or fragment thereof (claim 31); wherein the monoclonal antibody or fragment thereof binds a protein complex comprising a pro/latent TGFB1 (claim 32).
Regarding claims 20-21 and 27, the copending claims teach wherein the organ fibrosis is liver fibrosis, lung fibrosis, kidney fibrosis, skin fibrosis and/or cardiac fibrosis (claims 22-23).
Regarding claims 23-25, the copending claims teach wherein the fibrotic disorder is a muscular dystrophy (claim 26), wherein the muscular dystrophy is DMD (claim 27).
Regarding claims 29, the copending claims teach wherein the antibody or fragment thereof specifically binds an epitope within pro/latent TGFB1 (claim 34); wherein the epitope is within a prodomain of the pro/latent TGFB1 (claim 35).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
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/AMBER K FAUST/Examiner, Art Unit 1643
/GARY B NICKOL/Primary Examiner, Art Unit 1643
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