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
Claim 20 has been cancelled and claims 1-16 have been amended, as requested in the preliminary amendment filed on 02/23/2024. Following the amendment, claims 1-19 are pending in the instant application.
Claims 1-19 are under examination in the instant office action.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. However, it is noted that no English translation of the foreign priority document has been provided, and as such the claim to foreign priority has not been perfected.
Claims 1-19 have an effective filing date of August 24, 2022 corresponding to PCT/KR2022/012660.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 02/23/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The drawings are objected to because Figure 2 comprises text/axis labels that are blurry and difficult to read. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to for the use of the terms Opadry, FACS, and Enbrel, which are trade names or marks used in commerce, have been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claim 1 is objected to because of the following informalities: the claim currently reads "the . Appropriate correction is required.
Claim Interpretation
With regard to the sequence language in the instant application, the following are noted:
The recitation of, for example, “comprising an amino acid sequence represented by SEQ ID NO…” is being interpreted as open sequence language such that any reference amino acid sequence as few as two consecutive amino acid sequences of the recited SEQ ID NO(s) is sufficient to meet the limitation (i.e., fragments/truncations of the recited sequences are sufficient to meet the limitation). This interpretation is relevant to claims 6 and 8-11.
The recitation of, for example, “comprising any one selected from the group consisting of amino acid sequences represented by SEQ ID NOs: 7-10” is being interpreted as closed sequence language such that a reference amino acid sequence must comprise/consist of the full-length sequence of one of SEQ ID NOs: 7-10 to meet the limitation. This interpretation is relevant to claim 9.
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 1-19 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a WRITTEN DESCRIPTION rejection.
The claims are drawn to a method of (i) treating an autoimmune disease or (ii) a method of providing information required for diagnosing autoimmune diseases, comprising vimentin-specific antibodies or immunologically active fragments thereof. Thus, the claims identify the antibody by the function of binding vimentin. Claims 8-9 further limit the vimentin-specific antibody or fragment thereof by a partial structure, wherein the antibody (i) comprises a VH domain comprising a complementarity determining regions heavy chain (CDRH)1 comprising an amino acid sequence represented by SEQ ID NO: 1, a CDRH2 comprising an amino acid sequence represented by SEQ ID NO: 2 or 3, and a CDRH3 comprising an amino acid sequence represented by SEQ ID NO: 4 or 5 or (ii) comprises a VL domain comprising a complementarity determining regions light chain (CDRL)1 comprising an amino acid sequence represented by SEQ ID NO: 6, a CDRL2 comprising any one selected from the group consisting of amino acid sequences represented by SEQ ID NOs: 7 to 10, and a CDRL3 comprising an amino acid sequence represented by SEQ ID NO: 11 or 12. It is specifically noted that the “an amino acid sequence” language indicates that the CDRs may comprise any amino acid sequence of two or more consecutive residues in the recited SEQ ID NOs; truncations and fragments of the recited SEQ ID NOs are included. Thus, the claims encompass a vast genus of antibody variants comprising (i) fewer than six parental CDRs and (ii) truncated/fragmented HCDR1-3 or LCDR1-3 sequences and required to bind vimentin.
The instant specification discloses a single vimentin-specific antibody described by six parental CDRs at Pages 11-12: antibody hzVSF-V13 includes CDRH1 including an amino acid sequence represented by SEQ ID NO: 1, CDRH2 including an amino acid sequence represented by SEQ ID NO: 2, CDRH3 including an amino acid sequence represented by SEQ ID NO: 4, CDRLI including an amino acid sequence represented by SEQ ID NO: 6, CDRL2 including an amino acid sequence represented by SEQ ID NO: 7, and CDRL3 including an amino acid sequence represented by SEQ ID NO: 11.
To provide adequate written description and evidence of possession of the claimed antibody genus, the instant specification can structurally describe representative antibody variants that function to bind vimentin, or describe structural features common to the members of the genus, which features constitute a substantial portion of the genus. Alternatively, the specification can show that the claimed invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics (see University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) and Enzo Biochem, Inc. V. Gen-Probe Inc.).
In this case, the only factor present in the claims is a recitation of the antibody function, “vimentin-specific”, and partial sequence structure as stated above. The instant specification fails to describe structural features common to the members of the antibody genus, which features constitute a substantial portion of the genus because the instant specification fails to disclose representative antibody variant sequences and antibodies comprising fewer than six parental CDRs that function as claimed. A definition by function does not suffice to define the genus because it is only an indication of what the antibody does, rather than what it is. The specification fails to provide the HCDR1, HCDR2, HCDR3 and/or LCDR1, LCDR2, LCDR3 structural features coupled to the claimed functional characteristics. The instant specification fails to describe a representative number of antibody sequence variants for the genus of antibodies that function as claimed. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus required to make the claimed antibodies.
The claims broadly encompass any sequence variant having as few as two amino acids from (i) the recited HCDR1, HCDR2, and HCDR3 sequences or (ii) the recited LCDR1, LCDR2, and LCDR3 sequences that function to bind vimentin. Applicants have not established any reasonable structure-function correlation with regards to the sequences in the CDRs that can be altered/truncated and still maintain vimentin binding function. Given the well-known high level of polymorphism of antibody CDR sequences and structure, the skilled artisan would not have been in possession of the vast repertoire of antibodies encompassed by the claimed invention. One could not reasonably or predictably extrapolate the structure of a single parental antibody to the structure of any variants required to bind vimentin as broadly claimed. Therefore, one could not readily envision members of the broadly claimed genus.
Although Applicants may argue that it is possible to screen for antibodies that bind vimentin and function as claimed, the court found in (Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004) that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention. “As we held in Lilly, “[a]n adequate written description of a DNA … ‘requires a precise definition, such as by structure, formula, chemical name, or physical properties,’ not a mere wish or plan for obtaining the claimed chemical invention.” 119 F.3d at 1566 (quoting Fiers, 984 F.2d at 1171). For reasons stated above, that requirement applies just as well to non-DNA (or RNA) chemical inventions.” Knowledge of screening methods provides no information about the structure of any future antibodies yet to be discovered that may function as claimed. The vimentin antigen provides no information about the structure of an antibody that binds to it.
Given the lack of representative examples to support the full scope of the claimed variant antibodies, and lack of reasonable structure-function correlation with regards to the unknown variable sequences in the CDRs that provide vimentin-binding function, the present claims lack adequate written description. Thus, the specification does not provide an adequate written description of antibody variants that bind vimentin and comprise (i) as few as two defined consecutive amino acids in each recited HCDR or LCDR or (ii) fewer than six parental CDRs that is required to practice the claimed invention.
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 18 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 18 contains the trademark/trade name FACS. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe fluorescence activated cell sorting/flow cytometry/flow cytometers and, accordingly, the identification/description is indefinite.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 12-16 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Regarding claims 12-16, it is specifically noted that claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure. With regard to “adapted to”, “adapted for”, “wherein”, and/or “whereby” clauses, the determination of whether each of these clauses is a limitation in a claim depends on the specific facts of the case. See, e.g., Griffin v. Bertina, 285 F.3d 1029, 1034, 62 USPQ2d 1431 (Fed. Cir. 2002) (finding that a "wherein" clause limited a process claim where the clause gave "meaning and purpose to the manipulative steps"). In In re Giannelli, 739 F.3d 1375, 1378, 109 USPQ2d 1333, 1336 (Fed. Cir. 2014), the court found that an "adapted to" clause limited a machine claim where "the written description makes clear that 'adapted to,' as used in the [patent] application, has a narrower meaning, viz., that the claimed machine is designed or constructed to be used as a rowing machine whereby a pulling force is exerted on the handles." In Hoffer v. Microsoft Corp., 405 F.3d 1326, 1329, 74 USPQ2d 1481, 1483 (Fed. Cir. 2005), the court held that when a "‘whereby’ clause states a condition that is material to patentability, it cannot be ignored in order to change the substance of the invention." Id. However, the court noted that a "‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’" Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)). See MPEP 2111.04(I). In the instant case, it is noted that the “wherein” clauses of instant claims 12-16 do not serve to give meaning and purpose to the manipulative steps of claim 1 from which they depend, nor do they serve to limit the claims to a particular structure. As such, the “wherein” clauses of instant claims 12-16 are interpreted as intended results of a process step positively recited and will necessarily occur by way of performing the method of instant claim 1; thus, claims 12-16 fail to further limit the subject matter of instant claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 1-2, 5, 7, and 12-16 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by US 2015/0056208 A1 (herein after referred to as "Klareskog").
Klareskog teaches antibodies that can bind to certain citrullinated epitopes namely citrullinated enolase, vimentin, fibrinogen and citrullinated synthetic peptides; these antibodies can be used in diagnostics of rheumatoid arthritis, for therapy against rheumatoid arthritis and as research tools (Abstract; emphasis added). ELISA tests for antibodies against citrullinated forms of enolase, vimentin and/or fibrinogen peptides can be used for diagnosis of rheumatoid arthritis. Such tests show the presence or absence of antibodies in patient serum that react with citrullinated epitopes such peptides from as alpha enolase, vimentin and fibrinogen (Paragraph 0008). The term "antibody" as used herein refers to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e. molecules that contain an antigen binding site that specifically binds an antigen, whether natural or partially or wholly synthetically produced, and covering any polypeptide or protein having a binding domain which is, or is homologous to, an immunoglobin molecule; examples of antibodies are the immunoglobulin isotypes (e.g. IgG, IgE, IgM, IgD and IgA) and their isotypic subclasses (such as for IgG: IgGl, IgG2, IgG3), and fragments which comprise an antigen binding domain such as Fab, scFv, Fv, dAb and diabodies (Paragraph 0027). The invention provides antibodies A03, A04, A40, B05, CO2, C04, C05, D06, 127, G12, 109, 117, A02, A09, B07, C50, C07, D09, D10 and F12 with sequences of heavy chain and light chains CDRl, CDR2 and CDR3 as defined in Tables 1-3 (Paragraph 0036; see also Pages 3-4). Preferably the antibody binds to at least one citrullinated epitope, preferably to at least one citrullinated epitope selected from the group consisting of citrullinated human enolase peptide 1, (SEQ ID NO 121) (CEP-1), citrullinated human vimentin residues 60-75 (SEQ ID NO 122) (cit-vim), citrullinated human fibrinogen residues 36-52 (SEQ ID NO 123) (cit-fib), and citrullinated synthetic peptide (Immunoscan CCPlus Euro-Diagnostica) (CCP), even more preferably at least one epitope selected from the group consisting of CEP-1, cit-vim and cit-fib; the sequences of these peptides are shown in Table 5 (Paragraph 0037; see also Page 8). Another aspect of the invention is a method of treating rheumatoid arthritis comprising administering to a patient in need thereof an antibody according to the invention (Paragraph 0094). For therapeutic use, the antibody is suitable formulated together with buffers, preservatives, carriers and other excipients known to a person skilled in the art (i.e., a pharmaceutical composition) (Paragraph 0097). Thus, Klareskog teaches a method of treating rheumatoid arthritis comprising administering a pharmaceutical composition comprising a vimentin-specific antibody, wherein said vimentin-specific antibody (i) binds citrullinated vimentin and/or (ii) the immunologically active fragment is a Fab, scFv, or Fv. Klareskog therefore anticipates instant claims 1-2, 5, and 7.
Regarding claims 12-16, it is specifically noted that claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure. With regard to “adapted to”, “adapted for”, “wherein”, and/or “whereby” clauses, the determination of whether each of these clauses is a limitation in a claim depends on the specific facts of the case. See, e.g., Griffin v. Bertina, 285 F.3d 1029, 1034, 62 USPQ2d 1431 (Fed. Cir. 2002) (finding that a "wherein" clause limited a process claim where the clause gave "meaning and purpose to the manipulative steps"). In In re Giannelli, 739 F.3d 1375, 1378, 109 USPQ2d 1333, 1336 (Fed. Cir. 2014), the court found that an "adapted to" clause limited a machine claim where "the written description makes clear that 'adapted to,' as used in the [patent] application, has a narrower meaning, viz., that the claimed machine is designed or constructed to be used as a rowing machine whereby a pulling force is exerted on the handles." In Hoffer v. Microsoft Corp., 405 F.3d 1326, 1329, 74 USPQ2d 1481, 1483 (Fed. Cir. 2005), the court held that when a "‘whereby’ clause states a condition that is material to patentability, it cannot be ignored in order to change the substance of the invention." Id. However, the court noted that a "‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’" Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)). See MPEP 2111.04(I). In the instant case, it is noted that the “wherein” clauses of instant claims 12-16 do not serve to give meaning and purpose to the manipulative steps of claim 1 from which they depend, nor do they serve to limit the claims to a particular structure. As such, the “wherein” clauses of instant claims 12-16 are interpreted as intended results of a process step positively recited and will necessarily occur by way of performing the method of instant claim 1. Thus, Klareskog further anticipates instant claims 12-16.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2 and 5-19 are rejected under 35 U.S.C. 103 as being unpatentable over US 2015/0056208 A1 (herein after referred to as "Klareskog") in view of US 10,961,300 (herein after referred to as “Kim”) and non-patent literature by Musaelyan et. al. (Autoimmunity Reviews, 2018, 17, 926-934; herein after referred to as “Musaelyan”).
Klareskog teaches antibodies that can bind to certain citrullinated epitopes namely citrullinated enolase, vimentin, fibrinogen and citrullinated synthetic peptides; these antibodies can be used in diagnostics of rheumatoid arthritis, for therapy against rheumatoid arthritis and as research tools (Abstract; emphasis added). ELISA tests for antibodies against citrullinated forms of enolase, vimentin and/or fibrinogen peptides can be used for diagnosis of rheumatoid arthritis. Such tests show the presence or absence of antibodies in patient serum that react with citrullinated epitopes such peptides from as alpha enolase, vimentin and fibrinogen (Paragraph 0008). The term "antibody" as used herein refers to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e. molecules that contain an antigen binding site that specifically binds an antigen, whether natural or partially or wholly synthetically produced, and covering any polypeptide or protein having a binding domain which is, or is homologous to, an immunoglobin molecule; examples of antibodies are the immunoglobulin isotypes (e.g. IgG, IgE, IgM, IgD and IgA) and their isotypic subclasses (such as for IgG: IgGl, IgG2, IgG3), and fragments which comprise an antigen binding domain such as Fab, scFv, Fv, dAb and diabodies (Paragraph 0027). The invention provides antibodies A03, A04, A40, B05, CO2, C04, C05, D06, 127, G12, 109, 117, A02, A09, B07, C50, C07, D09, D10 and F12 with sequences of heavy chain and light chains CDRl, CDR2 and CDR3 as defined in Tables 1-3 (Paragraph 0036; see also Pages 3-4). Preferably the antibody binds to at least one citrullinated epitope, preferably to at least one citrullinated epitope selected from the group consisting of citrullinated human enolase peptide 1, (SEQ ID NO 121) (CEP-1), citrullinated human vimentin residues 60-75 (SEQ ID NO 122) (cit-vim), citrullinated human fibrinogen residues 36-52 (SEQ ID NO 123) (cit-fib), and citrullinated synthetic peptide (Immunoscan CCPlus Euro-Diagnostica) (CCP), even more preferably at least one epitope selected from the group consisting of CEP-1, cit-vim and cit-fib; the sequences of these peptides are shown in Table 5 (Paragraph 0037; see also Page 8). Another aspect of the invention is a method of treating rheumatoid arthritis comprising administering to a patient in need thereof an antibody according to the invention (Paragraph 0094). For therapeutic use, the antibody is suitable formulated together with buffers, preservatives, carriers and other excipients known to a person skilled in the art (i.e., a pharmaceutical composition) (Paragraph 0097). The antibodies according to the invention can be used in diagnosis or as a research tool; for example, one or more antibodies according to the invention may be included as positive controls in a diagnostic kit for testing for the presence of autoantibodies with reactivity against rheumatoid arthritis-specific antigens, in particular citrullinated enolase, citrullinated vimentin, citrullinated fibrinogen and/or collagen type II (Paragraph 0098). One further aspect of the invention is a diagnostic kit that comprises an antibody according to the invention wherein such a kit preferably comprises an ELISA plate or other platform for antibody analysis as well as reagents for detection of antibodies, such as labeled-anti-human antibodies and suitable buffers; thus the antibodies according to the invention can be used for in vitro diagnosis (Paragraph 0100).
However, Klareskog does not explicitly teach or suggest vimentin-specific antibodies that (i) are specific to vimentin including an amino acid sequence represented by SEQ ID NO: 21; (ii) comprise a CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2 or 3, and CDRH3 of SEQ ID NO: 4 or 5; (iii) CDRL1 of SEQ ID NO: 6, CDRL2 of one of SEQ ID NOs: 7-10, and CDRL3 of SEQ ID NO: 11 or 12; VH FRs 1-3 of SEQ ID NOs: 13-16, respectively; and (iv) VL FRs of SEQ ID NOs: 17-20. These deficiencies are remedied by Kim.
Kim teaches an antibody specifically binding to the isolated peptide of SEQ ID NO: 1 or a fragment binding to the peptide (Column 5, Lines 64-67). It is specifically noted that Kim SEQ ID NO: 1 is an antigenic region including an epitope, wherein it is noted that Kim SEQ ID NO: 1 comprises an exact match to instant SEQ ID NO: 21, and it may be an amino acid sequence of vimentin at amino acid positions 142 to 211 or at amino acid positions 211-294 (Column 6, Lines 53-59). Vimentin, which is a protein encoded by the VIM gene, supports and anchors intracellular organelles in place, and is known to be mainly involved in maintenance of cell shape, transport of proteins, and cell signaling (Column 6, Lines 64-67). The term "antibody" immunologically refers to a protein molecule which has the role of a ligand specifically recognizing an antigen, including an immunoglobulin molecule having reactivity to a specific antigen, and it may include all of a polyclonal antibody, a monoclonal antibody, a whole antibody, and an antibody fragment (Column 7, Lines 25-30); the terms "fragment", "fragment binding to a peptide", and "antibody fragment" refer to any fragment of the antibodies or peptide-binding fragment of the present invention having antigen-binding activity and may include a single chain antibody, Fd, Fab, Fab’, F(ab’)2, dsFv, or scFv (Column 7, Lines 43-50). A humanized antibody or the fragment binding to the peptide may include: (i) a heavy chain variable region including a heavy chain CDRl of SEQ ID NO: 2; a heavy chain CDR2 of SEQ ID NO: 3 or SEQ ID NO: 14 (in which the 9th amino acid of SEQ ID NO: 3, threonine, is substituted with aspartic acid); and a heavy chain CDR3 of SEQ ID NO: 4 or SEQ ID NO: 15 (in which the 4th amino acid of SEQ ID NO: 4, threonine, is substituted with asparagine); and (ii) a light chain variable region including a light chain CDRl of SEQ ID NO: 5; a light chain CDR2 of SEQ ID NO: 6, SEQ ID NO: 16 (in which the 3rd amino acid of SEQ ID NO: 6, threonine, is substituted with aspartic acid), SEQ ID NO: 17 (in which the 3rd amino acid of SEQ ID NO: 6, threonine, is substituted with aspartic acid and the 6th amino acid of SEQ ID NO: 6, alanine, is substituted with glycine), or SEQ ID NO: 18 (in which the 3rd amino acid of SEQ ID NO: 6, threonine, is substituted with aspartic acid; the 5th amino acid of SEQ ID NO: 6, leucine, is substituted with arginine; and the 6th amino acid of SEQ ID NO: 6, alanine, is substituted with glycine); and a light chain CDR3 of SEQ ID NO: 7 or SEQ ID NO: 19 (in which the 6th amino acid of SEQ ID NO: 7, serine, is substituted with threonine) (Column 8 Line 49 through Column 9, Line 4). It is specifically noted that Kim SEQ ID NOs: 2, 3, 14, 4, 15, 5, 6, 16, 17, 18, 7, and 19 comprise and/or consist of exact matches to instant SEQ ID NOs: 1, 3, 2, 4, 5, 6, 8, 7, 9, 10, and 12, respectively. Kim further teaches that the humanized antibody or the fragment binding to the peptide includes a human framework region (FR), wherein the antibody or fragment comprises: (i) a heavy chain FR1 of SEQ ID NO: 20, a heavy chain FR2 of SEQ ID NO: 21, a heavy chain FR3 of SEQ ID NO: 22 or SEQ ID NO: 28 (in which the 8th amino acid of SEQ ID NO: 22, lysine, is substituted with threonine; and the 10th amino acid of SEQ ID NO: 22, isoleucine, is substituted with alanine), and a heavy chain FR4 of SEQ ID NO: 23; and (ii) a light chain FR1 of SEQ ID NO: 24, a light chain FR2 of SEQ ID NO: 25, a light chain FR3 of SEQ ID NO: 26, and a light chain FR4 of SEQ ID NO: 27 (Column 9, Lines 5-20). It is specifically noted that Kim SEQ ID NOs: 20-27 are exact matches to instant SEQ ID NOs: 13-20, respectively. The humanized antibody or the fragment binding to the peptide may include a heavy chain variable region and a light chain variable region, respectively, of SEQ ID NO: 32 and SEQ ID NO: 34 (comprise instant SEQ ID NOs: 1/3/4 and 6/7/11, respectively); SEQ ID NO: 36 and SEQ ID NO: 38 (comprise instant SEQ ID NOs: 1/3/4 and 6/9/11, respectively); SEQ ID NO: 40 and SEQ ID NO: 42 (comprise instant SEQ ID NOs: 1/3/4 and 6/10/11, respectively); SEQ ID NO: 44 and SEQ ID NO: 46 (comprise instant SEQ ID NOs: 1/3/4 and 6/10/12, respectively); SEQ ID NO: 48 and SEQ ID NO: 50 (comprise instant SEQ ID NOs: 1/2/4 and 6/8/11, respectively); SEQ ID NO: 56 and SEQ ID NO: 58 (comprise instant SEQ ID NOs: 1/2/4 and 6/8/11, respectively); SEQ ID NO: 60 and SEQ ID NO: 62 (comprise instant SEQ ID NOs: 1/2/5 and 6/8/11, respectively); SEQ ID NO: 64 and SEQ ID NO: 66 (comprise instant SEQ ID NOs: 1/2/4 and 6/10/11, respectively); SEQ ID NO: 68 and SEQ ID NO: 70 (comprise instant SEQ ID NOs: 1/2/5 and 6/10/11, respectively); SEQ ID NO: 72 and SEQ ID NO: 74 (comprise instant SEQ ID NOs: 1/2/4 and 6/10/12, respectively); SEQ ID NO: 76 and SEQ ID NO: 78 (comprise instant SEQ ID NOs: 1/2/5 and 6/10/12, respectively); or SEQ ID NO: 80 and SEQ ID NO: 82 (comprise instant SEQ ID NOs: 1/2/4 and 6/7/11, respectively) (Column 11, Lines 1-13). Kim further provides an antiviral composition containing the antibody or the fragment binding to the peptide (Column 13, Lines 10-12); the composition may be in the form of a pharmaceutical composition, a quasi-drug composition, and a functional health food composition, wherein the pharmaceutical composition may further include a pharmaceutically acceptable carrier (Column 13, Lines 46-50). The composition may be one which suppresses the infiltration of immune cells or may be one which inhibits inflammatory reactions, and the composition of the invention was confirmed to significantly inhibit proinflammatory cytokines, such as IL-6, TNF-a, IFN-y, and CCL2 (MCP-1) (Column 15, Lines 12-17).
However, neither Klareskog nor Kim explicitly teach or suggest using antibodies specific to non-citrullinated vimentin in treatment nor for providing information for diagnosing an autoimmune disease comprising forming an antigen-antibody complex by reacting a sample isolated from a specimen with a vimentin-specific antibody or an immunologically active fragment thereof and detecting the formation of the complex. These deficiencies are remedied by Musaelyan.
Musaelyan teaches that vimentin is one of the antigens involved in the pathogenesis of rheumatoid arthritis (RA); generation of post-translationally modified vimentin in vivo can abolish primary immunotolerance and induce disease in susceptible host and drives autoimmune responses in in flamed RA joints and naturally occurring citrullinated post-translationally modified vimentin known as Sa antigen in RA presents in many tissues and can be purified from the placenta (Page 928, Column 2, Section 3). Antibodies against Sa antigen are very specific (96.9%) for RA and can be found in 30–36.6% patients with the disease; citrullination of vimentin and other proteins of the synovial membranes, including fibrin and alpha-enolase, leads to a synthesis of anti-citrullinated peptide antibodies (ACPA) that are recognized biomarkers for RA (Id.). Local inflammation of synovial membranes can generate post-translationally modified vimentin that becomes the autoantigenic target. The presence of intracellular citrullinated antigens like vimentin and alpha-enolase can be detected in the synovial lining of RA joint and correlate with systemic ACPA level; it is suggested that vimentin citrullination are associated with granulocyte and macrophage apoptosis that produces significant amounts on intracellular components including vimentin and also peptidyl- arginine deiminase-2 and peptidyl-arginine deiminase-4 enzymes that are in volved in inflammatory citrullination and fragmented extracellular DNA in the synovial fluid indicates an apoptosis in RA synovium and high levels of PAD expression in joint correlated with a systemic inflammatory activity (Page 929, Column 1, Fourth Paragraph). Vimentin can also be excreted by activated macrophages under the influence of TNFα (Id.). RA is characterized by a high neutrophil content in the synovial fluid that is typically over 2000 cells per μl, and the number of neutrophils correlates with the concentrations of IL-8; a specific form of apoptosis of neutrophilic granulocytes generates neutrophilic extracellular traps (NET) that are expulsion of DNA-protein complexes and enzymes from the cell (Page 929, Column 1, Fifth Paragraph). During NETosis externalization of vimentin and other intracellular constituents occurs together with peptidyl- arginine deiminase, myeloperoxidase, cathepsin G and other enzymes involved in proteolysis and post-translational modifications; high level of NETosis in the peripheral blood can be found in RA in contrast to osteoarthritis and controls, and NETosis also was found in synovial pannus, rheumatoid nodules and skin of RA patients and its severity correlates with ACPA, rheumatoid factor and other markers of systemic inflammation including CRP and ESR (Id.). Oxidative stress is another result of ubiquitous NETosis; in fibroblast cell line in vitro oxidative stress induces an expression of post-translationally modified vimentin that are recognized by ACPA from synovial fluid of RA patients (Id.). Thus, Musaelyan establishes the role of vimentin in rheumatoid arthritis, including the increased presence of vimentin and/or citrullinated vimentin in the blood, synovial pannus, rheumatoid nodules, and skin of RA patients.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the methods of Klareskog such that the vimentin-specific antibody is specific for vimentin comprising instant SEQ ID NO: 21 (i.e., a non-citrullinated epitope). One would have been motivated to make such a modification because vimentin-specific antibodies that are specific for vimentin comprising instant SEQ ID NO: 21 are known in the art, as taught by Kim, and the use of vimentin-specific antibodies to citrullinated epitopes are established in the treatment and/or diagnostic methods (e.g., ELISA) for rheumatoid arthritis, as taught by Klareskog, and Musaelyan establishes the role of vimentin, both citrullination and non-citrullinated, in the pathogenesis of rheumatoid arthritis and its increased presence in in the blood, synovial pannus, rheumatoid nodules, and skin of RA patients. One of ordinary skill in the art would have a reasonable expectation of success of applying the antibodies of Kim in the methods of Klareskog wherein it would reasonably be expected that targeting/detecting non-citrullinated vimentin would also be useful in therapeutic/diagnostic methods as suggested by Musaelyan.
Klareskog recognizes the need in the art for effective treatments and diagnostic methods for rheumatoid arthritis, implicates citrullinated vimentin, and discloses antibodies useful in such methods wherein said antibodies are specific for an epitope of citrullinated vimentin. Kim discloses vimentin-specific antibodies to a non-citrullinated epitope, and Musaelyan teaches that vimentin, both citrullinated and non-citrullinated, are implicated in the pathogenesis of rheumatoid arthritis and are increased/detectable in the blood, synovial pannus, rheumatoid nodules, and skin of RA patients. Given the recognized need for therapeutic and diagnostic methods, and given the known implications and increased presence of vimentin in cases of rheumatoid arthritis, one of skill in the art could have pursued applying vimentin-specific antibodies in therapeutic and diagnostic methods with a reasonable expectation of success.
Regarding claims 12-16, it is specifically noted that claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure. With regard to “adapted to”, “adapted for”, “wherein”, and/or “whereby” clauses, the determination of whether each of these clauses is a limitation in a claim depends on the specific facts of the case. See, e.g., Griffin v. Bertina, 285 F.3d 1029, 1034, 62 USPQ2d 1431 (Fed. Cir. 2002) (finding that a "wherein" clause limited a process claim where the clause gave "meaning and purpose to the manipulative steps"). In In re Giannelli, 739 F.3d 1375, 1378, 109 USPQ2d 1333, 1336 (Fed. Cir. 2014), the court found that an "adapted to" clause limited a machine claim where "the written description makes clear that 'adapted to,' as used in the [patent] application, has a narrower meaning, viz., that the claimed machine is designed or constructed to be used as a rowing machine whereby a pulling force is exerted on the handles." In Hoffer v. Microsoft Corp., 405 F.3d 1326, 1329, 74 USPQ2d 1481, 1483 (Fed. Cir. 2005), the court held that when a "‘whereby’ clause states a condition that is material to patentability, it cannot be ignored in order to change the substance of the invention." Id. However, the court noted that a "‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’" Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)). See MPEP 2111.04(I). In the instant case, it is noted that the “wherein” clauses of instant claims 12-16 do not serve to give meaning and purpose to the manipulative steps of claim 1 from which they depend, nor do they serve to limit the claims to a particular structure. As such, the “wherein” clauses of instant claims 12-16 are interpreted as intended results of a process step positively recited and will necessarily occur by way of performing the method of instant claim 1. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
Claims 1-2 and 5-19 are rejected under 35 U.S.C. 103 as being unpatentable over US 2015/0056208 A1 (herein after referred to as "Klareskog") in view of US 11,649,277 (herein after referred to as “Park”) in view of non-patent literature by Musaelyan et. al. (Autoimmunity Reviews, 2018, 17, 926-934; herein after referred to as “Musaelyan”).
Klareskog teaches antibodies that can bind to certain citrullinated epitopes namely citrullinated enolase, vimentin, fibrinogen and citrullinated synthetic peptides; these antibodies can be used in diagnostics of rheumatoid arthritis, for therapy against rheumatoid arthritis and as research tools (Abstract; emphasis added). ELISA tests for antibodies against citrullinated forms of enolase, vimentin and/or fibrinogen peptides can be used for diagnosis of rheumatoid arthritis. Such tests show the presence or absence of antibodies in patient serum that react with citrullinated epitopes such peptides from as alpha enolase, vimentin and fibrinogen (Paragraph 0008). The term "antibody" as used herein refers to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e. molecules that contain an antigen binding site that specifically binds an antigen, whether natural or partially or wholly synthetically produced, and covering any polypeptide or protein having a binding domain which is, or is homologous to, an immunoglobin molecule; examples of antibodies are the immunoglobulin isotypes (e.g. IgG, IgE, IgM, IgD and IgA) and their isotypic subclasses (such as for IgG: IgGl, IgG2, IgG3), and fragments which comprise an antigen binding domain such as Fab, scFv, Fv, dAb and diabodies (Paragraph 0027). The invention provides antibodies A03, A04, A40, B05, CO2, C04, C05, D06, 127, G12, 109, 117, A02, A09, B07, C50, C07, D09, D10 and F12 with sequences of heavy chain and light chains CDRl, CDR2 and CDR3 as defined in Tables 1-3 (Paragraph 0036; see also Pages 3-4). Preferably the antibody binds to at least one citrullinated epitope, preferably to at least one citrullinated epitope selected from the group consisting of citrullinated human enolase peptide 1, (SEQ ID NO 121) (CEP-1), citrullinated human vimentin residues 60-75 (SEQ ID NO 122) (cit-vim), citrullinated human fibrinogen residues 36-52 (SEQ ID NO 123) (cit-fib), and citrullinated synthetic peptide (Immunoscan CCPlus Euro-Diagnostica) (CCP), even more preferably at least one epitope selected from the group consisting of CEP-1, cit-vim and cit-fib; the sequences of these peptides are shown in Table 5 (Paragraph 0037; see also Page 8). Another aspect of the invention is a method of treating rheumatoid arthritis comprising administering to a patient in need thereof an antibody according to the invention (Paragraph 0094). For therapeutic use, the antibody is suitable formulated together with buffers, preservatives, carriers and other excipients known to a person skilled in the art (i.e., a pharmaceutical composition) (Paragraph 0097). The antibodies according to the invention can be used in diagnosis or as a research tool; for example, one or more antibodies according to the invention may be included as positive controls in a diagnostic kit for testing for the presence of autoantibodies with reactivity against rheumatoid arthritis-specific antigens, in particular citrullinated enolase, citrullinated vimentin, citrullinated fibrinogen and/or collagen type II (Paragraph 0098). One further aspect of the invention is a diagnostic kit that comprises an antibody according to the invention wherein such a kit preferably comprises an ELISA plate or other platform for antibody analysis as well as reagents for detection of antibodies, such as labeled-anti-human antibodies and suitable buffers; thus the antibodies according to the invention can be used for in vitro diagnosis (Paragraph 0100). However, Klareskog does not explicitly teach or suggest vimentin-specific antibodies that (i) are specific to vimentin including an amino acid sequence represented by SEQ ID NO: 21; (ii) comprise a CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2 or 3, and CDRH3 of SEQ ID NO: 4 or 5; (iii) CDRL1 of SEQ ID NO: 6, CDRL2 of one of SEQ ID NOs: 7-10, and CDRL3 of SEQ ID NO: 11 or 12; VH FRs 1-3 of SEQ ID NOs: 13-16, respectively; and (iv) VL FRs of SEQ ID NOs: 17-20. These deficiencies are remedied by Park.
Park teaches a pharmaceutical composition for treating skin diseases including, as an active ingredient, a material which specifically binds to a peptide derived from isolated vimentin (Column 1, Lines 29-32). Park teaches an antibody which specifically binds to the peptide of SEQ ID NO: 1 or a fragment binding to the peptide can effectively prevent and treat skin diseases expressing a vimentin-derived peptide, and thus can be effectively used as a therapeutic agent for various skin diseases, of which the specific etiology has not yet been clarified (Column 3, Lines 13-20). It is specifically noted that Park SEQ ID NO: 1 comprises an exact match to instant SEQ ID NO: 21, The term "antibody" immunologically refers to a protein molecule which has the role of a ligand specifically recognizing an antigen, including an immunoglobulin molecule having reactivity to a specific antigen, and it may include all of a polyclonal antibody, a monoclonal antibody, a whole antibody, and an antibody fragment (Column 6, Lines 43-49); the terms "fragment", "fragment binding to a peptide", and "antibody fragment" refer to any fragment of the antibodies or peptide-binding fragment of the present invention having antigen-binding activity and may include a single chain antibody, Fd, Fab, Fab’, F(ab’)2, dsFv, or scFv (Column 6, Lines 61-67). A humanized antibody or the fragment binding to the peptide may include: (i) a heavy chain variable region including a heavy chain CDRl of SEQ ID NO: 2; a heavy chain CDR2 of SEQ ID NO: 3 or SEQ ID NO: 14 (in which the 9th amino acid of SEQ ID NO: 3, threonine, is substituted with aspartic acid); and a heavy chain CDR3 of SEQ ID NO: 4 or SEQ ID NO: 15 (in which the 4th amino acid of SEQ ID NO: 4, threonine, is substituted with asparagine); and (ii) a light chain variable region including a light chain CDRl of SEQ ID NO: 5; a light chain CDR2 of SEQ ID NO: 6, SEQ ID NO: 16 (in which the 3rd amino acid of SEQ ID NO: 6, threonine, is substituted with aspartic acid), SEQ ID NO: 17 (in which the 3rd amino acid of SEQ ID NO: 6, threonine, is substituted with aspartic acid and the 6th amino acid of SEQ ID NO: 6, alanine, is substituted with glycine), or SEQ ID NO: 18 (in which the 3rd amino acid of SEQ ID NO: 6, threonine, is substituted with aspartic acid; the 5th amino acid of SEQ ID NO: 6, leucine, is substituted with arginine; and the 6th amino acid of SEQ ID NO: 6, alanine, is substituted with glycine); and a light chain CDR3 of SEQ ID NO: 7 or SEQ ID NO: 19 (in which the 6th amino acid of SEQ ID NO: 7, serine, is substituted with threonine) (Column 8, Lines 4-25). It is specifically noted that Park SEQ ID NOs: 2, 3, 14, 4, 15, 5, 6, 16, 17, 18, 7, and 19 comprise and/or consist of exact matches to instant SEQ ID NOs: 1, 3, 2, 4, 5, 6, 8, 7, 9, 10, and 12, respectively. Park further teaches that the humanized antibody or the fragment binding to the peptide includes a human framework region (FR), wherein the antibody or fragment comprises: (i) a heavy chain FR1 of SEQ ID NO: 20, a heavy chain FR2 of SEQ ID NO: 21, a heavy chain FR3 of SEQ ID NO: 22 or SEQ ID NO: 28 (in which the 8th amino acid of SEQ ID NO: 22, lysine, is substituted with threonine; and the 10th amino acid of SEQ ID NO: 22, isoleucine, is substituted with alanine), and a heavy chain FR4 of SEQ ID NO: 23; and (ii) a light chain FR1 of SEQ ID NO: 24, a light chain FR2 of SEQ ID NO: 25, a light chain FR3 of SEQ ID NO: 26, and a light chain FR4 of SEQ ID NO: 27 (Column 8, Lines 26-40). It is specifically noted that Park SEQ ID NOs: 20-27 are exact matches to instant SEQ ID NOs: 13-20, respectively. The humanized antibody or the fragment binding to the peptide may include a heavy chain variable region and a light chain variable region, respectively, of SEQ ID NO: 32 and SEQ ID NO: 34 (comprise instant SEQ ID NOs: 1/3/4 and 6/7/11, respectively); SEQ ID NO: 36 and SEQ ID NO: 38 (comprise instant SEQ ID NOs: 1/3/4 and 6/9/11, respectively); SEQ ID NO: 40 and SEQ ID NO: 42 (comprise instant SEQ ID NOs: 1/3/4 and 6/10/11, respectively); SEQ ID NO: 44 and SEQ ID NO: 46 (comprise instant SEQ ID NOs: 1/3/4 and 6/10/12, respectively); SEQ ID NO: 48 and SEQ ID NO: 50 (comprise instant SEQ ID NOs: 1/2/4 and 6/8/11, respectively); SEQ ID NO: 56 and SEQ ID NO: 58 (comprise instant SEQ ID NOs: 1/2/4 and 6/8/11, respectively); SEQ ID NO: 60 and SEQ ID NO: 62 (comprise instant SEQ ID NOs: 1/2/5 and 6/8/11, respectively); SEQ ID NO: 64 and SEQ ID NO: 66 (comprise instant SEQ ID NOs: 1/2/4 and 6/10/11, respectively); SEQ ID NO: 68 and SEQ ID NO: 70 (comprise instant SEQ ID NOs: 1/2/5 and 6/10/11, respectively); SEQ ID NO: 72 and SEQ ID NO: 74 (comprise instant SEQ ID NOs: 1/2/4 and 6/10/12, respectively); SEQ ID NO: 76 and SEQ ID NO: 78 (comprise instant SEQ ID NOs: 1/2/5 and 6/10/12, respectively); or SEQ ID NO: 80 and SEQ ID NO: 82 (comprise instant SEQ ID NOs: 1/2/4 and 6/7/11, respectively) (Column 10, Lines 16-28).
However, neither Klareskog nor Park explicitly teach or suggest using antibodies specific to non-citrullinated vimentin in treatment nor for providing information for diagnosing an autoimmune disease comprising forming an antigen-antibody complex by reacting a sample isolated from a specimen with a vimentin-specific antibody or an immunologically active fragment thereof and detecting the formation of the complex. These deficiencies are remedied by Musaelyan.
Musaelyan teaches that vimentin is one of the antigens involved in the pathogenesis of rheumatoid arthritis (RA); generation of post-translationally modified vimentin in vivo can abolish primary immunotolerance and induce disease in susceptible host and drives autoimmune responses in in flamed RA joints and naturally occurring citrullinated post-translationally modified vimentin known as Sa antigen in RA presents in many tissues and can be purified from the placenta (Page 928, Column 2, Section 3). Antibodies against Sa antigen are very specific (96.9%) for RA and can be found in 30–36.6% patients with the disease; citrullination of vimentin and other proteins of the synovial membranes, including fibrin and alpha-enolase, leads to a synthesis of anti-citrullinated peptide antibodies (ACPA) that are recognized biomarkers for RA (Id.). Local inflammation of synovial membranes can generate post-translationally modified vimentin that becomes the autoantigenic target. The presence of intracellular citrullinated antigens like vimentin and alpha-enolase can be detected in the synovial lining of RA joint and correlate with systemic ACPA level; it is suggested that vimentin citrullination are associated with granulocyte and macrophage apoptosis that produces significant amounts on intracellular components including vimentin and also peptidyl- arginine deiminase-2 and peptidyl-arginine deiminase-4 enzymes that are in volved in inflammatory citrullination and fragmented extracellular DNA in the synovial fluid indicates an apoptosis in RA synovium and high levels of PAD expression in joint correlated with a systemic inflammatory activity (Page 929, Column 1, Fourth Paragraph). Vimentin can also be excreted by activated macrophages under the influence of TNFα (Id.). RA is characterized by a high neutrophil content in the synovial fluid that is typically over 2000 cells per μl, and the number of neutrophils correlates with the concentrations of IL-8; a specific form of apoptosis of neutrophilic granulocytes generates neutrophilic extracellular traps (NET) that are expulsion of DNA-protein complexes and enzymes from the cell (Page 929, Column 1, Fifth Paragraph). During NETosis externalization of vimentin and other intracellular constituents occurs together with peptidyl- arginine deiminase, myeloperoxidase, cathepsin G and other enzymes involved in proteolysis and post-translational modifications; high level of NETosis in the peripheral blood can be found in RA in contrast to osteoarthritis and controls, and NETosis also was found in synovial pannus, rheumatoid nodules and skin of RA patients and its severity correlates with ACPA, rheumatoid factor and other markers of systemic inflammation including CRP and ESR (Id.). Oxidative stress is another result of ubiquitous NETosis; in fibroblast cell line in vitro oxidative stress induces an expression of post-translationally modified vimentin that are recognized by ACPA from synovial fluid of RA patients (Id.). Thus, Musaelyan establishes the role of vimentin in rheumatoid arthritis, including the increased presence of vimentin and/or citrullinated vimentin in the blood, synovial pannus, rheumatoid nodules, and skin of RA patients.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the methods of Klareskog such that the vimentin-specific antibody is specific for vimentin comprising instant SEQ ID NO: 21 (i.e., a non-citrullinated epitope). One would have been motivated to make such a modification because vimentin-specific antibodies that are specific for vimentin comprising instant SEQ ID NO: 21 are known in the art, as taught by Park, and the use of vimentin-specific antibodies to citrullinated epitopes are established in the treatment and/or diagnostic methods (e.g., ELISA) for rheumatoid arthritis, as taught by Klareskog, and Musaelyan establishes the role of vimentin, both citrullination and non-citrullinated, in the pathogenesis of rheumatoid arthritis and its increased presence in in the blood, synovial pannus, rheumatoid nodules, and skin of RA patients. One of ordinary skill in the art would have a reasonable expectation of success of applying the antibodies of Park in the methods of Klareskog wherein it would reasonably be expected that targeting non-citrullinated vimentin would also be useful in therapeutic/diagnostic methods as suggested by Musaelyan.
Klareskog recognizes the need in the art for effective treatments and diagnostic methods for rheumatoid arthritis, implicates citrullinated vimentin, and discloses antibodies useful in such methods wherein said antibodies are specific for an epitope of citrullinated vimentin. Park discloses vimentin-specific antibodies to a non-citrullinated epitope, and Musaelyan teaches that vimentin, both citrullinated and non-citrullinated, are implicated in the pathogenesis of rheumatoid arthritis and are increased/detectable in the blood, synovial pannus, rheumatoid nodules, and skin of RA patients. Given the recognized need for therapeutic and diagnostic methods, and given the known implications and increased presence of vimentin in cases of rheumatoid arthritis, one of skill in the art could have pursued applying vimentin-specific antibodies in therapeutic and diagnostic methods with a reasonable expectation of success.
Regarding claims 12-16, it is specifically noted that claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure. With regard to “adapted to”, “adapted for”, “wherein”, and/or “whereby” clauses, the determination of whether each of these clauses is a limitation in a claim depends on the specific facts of the case. See, e.g., Griffin v. Bertina, 285 F.3d 1029, 1034, 62 USPQ2d 1431 (Fed. Cir. 2002) (finding that a "wherein" clause limited a process claim where the clause gave "meaning and purpose to the manipulative steps"). In In re Giannelli, 739 F.3d 1375, 1378, 109 USPQ2d 1333, 1336 (Fed. Cir. 2014), the court found that an "adapted to" clause limited a machine claim where "the written description makes clear that 'adapted to,' as used in the [patent] application, has a narrower meaning, viz., that the claimed machine is designed or constructed to be used as a rowing machine whereby a pulling force is exerted on the handles." In Hoffer v. Microsoft Corp., 405 F.3d 1326, 1329, 74 USPQ2d 1481, 1483 (Fed. Cir. 2005), the court held that when a "‘whereby’ clause states a condition that is material to patentability, it cannot be ignored in order to change the substance of the invention." Id. However, the court noted that a "‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’" Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)). See MPEP 2111.04(I). In the instant case, it is noted that the “wherein” clauses of instant claims 12-16 do not serve to give meaning and purpose to the manipulative steps of claim 1 from which they depend, nor do they serve to limit the claims to a particular structure. As such, the “wherein” clauses of instant claims 12-16 are interpreted as intended results of a process step positively recited and will necessarily occur by way of performing the method of instant claim 1. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
Claims 3-4 are rejected under 35 U.S.C. 103 as being unpatentable over US 2015/0056208 A1 (herein after referred to as "Klareskog"), US 10,961,300 (herein after referred to as “Kim”), and non-patent literature by Musaelyan et. al. (Autoimmunity Reviews, 2018, 17, 926-934; herein after referred to as “Musaelyan”), as applied to claims 1-2 and 5-19 above, and further in view of non-patent literature by Rubbert-Roth et. al. (Arthritis Research & Therapy, 2009, 11(Suppl 1), 1-12; herein after referred to as “Rubbert-Roth”) and non-patent literature by Takanashi et. al. (Rheumatology, 2021, 60, 5247-5256; herein after referred to as “Takanashi”).
The method of claim 1 is rendered obvious by the combination of Klareskog, Kim, and Musaelyan. However, none of the cited references explicitly teach or suggest treating intractable rheumatoid arthritis with metabolic disorder nor intractable rheumatoid arthritis with metabolic disorder that is TNFα inhibitor refractory. These deficiencies are remedied by Rubbert-Roth and Takanashi.
Rubbert-Roth teaches that conventional disease-modifying antirheumatic drugs such as methotrexate are the mainstay of treatment for rheumatoid arthritis, and more recently, biologic agents such as etanercept, infliximab and adalimumab, which act by inhibiting tumour necrosis factor (TNF), have become available; TNF inhibitors have proved to be very effective in patients not responding to conventional disease modifying antirheumatic drugs, however about 20% to 40% of patients treated with a TNF inhibitor fail to achieve a 20% improvement in American College of Rheumatology criteria, and more lose response over time (secondary failure or acquired therapeutic resistance) or experience adverse events following treatment with a TNF inhibitor (Abstract). In this group of patients, therapeutic options were limited until recently and an established treatment approach was to switch from one TNF inhibitor to another. In recent years, therapeutic options in these patients have increased with the introduction of biologic agents with novel mechanisms of action, such as rituximab and abatacept (Id.). There are now three agents available in TNF inhibitor treatment class: etanercept, infliximab and adalimumab, which are very effective at improving the signs and symptoms, and at slowing or preventing structural damage in patients with RA; newer TNF inhibitors are also in clinical development for the treatment of RA and include golimumab and certolizumab pegol (Page 1, Column 2, First Full Paragraph). Until recently, therapeutic options were limited for patients not responding satisfactorily to TNF inhibitors, and who typically have failed many conventional DMARDs and combinations of DMARDs; switching from one TNF inhibitor to another has become an established treatment approach for patients who failed or were intolerant of treatment with an initial TNF inhibitor (Page 2, Column 1, First Full Paragraph). The Open-label, Pilot Protocol of patients with rheumatoid arthritis who Switch to Infliximab after an incomplete response to Etanercept (OPPOSITE) trial was a small, randomized study, involving 28 patients, which suggested a more favorable outcome in patients who switched to infliximab, however, the majority of patients did not achieve an ACR50 response; efficacy results with subsequent TNF inhibitor treatment appear to differ according to the reason for switching Page 2, Column 2, Fourth Paragraph). Of 6,739 patients with RA whose primary treatment with a TNF inhibitor (adalimumab, etanercept or infliximab) was recorded in a large UK national bio logics register, 856 were switched to a second TNF inhibitor because of inefficacy (503 patients) or adverse events (353 patients); patients who had discontinued the first inhibitor because of inefficacy were more likely to fail treatment with a second inhibitor for the same reason (hazard ratio = 2.7, 95% confidence interval [CI] = 2.1 to 3.4) rather than toxicity (hazard ratio = 1.1, 95% CI = 0.9 to 1.5), and similarly, rates of drug discontinuation for adverse events were higher in patients who had previously discontinued because of intolerance (hazard ratio = 2.3, 95% CI = 1.9 to 2.9) than in those who had previously discontinued because of inefficacy (hazard ratio = 1.2, 95% CI = 0.8 to 1.6) (Id.). Those patients failing TNF inhibitor therapy because of lack of efficacy can be subdivided into those who never achieved an adequate response (primary failure or inefficacy) and those who lost response over time (secondary failure or acquired therapeutic resistance); in general, a second TNF inhibitor appears to be more effective in patients with a history of secondary failure rather than primary failure, but some heterogeneity has been seen in small studies (Page 3, Column 1). Overall, findings suggest that the decline in efficacy after a switch to a second TNF inhibitor may in part be due to a class effect and also to a channelling bias favoring patients with more severe disease; thus, the rationale for introducing agents with a different mode of action may be to overcome issues related to class, particularly in cases of primary failure or recurrence of class-associated adverse events (Page 4, Column 2, Second Full Paragraph).
Takanashi teaches that widespread use of a treat-to-target strategy and remarkable progress in therapeutic agents has allowed more than half of patients with RA to achieve remission or low disease activity in clinical practice, however quite a few patients with RA who have not achieved treatment targets remain, and the concept of difficult-to treat RA (D2T RA; i.e., intractable RA) has emerged as the greatest unmet need in recent years; the prevalence of D2T RA, also referred to as refractory or problematic RA, is assumed to range from 5% to 20% (Page 5247, Introduction). A total of 2044 patients with RA were identified, and after excluding patients with insufficient information, 1709 patients were enrolled in the analysis and their clinical characteristics are summarized in Table 1; on the basis of the EULAR definition, 173 patients (10.1%) were classified as D2T RA (Fig. 1) (Page 5248, Column 2, Second Full Paragraph; see also Page 5249). Patients with D2T RA were classified into three groups based on the reason for the D2T RA: (i) multi-drug resistance (34.1%), comorbidities (9.8%), and socio-economic reasons (56.1%) (Fig. 1) (Page 5250, Column 1, Reasons for the D2T RA). The clinical characteristics of the D2T RA patients were quite different owing to the different reasons for the D2T RA (Table 2): the multi-drug-resistance group had the highest tender joint count and evaluator global assessment score among the three groups, even though >95% of the patients were treated with bDMARDs or JAKis; the patients in the comorbidity group showed the highest rate of admission due to infection, RDCI and the most common comorbidities of lung involvement and were significantly older, had the longest disease duration, and showed the smallest physique, with the duration from RA diagnosis to treatment initiation with a bDMARD or JAKi being longest in the comorbidity group (Id.). Table 3 and Fig. 2 suggest that switching biologic agents with different modes of action was useful, as approximately half of the patients achieved remission or low disease activity according to both the DAS28 and CDAI at the third or fourth mode of action (61.0%, 59.1%, 51.1% and 42.9% at the first, second, third and fourth switch to bDMARDs or JAKis with different modes of action, respectively); the switch to a
drug with the same mode of action due to secondary failure appeared to be reasonable, because 85% of the patients who had once responded to a drug with a certain mode of action switched to another drug with the same mode of action, and most of them achieved remission or low disease activity (Page 2520, Column 2, First Paragraph). On the other hand, few patients in the multi-drug-resistant D2T RA group failed to respond to several drugs with multiple modes of action; Approximately half of the patients achieved remission or low disease activity at the third or fourth mode of action, indicating the use fulness of switching to other drugs with different modes of action (Page 2520, Column 2, Second Paragraph). It is specifically noted that while Takanashi groups D2T RA patients into three groups, there is overlap between groups. For example, in Table 2 it is noted that a percentage of D2T RA patients in the multi-drug resistant group also have comorbidities including hypertension (15.3%), diabetes (3.3), and reduced kidney function (eGFR, ml/min/1.73 m2 (20.8%) and eGFR < 60 ml/min/1.73 m2 (25.4%)). Thus, there are subsets of RA patients that are (i) difficult to treat (i.e., have intractable RA), (ii) are multi-drug resistant (including resistance to TNF inhibitors/multiple TNF inhibitors), and (iii) have metabolic disorder.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to use the therapeutic method rendered obvious by Klareskog, Kim, and Musaelyan in rheumatoid arthritis patients who have (i) intractable rheumatoid arthritis with metabolic disorder and (ii) are refractory/resistant to TNFα inhibitors. One would have been motivated to make such a modification because: (i) Rubbert-Roth teaches that TNF inhibitors (including TNFα inhibitors) have proved to be very effective in patients not responding to conventional disease modifying antirheumatic drugs, but about 20% to 40% of patients treated with a TNF inhibitor fail to achieve a 20% improvement in American College of Rheumatology criteria, and more lose response over time (secondary failure or acquired therapeutic resistance) or experience adverse events following treatment with a TNF inhibitor and suggests that introducing agents with a different mode of action may be to overcome issues related to class, particularly in cases of primary failure or recurrence of class-associated adverse events; and (ii) Takanashi teaches that there are subsets of RA patients that are (i) difficult to treat (i.e., have intractable RA), (ii) are multi-drug resistant (including resistance to TNF inhibitors/multiple TNF inhibitors), and (iii) have metabolic disorder. One of ordinary skill in the art would have a reasonable expectation of success of applying the therapeutic method rendered obvious by Klareskog, Kim, and Musaelyan in cases of rheumatoid arthritis patients who have (i) intractable rheumatoid arthritis with metabolic disorder and (ii) are refractory/resistant to TNFα inhibitors because it is established in the art that TNF inhibitor therapies (e.g., TNFα inhibitors) are not efficacious for certain subsets of patients, including subsets of patients who have intractable/difficult to treat rheumatoid arthritis that also have metabolic disorder comorbidities, and that in such cases using therapies that use a different mode of action are suggested.
Claims 3-4 are rejected under 35 U.S.C. 103 as being unpatentable over US 2015/0056208 A1 (herein after referred to as "Klareskog"), US 11,649,277 (herein after referred to as “Park”), and non-patent literature by Musaelyan et. al. (Autoimmunity Reviews, 2018, 17, 926-934; herein after referred to as “Musaelyan”), as applied to claims 1-2 and 5-19 above, and further in view of non-patent literature by Rubbert-Roth et. al. (Arthritis Research & Therapy, 2009, 11(Suppl 1), 1-12; herein after referred to as “Rubbert-Roth”) and non-patent literature by Takanashi et. al. (Rheumatology, 2021, 60, 5247-5256; herein after referred to as “Takanashi”).
The method of claim 1 is rendered obvious by the combination of Klareskog, Park, and Musaelyan. However, none of the cited references explicitly teach or suggest treating intractable rheumatoid arthritis with metabolic disorder nor intractable rheumatoid arthritis with metabolic disorder that is TNFα inhibitor refractory. These deficiencies are remedied by Rubbert-Roth and Takanashi.
Rubbert-Roth teaches that conventional disease-modifying antirheumatic drugs such as methotrexate are the mainstay of treatment for rheumatoid arthritis, and more recently, biologic agents such as etanercept, infliximab and adalimumab, which act by inhibiting tumour necrosis factor (TNF), have become available; TNF inhibitors have proved to be very effective in patients not responding to conventional disease modifying antirheumatic drugs, however about 20% to 40% of patients treated with a TNF inhibitor fail to achieve a 20% improvement in American College of Rheumatology criteria, and more lose response over time (secondary failure or acquired therapeutic resistance) or experience adverse events following treatment with a TNF inhibitor (Abstract). In this group of patients, therapeutic options were limited until recently and an established treatment approach was to switch from one TNF inhibitor to another. In recent years, therapeutic options in these patients have increased with the introduction of biologic agents with novel mechanisms of action, such as rituximab and abatacept (Id.). There are now three agents available in TNF inhibitor treatment class: etanercept, infliximab and adalimumab, which are very effective at improving the signs and symptoms, and at slowing or preventing structural damage in patients with RA; newer TNF inhibitors are also in clinical development for the treatment of RA and include golimumab and certolizumab pegol (Page 1, Column 2, First Full Paragraph). Until recently, therapeutic options were limited for patients not responding satisfactorily to TNF inhibitors, and who typically have failed many conventional DMARDs and combinations of DMARDs; switching from one TNF inhibitor to another has become an established treatment approach for patients who failed or were intolerant of treatment with an initial TNF inhibitor (Page 2, Column 1, First Full Paragraph). The Open-label, Pilot Protocol of patients with rheumatoid arthritis who Switch to Infliximab after an incomplete response to Etanercept (OPPOSITE) trial was a small, randomized study, involving 28 patients, which suggested a more favorable outcome in patients who switched to infliximab, however, the majority of patients did not achieve an ACR50 response; efficacy results with subsequent TNF inhibitor treatment appear to differ according to the reason for switching Page 2, Column 2, Fourth Paragraph). Of 6,739 patients with RA whose primary treatment with a TNF inhibitor (adalimumab, etanercept or infliximab) was recorded in a large UK national bio logics register, 856 were switched to a second TNF inhibitor because of inefficacy (503 patients) or adverse events (353 patients); patients who had discontinued the first inhibitor because of inefficacy were more likely to fail treatment with a second inhibitor for the same reason (hazard ratio = 2.7, 95% confidence interval [CI] = 2.1 to 3.4) rather than toxicity (hazard ratio = 1.1, 95% CI = 0.9 to 1.5), and similarly, rates of drug discontinuation for adverse events were higher in patients who had previously discontinued because of intolerance (hazard ratio = 2.3, 95% CI = 1.9 to 2.9) than in those who had previously discontinued because of inefficacy (hazard ratio = 1.2, 95% CI = 0.8 to 1.6) (Id.). Those patients failing TNF inhibitor therapy because of lack of efficacy can be subdivided into those who never achieved an adequate response (primary failure or inefficacy) and those who lost response over time (secondary failure or acquired therapeutic resistance); in general, a second TNF inhibitor appears to be more effective in patients with a history of secondary failure rather than primary failure, but some heterogeneity has been seen in small studies (Page 3, Column 1). Overall, findings suggest that the decline in efficacy after a switch to a second TNF inhibitor may in part be due to a class effect and also to a channelling bias favoring patients with more severe disease; thus, the rationale for introducing agents with a different mode of action may be to overcome issues related to class, particularly in cases of primary failure or recurrence of class-associated adverse events (Page 4, Column 2, Second Full Paragraph).
Takanashi teaches that widespread use of a treat-to-target strategy and remarkable progress in therapeutic agents has allowed more than half of patients with RA to achieve remission or low disease activity in clinical practice, however quite a few patients with RA who have not achieved treatment targets remain, and the concept of difficult-to treat RA (D2T RA; i.e., intractable RA) has emerged as the greatest unmet need in recent years; the prevalence of D2T RA, also referred to as refractory or problematic RA, is assumed to range from 5% to 20% (Page 5247, Introduction). A total of 2044 patients with RA were identified, and after excluding patients with insufficient information, 1709 patients were enrolled in the analysis and their clinical characteristics are summarized in Table 1; on the basis of the EULAR definition, 173 patients (10.1%) were classified as D2T RA (Fig. 1) (Page 5248, Column 2, Second Full Paragraph; see also Page 5249). Patients with D2T RA were classified into three groups based on the reason for the D2T RA: (i) multi-drug resistance (34.1%), comorbidities (9.8%), and socio-economic reasons (56.1%) (Fig. 1) (Page 5250, Column 1, Reasons for the D2T RA). The clinical characteristics of the D2T RA patients were quite different owing to the different reasons for the D2T RA (Table 2): the multi-drug-resistance group had the highest tender joint count and evaluator global assessment score among the three groups, even though >95% of the patients were treated with bDMARDs or JAKis; the patients in the comorbidity group showed the highest rate of admission due to infection, RDCI and the most common comorbidities of lung involvement and were significantly older, had the longest disease duration, and showed the smallest physique, with the duration from RA diagnosis to treatment initiation with a bDMARD or JAKi being longest in the comorbidity group (Id.). Table 3 and Fig. 2 suggest that switching biologic agents with different modes of action was useful, as approximately half of the patients achieved remission or low disease activity according to both the DAS28 and CDAI at the third or fourth mode of action (61.0%, 59.1%, 51.1% and 42.9% at the first, second, third and fourth switch to bDMARDs or JAKis with different modes of action, respectively); the switch to a
drug with the same mode of action due to secondary failure appeared to be reasonable, because 85% of the patients who had once responded to a drug with a certain mode of action switched to another drug with the same mode of action, and most of them achieved remission or low disease activity (Page 2520, Column 2, First Paragraph). On the other hand, few patients in the multi-drug-resistant D2T RA group failed to respond to several drugs with multiple modes of action; Approximately half of the patients achieved remission or low disease activity at the third or fourth mode of action, indicating the use fulness of switching to other drugs with different modes of action (Page 2520, Column 2, Second Paragraph). It is specifically noted that while Takanashi groups D2T RA patients into three groups, there is overlap between groups. For example, in Table 2 it is noted that a percentage of D2T RA patients in the multi-drug resistant group also have comorbidities including hypertension (15.3%), diabetes (3.3), and reduced kidney function (eGFR, ml/min/1.73 m2 (20.8%) and eGFR < 60 ml/min/1.73 m2 (25.4%)). Thus, there are subsets of RA patients that are (i) difficult to treat (i.e., have intractable RA), (ii) are multi-drug resistant (including resistance to TNF inhibitors/multiple TNF inhibitors), and (iii) have metabolic disorder.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to use the therapeutic method rendered obvious by Klareskog, Park, and Musaelyan in rheumatoid arthritis patients who have (i) intractable rheumatoid arthritis with metabolic disorder and (ii) are refractory/resistant to TNFα inhibitors. One would have been motivated to make such a modification because: (i) Rubbert-Roth teaches that TNF inhibitors (including TNFα inhibitors) have proved to be very effective in patients not responding to conventional disease modifying antirheumatic drugs, but about 20% to 40% of patients treated with a TNF inhibitor fail to achieve a 20% improvement in American College of Rheumatology criteria, and more lose response over time (secondary failure or acquired therapeutic resistance) or experience adverse events following treatment with a TNF inhibitor and suggests that introducing agents with a different mode of action may be to overcome issues related to class, particularly in cases of primary failure or recurrence of class-associated adverse events; and (ii) Takanashi teaches that there are subsets of RA patients that are (i) difficult to treat (i.e., have intractable RA), (ii) are multi-drug resistant (including resistance to TNF inhibitors/multiple TNF inhibitors), and (iii) have metabolic disorder. One of ordinary skill in the art would have a reasonable expectation of success of applying the therapeutic method rendered obvious by Klareskog, Park, and Musaelyan in cases of rheumatoid arthritis patients who have (i) intractable rheumatoid arthritis with metabolic disorder and (ii) are refractory/resistant to TNFα inhibitors because it is established in the art that TNF inhibitor therapies (e.g., TNFα inhibitors) are not efficacious for certain subsets of patients, including subsets of patients who have intractable/difficult to treat rheumatoid arthritis that also have metabolic disorder comorbidities, and that in such cases using therapies that use a different mode of action are suggested.
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).
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Claims 1-19 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 15, and 17-18 of U.S. Patent No. 10,961,300 (herein after referred to as “Kim”) in view of US 2015/0056208 A1 (herein after referred to as "Klareskog"), non-patent literature by Musaelyan et. al. (Autoimmunity Reviews, 2018, 17, 926-934; herein after referred to as “Musaelyan”), non-patent literature by Rubbert-Roth et. al. (Arthritis Research & Therapy, 2009, 11(Suppl 1), 1-12; herein after referred to as “Rubbert-Roth”), and non-patent literature by Takanashi et. al. (Rheumatology, 2021, 60, 5247-5256; herein after referred to as “Takanashi”).
Claim 1 of Kim is drawn to a humanized antibody specifically binding to the peptide of SEQ ID NO: 1, wherein the humanized antibody or fragment thereof comprises: (i) a heavy chain variable region including a heavy chain CDRl of SEQ ID NO: 2; a heavy chain CDR2 of SEQ ID NO: 3 or SEQ ID NO: 14; and a heavy chain CDR3 of SEQ ID NO: 4 or SEQ ID NO: 15; and (ii) a light chain variable region including a light chain CDRl of SEQ ID NO: 5; a light chain CDR2 of SEQ ID NO: 6, SEQ ID NO: 16, SEQ ID NO: 17, or SEQ ID NO: 18; and a light chain CDR3 of SEQ ID NO: 7 or SEQ ID NO: 19. It is specifically noted that Kim SEQ ID NOs: 2, 3, 14, 4, 15, 5, 6, 16, 17, 18, 7, and 19 comprise and/or consist of exact matches to instant SEQ ID NOs: 1, 3, 2, 4, 5, 6, 8, 7, 9, 10, and 12, respectively. Claim 2 of Kim further limits the method of claim 1, wherein the humanized antibody or fragment thereof comprises: (i) a heavy chain FR1 of SEQ ID NO: 20, a heavy chain FR2 of SEQ ID NO: 21, a heavy chain FR3 of SEQ ID NO: 22 or SEQ ID NO: 28, and a heavy chain FR4 of SEQ ID NO: 23; and (ii) a light chain FR1 of SEQ ID NO: 24, a light chain FR2 of SEQ ID NO: 25, a light chain FR3 of SEQ ID NO: 26, and a light chain FR4 of SEQ ID NO: 27. It is specifically noted that Kim SEQ ID NOs: 20-27 are exact matches to instant SEQ ID NOs: 13-20, respectively. Claim 3 of Kim further limits the antibody of claim 1, wherein claim 3 further specifies the exact CDR combinations of the antibody. Claim 4 of Kim further limits the antibody of claim 1, wherein the humanized antibody comprises a heavy chain variable region and a light chain variable region, respectively, of SEQ ID NO: 32 and SEQ ID NO: 34 (comprise instant SEQ ID NOs: 1/3/4 and 6/7/11, respectively); SEQ ID NO: 36 and SEQ ID NO: 38 (comprise instant SEQ ID NOs: 1/3/4 and 6/9/11, respectively); SEQ ID NO: 40 and SEQ ID NO: 42 (comprise instant SEQ ID NOs: 1/3/4 and 6/10/11, respectively); SEQ ID NO: 44 and SEQ ID NO: 46 (comprise instant SEQ ID NOs: 1/3/4 and 6/10/12, respectively); SEQ ID NO: 48 and SEQ ID NO: 50 (comprise instant SEQ ID NOs: 1/2/4 and 6/8/11, respectively); SEQ ID NO: 56 and SEQ ID NO: 58 (comprise instant SEQ ID NOs: 1/2/4 and 6/8/11, respectively); SEQ ID NO: 60 and SEQ ID NO: 62 (comprise instant SEQ ID NOs: 1/2/5 and 6/8/11, respectively); SEQ ID NO: 64 and SEQ ID NO: 66 (comprise instant SEQ ID NOs: 1/2/4 and 6/10/11, respectively); SEQ ID NO: 68 and SEQ ID NO: 70 (comprise instant SEQ ID NOs: 1/2/5 and 6/10/11, respectively); SEQ ID NO: 72 and SEQ ID NO: 74 (comprise instant SEQ ID NOs: 1/2/4 and 6/10/12, respectively); SEQ ID NO: 76 and SEQ ID NO: 78 (comprise instant SEQ ID NOs: 1/2/5 and 6/10/12, respectively); or SEQ ID NO: 80 and SEQ ID NO: 82 (comprise instant SEQ ID NOs: 1/2/4 and 6/7/11, respectively). Claim 15 of Kim is generally drawn to a method of treating an infection or inflammatory viral disease comprising administering an antiviral composition comprising the humanized antibody according to claim 1 to an individual in need thereof. Kim claims 17-18 further limit the method of claim 15 wherein (i) the composition suppresses immune cell infiltration and (ii) the composition inhibits inflammatory responses, respectively.
However, Kim does not claim a method of treating an autoimmune disease, nor a method for providing information necessary to diagnose an autoimmune disease, using a vimentin-specific antibody. These deficiencies are remedied by Klareskog, Musaelyan, Rubbert-Roth, and Takanashi.
Klareskog teaches antibodies that can bind to certain citrullinated epitopes namely citrullinated enolase, vimentin, fibrinogen and citrullinated synthetic peptides; these antibodies can be used in diagnostics of rheumatoid arthritis, for therapy against rheumatoid arthritis and as research tools (Abstract; emphasis added). ELISA tests for antibodies against citrullinated forms of enolase, vimentin and/or fibrinogen peptides can be used for diagnosis of rheumatoid arthritis. Such tests show the presence or absence of antibodies in patient serum that react with citrullinated epitopes such peptides from as alpha enolase, vimentin and fibrinogen (Paragraph 0008). The term "antibody" as used herein refers to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e. molecules that contain an antigen binding site that specifically binds an antigen, whether natural or partially or wholly synthetically produced, and covering any polypeptide or protein having a binding domain which is, or is homologous to, an immunoglobin molecule; examples of antibodies are the immunoglobulin isotypes (e.g. IgG, IgE, IgM, IgD and IgA) and their isotypic subclasses (such as for IgG: IgGl, IgG2, IgG3), and fragments which comprise an antigen binding domain such as Fab, scFv, Fv, dAb and diabodies (Paragraph 0027). The invention provides antibodies A03, A04, A40, B05, CO2, C04, C05, D06, 127, G12, 109, 117, A02, A09, B07, C50, C07, D09, D10 and F12 with sequences of heavy chain and light chains CDRl, CDR2 and CDR3 as defined in Tables 1-3 (Paragraph 0036; see also Pages 3-4). Preferably the antibody binds to at least one citrullinated epitope, preferably to at least one citrullinated epitope selected from the group consisting of citrullinated human enolase peptide 1, (SEQ ID NO 121) (CEP-1), citrullinated human vimentin residues 60-75 (SEQ ID NO 122) (cit-vim), citrullinated human fibrinogen residues 36-52 (SEQ ID NO 123) (cit-fib), and citrullinated synthetic peptide (Immunoscan CCPlus Euro-Diagnostica) (CCP), even more preferably at least one epitope selected from the group consisting of CEP-1, cit-vim and cit-fib; the sequences of these peptides are shown in Table 5 (Paragraph 0037; see also Page 8). Another aspect of the invention is a method of treating rheumatoid arthritis comprising administering to a patient in need thereof an antibody according to the invention (Paragraph 0094). For therapeutic use, the antibody is suitable formulated together with buffers, preservatives, carriers and other excipients known to a person skilled in the art (i.e., a pharmaceutical composition) (Paragraph 0097). The antibodies according to the invention can be used in diagnosis or as a research tool; for example, one or more antibodies according to the invention may be included as positive controls in a diagnostic kit for testing for the presence of autoantibodies with reactivity against rheumatoid arthritis-specific antigens, in particular citrullinated enolase, citrullinated vimentin, citrullinated fibrinogen and/or collagen type II (Paragraph 0098). One further aspect of the invention is a diagnostic kit that comprises an antibody according to the invention wherein such a kit preferably comprises an ELISA plate or other platform for antibody analysis as well as reagents for detection of antibodies, such as labeled-anti-human antibodies and suitable buffers; thus the antibodies according to the invention can be used for in vitro diagnosis (Paragraph 0100).
However, Klareskog nor the claims of Kim explicitly read on using antibodies specific to non-citrullinated vimentin in treatment of, for example, rheumatoid arthritis, nor for providing information for diagnosing an autoimmune disease such as rheumatoid arthritis comprising forming an antigen-antibody complex by reacting a sample isolated from a specimen with a vimentin-specific antibody or an immunologically active fragment thereof and detecting the formation of the complex. These deficiencies are remedied by Musaelyan.
Musaelyan teaches that vimentin is one of the antigens involved in the pathogenesis of rheumatoid arthritis (RA); generation of post-translationally modified vimentin in vivo can abolish primary immunotolerance and induce disease in susceptible host and drives autoimmune responses in in flamed RA joints and naturally occurring citrullinated post-translationally modified vimentin known as Sa antigen in RA presents in many tissues and can be purified from the placenta (Page 928, Column 2, Section 3). Antibodies against Sa antigen are very specific (96.9%) for RA and can be found in 30–36.6% patients with the disease; citrullination of vimentin and other proteins of the synovial membranes, including fibrin and alpha-enolase, leads to a synthesis of anti-citrullinated peptide antibodies (ACPA) that are recognized biomarkers for RA (Id.). Local inflammation of synovial membranes can generate post-translationally modified vimentin that becomes the autoantigenic target. The presence of intracellular citrullinated antigens like vimentin and alpha-enolase can be detected in the synovial lining of RA joint and correlate with systemic ACPA level; it is suggested that vimentin citrullination are associated with granulocyte and macrophage apoptosis that produces significant amounts on intracellular components including vimentin and also peptidyl- arginine deiminase-2 and peptidyl-arginine deiminase-4 enzymes that are in volved in inflammatory citrullination and fragmented extracellular DNA in the synovial fluid indicates an apoptosis in RA synovium and high levels of PAD expression in joint correlated with a systemic inflammatory activity (Page 929, Column 1, Fourth Paragraph). Vimentin can also be excreted by activated macrophages under the influence of TNFα (Id.). RA is characterized by a high neutrophil content in the synovial fluid that is typically over 2000 cells per μl, and the number of neutrophils correlates with the concentrations of IL-8; a specific form of apoptosis of neutrophilic granulocytes generates neutrophilic extracellular traps (NET) that are expulsion of DNA-protein complexes and enzymes from the cell (Page 929, Column 1, Fifth Paragraph). During NETosis externalization of vimentin and other intracellular constituents occurs together with peptidyl- arginine deiminase, myeloperoxidase, cathepsin G and other enzymes involved in proteolysis and post-translational modifications; high level of NETosis in the peripheral blood can be found in RA in contrast to osteoarthritis and controls, and NETosis also was found in synovial pannus, rheumatoid nodules and skin of RA patients and its severity correlates with ACPA, rheumatoid factor and other markers of systemic inflammation including CRP and ESR (Id.). Oxidative stress is another result of ubiquitous NETosis; in fibroblast cell line in vitro oxidative stress induces an expression of post-translationally modified vimentin that are recognized by ACPA from synovial fluid of RA patients (Id.). Thus, Musaelyan establishes the role of vimentin in rheumatoid arthritis, including the increased presence of vimentin and/or citrullinated vimentin in the blood, synovial pannus, rheumatoid nodules, and skin of RA patients.
However, none of the cited references nor the claims of Kim explicitly read on treating intractable rheumatoid arthritis with metabolic disorder nor intractable rheumatoid arthritis with metabolic disorder that is TNFα inhibitor refractory. These deficiencies are remedied by Rubbert-Roth and Takanashi.
Rubbert-Roth teaches that conventional disease-modifying antirheumatic drugs such as methotrexate are the mainstay of treatment for rheumatoid arthritis, and more recently, biologic agents such as etanercept, infliximab and adalimumab, which act by inhibiting tumour necrosis factor (TNF), have become available; TNF inhibitors have proved to be very effective in patients not responding to conventional disease modifying antirheumatic drugs, however about 20% to 40% of patients treated with a TNF inhibitor fail to achieve a 20% improvement in American College of Rheumatology criteria, and more lose response over time (secondary failure or acquired therapeutic resistance) or experience adverse events following treatment with a TNF inhibitor (Abstract). In this group of patients, therapeutic options were limited until recently and an established treatment approach was to switch from one TNF inhibitor to another. In recent years, therapeutic options in these patients have increased with the introduction of biologic agents with novel mechanisms of action, such as rituximab and abatacept (Id.). There are now three agents available in TNF inhibitor treatment class: etanercept, infliximab and adalimumab, which are very effective at improving the signs and symptoms, and at slowing or preventing structural damage in patients with RA; newer TNF inhibitors are also in clinical development for the treatment of RA and include golimumab and certolizumab pegol (Page 1, Column 2, First Full Paragraph). Until recently, therapeutic options were limited for patients not responding satisfactorily to TNF inhibitors, and who typically have failed many conventional DMARDs and combinations of DMARDs; switching from one TNF inhibitor to another has become an established treatment approach for patients who failed or were intolerant of treatment with an initial TNF inhibitor (Page 2, Column 1, First Full Paragraph). The Open-label, Pilot Protocol of patients with rheumatoid arthritis who Switch to Infliximab after an incomplete response to Etanercept (OPPOSITE) trial was a small, randomized study, involving 28 patients, which suggested a more favorable outcome in patients who switched to infliximab, however, the majority of patients did not achieve an ACR50 response; efficacy results with subsequent TNF inhibitor treatment appear to differ according to the reason for switching Page 2, Column 2, Fourth Paragraph). Of 6,739 patients with RA whose primary treatment with a TNF inhibitor (adalimumab, etanercept or infliximab) was recorded in a large UK national bio logics register, 856 were switched to a second TNF inhibitor because of inefficacy (503 patients) or adverse events (353 patients); patients who had discontinued the first inhibitor because of inefficacy were more likely to fail treatment with a second inhibitor for the same reason (hazard ratio = 2.7, 95% confidence interval [CI] = 2.1 to 3.4) rather than toxicity (hazard ratio = 1.1, 95% CI = 0.9 to 1.5), and similarly, rates of drug discontinuation for adverse events were higher in patients who had previously discontinued because of intolerance (hazard ratio = 2.3, 95% CI = 1.9 to 2.9) than in those who had previously discontinued because of inefficacy (hazard ratio = 1.2, 95% CI = 0.8 to 1.6) (Id.). Those patients failing TNF inhibitor therapy because of lack of efficacy can be subdivided into those who never achieved an adequate response (primary failure or inefficacy) and those who lost response over time (secondary failure or acquired therapeutic resistance); in general, a second TNF inhibitor appears to be more effective in patients with a history of secondary failure rather than primary failure, but some heterogeneity has been seen in small studies (Page 3, Column 1). Overall, findings suggest that the decline in efficacy after a switch to a second TNF inhibitor may in part be due to a class effect and also to a channelling bias favoring patients with more severe disease; thus, the rationale for introducing agents with a different mode of action may be to overcome issues related to class, particularly in cases of primary failure or recurrence of class-associated adverse events (Page 4, Column 2, Second Full Paragraph).
Takanashi teaches that widespread use of a treat-to-target strategy and remarkable progress in therapeutic agents has allowed more than half of patients with RA to achieve remission or low disease activity in clinical practice, however quite a few patients with RA who have not achieved treatment targets remain, and the concept of difficult-to treat RA (D2T RA; i.e., intractable RA) has emerged as the greatest unmet need in recent years; the prevalence of D2T RA, also referred to as refractory or problematic RA, is assumed to range from 5% to 20% (Page 5247, Introduction). A total of 2044 patients with RA were identified, and after excluding patients with insufficient information, 1709 patients were enrolled in the analysis and their clinical characteristics are summarized in Table 1; on the basis of the EULAR definition, 173 patients (10.1%) were classified as D2T RA (Fig. 1) (Page 5248, Column 2, Second Full Paragraph; see also Page 5249). Patients with D2T RA were classified into three groups based on the reason for the D2T RA: (i) multi-drug resistance (34.1%), comorbidities (9.8%), and socio-economic reasons (56.1%) (Fig. 1) (Page 5250, Column 1, Reasons for the D2T RA). The clinical characteristics of the D2T RA patients were quite different owing to the different reasons for the D2T RA (Table 2): the multi-drug-resistance group had the highest tender joint count and evaluator global assessment score among the three groups, even though >95% of the patients were treated with bDMARDs or JAKis; the patients in the comorbidity group showed the highest rate of admission due to infection, RDCI and the most common comorbidities of lung involvement and were significantly older, had the longest disease duration, and showed the smallest physique, with the duration from RA diagnosis to treatment initiation with a bDMARD or JAKi being longest in the comorbidity group (Id.). Table 3 and Fig. 2 suggest that switching biologic agents with different modes of action was useful, as approximately half of the patients achieved remission or low disease activity according to both the DAS28 and CDAI at the third or fourth mode of action (61.0%, 59.1%, 51.1% and 42.9% at the first, second, third and fourth switch to bDMARDs or JAKis with different modes of action, respectively); the switch to a
drug with the same mode of action due to secondary failure appeared to be reasonable, because 85% of the patients who had once responded to a drug with a certain mode of action switched to another drug with the same mode of action, and most of them achieved remission or low disease activity (Page 2520, Column 2, First Paragraph). On the other hand, few patients in the multi-drug-resistant D2T RA group failed to respond to several drugs with multiple modes of action; Approximately half of the patients achieved remission or low disease activity at the third or fourth mode of action, indicating the use fulness of switching to other drugs with different modes of action (Page 2520, Column 2, Second Paragraph). It is specifically noted that while Takanashi groups D2T RA patients into three groups, there is overlap between groups. For example, in Table 2 it is noted that a percentage of D2T RA patients in the multi-drug resistant group also have comorbidities including hypertension (15.3%), diabetes (3.3), and reduced kidney function (eGFR, ml/min/1.73 m2 (20.8%) and eGFR < 60 ml/min/1.73 m2 (25.4%)). Thus, there are subsets of RA patients that are (i) difficult to treat (i.e., have intractable RA), (ii) are multi-drug resistant (including resistance to TNF inhibitors/multiple TNF inhibitors), and (iii) have metabolic disorder.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to use the humanized antibody of Kim, and subsequently modify the method of Kim, such that the humanized antibody, specific for vimentin comprising instant SEQ ID NO: 21 (i.e., a non-citrullinated epitope), is used for the treatment and/or to gather information needed to diagnose rheumatoid arthritis patients, specifically patients having intractable rheumatoid arthritis with metabolic disorder and that are refractory/resistant to TNFα inhibitors. One would have been motivated to make such a modification because vimentin-specific antibodies that are specific for vimentin comprising instant SEQ ID NO: 21 are claimed by Kim, and the use of vimentin-specific antibodies to citrullinated epitopes are established in the treatment and/or diagnostic methods for rheumatoid arthritis, as taught by Klareskog, and Musaelyan establishes the role of vimentin, both citrullination and non-citrullinated, in the pathogenesis of rheumatoid arthritis and its increased presence in in the blood, synovial pannus, rheumatoid nodules, and skin of RA patients. Furthermore, Rubbert-Roth teaches that TNF inhibitors (including TNFα inhibitors) have proved to be very effective in patients not responding to conventional disease modifying antirheumatic drugs, but about 20% to 40% of patients treated with a TNF inhibitor fail to achieve a 20% improvement in American College of Rheumatology criteria, and more lose response over time (secondary failure or acquired therapeutic resistance) or experience adverse events following treatment with a TNF inhibitor and suggests that introducing agents with a different mode of action may be to overcome issues related to class, particularly in cases of primary failure or recurrence of class-associated adverse events, and Takanashi teaches that there are subsets of RA patients that are (i) difficult to treat (i.e., have intractable RA), (ii) are multi-drug resistant (including resistance to TNF inhibitors/multiple TNF inhibitors), and (iii) have metabolic disorder. Klareskog recognizes the need in the art for effective treatments and diagnostic methods for rheumatoid arthritis, implicates citrullinated vimentin, and discloses antibodies useful in such methods wherein said antibodies are specific for an epitope of citrullinated vimentin; Musaelyan teaches that vimentin, both citrullinated and non-citrullinated, are implicated in the pathogenesis of rheumatoid arthritis and are increased/detectable in the blood, synovial pannus, rheumatoid nodules, and skin of RA patients; and Rubbert-Roth and Takanashi indicate that treatment of rheumatoid arthritis can be difficult, especially for patients categorized as difficult to treat who have comorbidities and/or have failed previous therapeutic treatments (e.g., TNF inhibitors), and that in such cases therapeutic interventions with alternate mechanisms of action are recommended. Given the recognized need for therapeutic and diagnostic methods, especially in difficult to treat patients, and given the known implications and increased presence of vimentin in cases of rheumatoid arthritis, one of skill in the art could have pursued applying vimentin-specific antibodies in therapeutic and diagnostic methods with a reasonable expectation of success.
Claims 1-19 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 of U.S. Patent No. 11,649,277 (herein after referred to as “Park”) in view of US 2015/0056208 A1 (herein after referred to as "Klareskog"), non-patent literature by Musaelyan et. al. (Autoimmunity Reviews, 2018, 17, 926-934; herein after referred to as “Musaelyan”), non-patent literature by Rubbert-Roth et. al. (Arthritis Research & Therapy, 2009, 11(Suppl 1), 1-12; herein after referred to as “Rubbert-Roth”), and non-patent literature by Takanashi et. al. (Rheumatology, 2021, 60, 5247-5256; herein after referred to as “Takanashi”).
Claim 1 of Park is generally drawn to a method for treating a skin disease, comprising administering or applying a pharmaceutical composition comprising a humanized antibody or fragment thereof which specifically binds to a peptide of SEQ ID NO: 1 to an individual in need thereof. It is specifically noted that Park SEQ ID NO: 1 comprises an exact match to instant SEQ ID NO: 21. the terms "fragment", "fragment binding to a peptide", and "antibody fragment" is defined as any fragment of the antibodies or peptide-binding fragment of the invention having antigen-binding activity and may include a single chain antibody, Fd, Fab, Fab’, F(ab’)2, dsFv, or scFv (Column 6, Lines 61-67). Claim 2 of Park further limits the method of claim 1, wherein the humanized antibody or fragment thereof comprises: (i) a heavy chain variable region including a heavy chain CDRl of SEQ ID NO: 2; a heavy chain CDR2 of SEQ ID NO: 3 or SEQ ID NO: 14; and a heavy chain CDR3 of SEQ ID NO: 4 or SEQ ID NO: 15; and (ii) a light chain variable region including a light chain CDRl of SEQ ID NO: 5; a light chain CDR2 of SEQ ID NO: 6, SEQ ID NO: 16, SEQ ID NO: 17, or SEQ ID NO: 18; and a light chain CDR3 of SEQ ID NO: 7 or SEQ ID NO: 19. It is specifically noted that Park SEQ ID NOs: 2, 3, 14, 4, 15, 5, 6, 16, 17, 18, 7, and 19 comprise and/or consist of exact matches to instant SEQ ID NOs: 1, 3, 2, 4, 5, 6, 8, 7, 9, 10, and 12, respectively. Claim 4 of Park further limits the method of claim 2, wherein the humanized antibody or fragment thereof comprises: (i) a heavy chain FR1 of SEQ ID NO: 20, a heavy chain FR2 of SEQ ID NO: 21, a heavy chain FR3 of SEQ ID NO: 22 or SEQ ID NO: 28, and a heavy chain FR4 of SEQ ID NO: 23; and (ii) a light chain FR1 of SEQ ID NO: 24, a light chain FR2 of SEQ ID NO: 25, a light chain FR3 of SEQ ID NO: 26, and a light chain FR4 of SEQ ID NO: 27. It is specifically noted that Park SEQ ID NOs: 20-27 are exact matches to instant SEQ ID NOs: 13-20, respectively. Claim 3 of Park is generally drawn to a method for ameliorating a skin disease, comprising administering or applying a pharmaceutical composition comprising a humanized antibody or fragment thereof which specifically binds to a peptide of SEQ ID NO: 1 to an individual in need thereof.
However, Park does not claim a method of treating an autoimmune disease, nor a method for providing information necessary to diagnose an autoimmune disease, using a vimentin-specific antibody. These deficiencies are remedied by Klareskog, Musaelyan, Rubbert-Roth, and Takanashi.
Klareskog teaches antibodies that can bind to certain citrullinated epitopes namely citrullinated enolase, vimentin, fibrinogen and citrullinated synthetic peptides; these antibodies can be used in diagnostics of rheumatoid arthritis, for therapy against rheumatoid arthritis and as research tools (Abstract; emphasis added). ELISA tests for antibodies against citrullinated forms of enolase, vimentin and/or fibrinogen peptides can be used for diagnosis of rheumatoid arthritis. Such tests show the presence or absence of antibodies in patient serum that react with citrullinated epitopes such peptides from as alpha enolase, vimentin and fibrinogen (Paragraph 0008). The term "antibody" as used herein refers to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e. molecules that contain an antigen binding site that specifically binds an antigen, whether natural or partially or wholly synthetically produced, and covering any polypeptide or protein having a binding domain which is, or is homologous to, an immunoglobin molecule; examples of antibodies are the immunoglobulin isotypes (e.g. IgG, IgE, IgM, IgD and IgA) and their isotypic subclasses (such as for IgG: IgGl, IgG2, IgG3), and fragments which comprise an antigen binding domain such as Fab, scFv, Fv, dAb and diabodies (Paragraph 0027). The invention provides antibodies A03, A04, A40, B05, CO2, C04, C05, D06, 127, G12, 109, 117, A02, A09, B07, C50, C07, D09, D10 and F12 with sequences of heavy chain and light chains CDRl, CDR2 and CDR3 as defined in Tables 1-3 (Paragraph 0036; see also Pages 3-4). Preferably the antibody binds to at least one citrullinated epitope, preferably to at least one citrullinated epitope selected from the group consisting of citrullinated human enolase peptide 1, (SEQ ID NO 121) (CEP-1), citrullinated human vimentin residues 60-75 (SEQ ID NO 122) (cit-vim), citrullinated human fibrinogen residues 36-52 (SEQ ID NO 123) (cit-fib), and citrullinated synthetic peptide (Immunoscan CCPlus Euro-Diagnostica) (CCP), even more preferably at least one epitope selected from the group consisting of CEP-1, cit-vim and cit-fib; the sequences of these peptides are shown in Table 5 (Paragraph 0037; see also Page 8). Another aspect of the invention is a method of treating rheumatoid arthritis comprising administering to a patient in need thereof an antibody according to the invention (Paragraph 0094). For therapeutic use, the antibody is suitable formulated together with buffers, preservatives, carriers and other excipients known to a person skilled in the art (i.e., a pharmaceutical composition) (Paragraph 0097). The antibodies according to the invention can be used in diagnosis or as a research tool; for example, one or more antibodies according to the invention may be included as positive controls in a diagnostic kit for testing for the presence of autoantibodies with reactivity against rheumatoid arthritis-specific antigens, in particular citrullinated enolase, citrullinated vimentin, citrullinated fibrinogen and/or collagen type II (Paragraph 0098). One further aspect of the invention is a diagnostic kit that comprises an antibody according to the invention. Such a kit preferably comprises an ELISA plate or other platform for antibody analysis as well as reagents for detection of antibodies, such as labeled-anti-human antibodies and suitable buffers; thus the antibodies according to the invention can be used for in vitro diagnosis (Paragraph 0100).
However, Klareskog nor the claims of Park explicitly read on using antibodies specific to non-citrullinated vimentin in treatment of, for example, rheumatoid arthritis, nor for providing information for diagnosing an autoimmune disease such as rheumatoid arthritis comprising forming an antigen-antibody complex by reacting a sample isolated from a specimen with a vimentin-specific antibody or an immunologically active fragment thereof and detecting the formation of the complex. These deficiencies are remedied by Musaelyan.
Musaelyan teaches that vimentin is one of the antigens involved in the pathogenesis of rheumatoid arthritis (RA); generation of post-translationally modified vimentin in vivo can abolish primary immunotolerance and induce disease in susceptible host and drives autoimmune responses in in flamed RA joints and naturally occurring citrullinated post-translationally modified vimentin known as Sa antigen in RA presents in many tissues and can be purified from the placenta (Page 928, Column 2, Section 3). Antibodies against Sa antigen are very specific (96.9%) for RA and can be found in 30–36.6% patients with the disease; citrullination of vimentin and other proteins of the synovial membranes, including fibrin and alpha-enolase, leads to a synthesis of anti-citrullinated peptide antibodies (ACPA) that are recognized biomarkers for RA (Id.). Local inflammation of synovial membranes can generate post-translationally modified vimentin that becomes the autoantigenic target. The presence of intracellular citrullinated antigens like vimentin and alpha-enolase can be detected in the synovial lining of RA joint and correlate with systemic ACPA level; it is suggested that vimentin citrullination are associated with granulocyte and macrophage apoptosis that produces significant amounts on intracellular components including vimentin and also peptidyl- arginine deiminase-2 and peptidyl-arginine deiminase-4 enzymes that are in volved in inflammatory citrullination and fragmented extracellular DNA in the synovial fluid indicates an apoptosis in RA synovium and high levels of PAD expression in joint correlated with a systemic inflammatory activity (Page 929, Column 1, Fourth Paragraph). Vimentin can also be excreted by activated macrophages under the influence of TNFα (Id.). RA is characterized by a high neutrophil content in the synovial fluid that is typically over 2000 cells per μl, and the number of neutrophils correlates with the concentrations of IL-8; a specific form of apoptosis of neutrophilic granulocytes generates neutrophilic extracellular traps (NET) that are expulsion of DNA-protein complexes and enzymes from the cell (Page 929, Column 1, Fifth Paragraph). During NETosis externalization of vimentin and other intracellular constituents occurs together with peptidyl- arginine deiminase, myeloperoxidase, cathepsin G and other enzymes involved in proteolysis and post-translational modifications; high level of NETosis in the peripheral blood can be found in RA in contrast to osteoarthritis and controls, and NETosis also was found in synovial pannus, rheumatoid nodules and skin of RA patients and its severity correlates with ACPA, rheumatoid factor and other markers of systemic inflammation including CRP and ESR (Id.). Oxidative stress is another result of ubiquitous NETosis; in fibroblast cell line in vitro oxidative stress induces an expression of post-translationally modified vimentin that are recognized by ACPA from synovial fluid of RA patients (Id.). Thus, Musaelyan establishes the role of vimentin in rheumatoid arthritis, including the increased presence of vimentin and/or citrullinated vimentin in the blood, synovial pannus, rheumatoid nodules, and skin of RA patients.
However, none of the cited references nor the claims of Park explicitly read on treating intractable rheumatoid arthritis with metabolic disorder nor intractable rheumatoid arthritis with metabolic disorder that is TNFα inhibitor refractory. These deficiencies are remedied by Rubbert-Roth and Takanashi.
Rubbert-Roth teaches that conventional disease-modifying antirheumatic drugs such as methotrexate are the mainstay of treatment for rheumatoid arthritis, and more recently, biologic agents such as etanercept, infliximab and adalimumab, which act by inhibiting tumour necrosis factor (TNF), have become available; TNF inhibitors have proved to be very effective in patients not responding to conventional disease modifying antirheumatic drugs, however about 20% to 40% of patients treated with a TNF inhibitor fail to achieve a 20% improvement in American College of Rheumatology criteria, and more lose response over time (secondary failure or acquired therapeutic resistance) or experience adverse events following treatment with a TNF inhibitor (Abstract). In this group of patients, therapeutic options were limited until recently and an established treatment approach was to switch from one TNF inhibitor to another. In recent years, therapeutic options in these patients have increased with the introduction of biologic agents with novel mechanisms of action, such as rituximab and abatacept (Id.). There are now three agents available in TNF inhibitor treatment class: etanercept, infliximab and adalimumab, which are very effective at improving the signs and symptoms, and at slowing or preventing structural damage in patients with RA; newer TNF inhibitors are also in clinical development for the treatment of RA and include golimumab and certolizumab pegol (Page 1, Column 2, First Full Paragraph). Until recently, therapeutic options were limited for patients not responding satisfactorily to TNF inhibitors, and who typically have failed many conventional DMARDs and combinations of DMARDs; switching from one TNF inhibitor to another has become an established treatment approach for patients who failed or were intolerant of treatment with an initial TNF inhibitor (Page 2, Column 1, First Full Paragraph). The Open-label, Pilot Protocol of patients with rheumatoid arthritis who Switch to Infliximab after an incomplete response to Etanercept (OPPOSITE) trial was a small, randomized study, involving 28 patients, which suggested a more favorable outcome in patients who switched to infliximab, however, the majority of patients did not achieve an ACR50 response; efficacy results with subsequent TNF inhibitor treatment appear to differ according to the reason for switching Page 2, Column 2, Fourth Paragraph). Of 6,739 patients with RA whose primary treatment with a TNF inhibitor (adalimumab, etanercept or infliximab) was recorded in a large UK national bio logics register, 856 were switched to a second TNF inhibitor because of inefficacy (503 patients) or adverse events (353 patients); patients who had discontinued the first inhibitor because of inefficacy were more likely to fail treatment with a second inhibitor for the same reason (hazard ratio = 2.7, 95% confidence interval [CI] = 2.1 to 3.4) rather than toxicity (hazard ratio = 1.1, 95% CI = 0.9 to 1.5), and similarly, rates of drug discontinuation for adverse events were higher in patients who had previously discontinued because of intolerance (hazard ratio = 2.3, 95% CI = 1.9 to 2.9) than in those who had previously discontinued because of inefficacy (hazard ratio = 1.2, 95% CI = 0.8 to 1.6) (Id.). Those patients failing TNF inhibitor therapy because of lack of efficacy can be subdivided into those who never achieved an adequate response (primary failure or inefficacy) and those who lost response over time (secondary failure or acquired therapeutic resistance); in general, a second TNF inhibitor appears to be more effective in patients with a history of secondary failure rather than primary failure, but some heterogeneity has been seen in small studies (Page 3, Column 1). Overall, findings suggest that the decline in efficacy after a switch to a second TNF inhibitor may in part be due to a class effect and also to a channelling bias favoring patients with more severe disease; thus, the rationale for introducing agents with a different mode of action may be to overcome issues related to class, particularly in cases of primary failure or recurrence of class-associated adverse events (Page 4, Column 2, Second Full Paragraph).
Takanashi teaches that widespread use of a treat-to-target strategy and remarkable progress in therapeutic agents has allowed more than half of patients with RA to achieve remission or low disease activity in clinical practice, however quite a few patients with RA who have not achieved treatment targets remain, and the concept of difficult-to treat RA (D2T RA; i.e., intractable RA) has emerged as the greatest unmet need in recent years; the prevalence of D2T RA, also referred to as refractory or problematic RA, is assumed to range from 5% to 20% (Page 5247, Introduction). A total of 2044 patients with RA were identified, and after excluding patients with insufficient information, 1709 patients were enrolled in the analysis and their clinical characteristics are summarized in Table 1; on the basis of the EULAR definition, 173 patients (10.1%) were classified as D2T RA (Fig. 1) (Page 5248, Column 2, Second Full Paragraph; see also Page 5249). Patients with D2T RA were classified into three groups based on the reason for the D2T RA: (i) multi-drug resistance (34.1%), comorbidities (9.8%), and socio-economic reasons (56.1%) (Fig. 1) (Page 5250, Column 1, Reasons for the D2T RA). The clinical characteristics of the D2T RA patients were quite different owing to the different reasons for the D2T RA (Table 2): the multi-drug-resistance group had the highest tender joint count and evaluator global assessment score among the three groups, even though >95% of the patients were treated with bDMARDs or JAKis; the patients in the comorbidity group showed the highest rate of admission due to infection, RDCI and the most common comorbidities of lung involvement and were significantly older, had the longest disease duration, and showed the smallest physique, with the duration from RA diagnosis to treatment initiation with a bDMARD or JAKi being longest in the comorbidity group (Id.). Table 3 and Fig. 2 suggest that switching biologic agents with different modes of action was useful, as approximately half of the patients achieved remission or low disease activity according to both the DAS28 and CDAI at the third or fourth mode of action (61.0%, 59.1%, 51.1% and 42.9% at the first, second, third and fourth switch to bDMARDs or JAKis with different modes of action, respectively); the switch to a
drug with the same mode of action due to secondary failure appeared to be reasonable, because 85% of the patients who had once responded to a drug with a certain mode of action switched to another drug with the same mode of action, and most of them achieved remission or low disease activity (Page 2520, Column 2, First Paragraph). On the other hand, few patients in the multi-drug-resistant D2T RA group failed to respond to several drugs with multiple modes of action; Approximately half of the patients achieved remission or low disease activity at the third or fourth mode of action, indicating the use fulness of switching to other drugs with different modes of action (Page 2520, Column 2, Second Paragraph). It is specifically noted that while Takanashi groups D2T RA patients into three groups, there is overlap between groups. For example, in Table 2 it is noted that a percentage of D2T RA patients in the multi-drug resistant group also have comorbidities including hypertension (15.3%), diabetes (3.3), and reduced kidney function (eGFR, ml/min/1.73 m2 (20.8%) and eGFR < 60 ml/min/1.73 m2 (25.4%)). Thus, there are subsets of RA patients that are (i) difficult to treat (i.e., have intractable RA), (ii) are multi-drug resistant (including resistance to TNF inhibitors/multiple TNF inhibitors), and (iii) have metabolic disorder.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the method of Park, such that the humanized antibody, specific for vimentin comprising instant SEQ ID NO: 21 (i.e., a non-citrullinated epitope), is used for the treatment and/or to gather information needed to diagnose rheumatoid arthritis patients, specifically patients having intractable rheumatoid arthritis with metabolic disorder and that are refractory/resistant to TNFα inhibitors. One would have been motivated to make such a modification because vimentin-specific antibodies that are specific for vimentin comprising instant SEQ ID NO: 21 are claimed by Park, and the use of vimentin-specific antibodies to citrullinated epitopes are established in the treatment and/or diagnostic methods for rheumatoid arthritis, as taught by Klareskog, and Musaelyan establishes the role of vimentin, both citrullination and non-citrullinated, in the pathogenesis of rheumatoid arthritis and its increased presence in in the blood, synovial pannus, rheumatoid nodules, and skin of RA patients. Furthermore, Rubbert-Roth teaches that TNF inhibitors (including TNFα inhibitors) have proved to be very effective in patients not responding to conventional disease modifying antirheumatic drugs, but about 20% to 40% of patients treated with a TNF inhibitor fail to achieve a 20% improvement in American College of Rheumatology criteria, and more lose response over time (secondary failure or acquired therapeutic resistance) or experience adverse events following treatment with a TNF inhibitor and suggests that introducing agents with a different mode of action may be to overcome issues related to class, particularly in cases of primary failure or recurrence of class-associated adverse events, and Takanashi teaches that there are subsets of RA patients that are (i) difficult to treat (i.e., have intractable RA), (ii) are multi-drug resistant (including resistance to TNF inhibitors/multiple TNF inhibitors), and (iii) have metabolic disorder. Klareskog recognizes the need in the art for effective treatments and diagnostic methods for rheumatoid arthritis, implicates citrullinated vimentin, and discloses antibodies useful in such methods wherein said antibodies are specific for an epitope of citrullinated vimentin; Musaelyan teaches that vimentin, both citrullinated and non-citrullinated, are implicated in the pathogenesis of rheumatoid arthritis and are increased/detectable in the blood, synovial pannus, rheumatoid nodules, and skin of RA patients; and Rubbert-Roth and Takanashi indicate that treatment of rheumatoid arthritis can be difficult, especially for patients categorized as difficult to treat who have comorbidities and/or have failed previous therapeutic treatments (e.g., TNF inhibitors), and that in such cases therapeutic interventions with alternate mechanisms of action are recommended. Given the recognized need for therapeutic and diagnostic methods, especially in difficult to treat patients, and given the known implications and increased presence of vimentin in cases of rheumatoid arthritis, one of skill in the art could have pursued applying vimentin-specific antibodies in therapeutic and diagnostic methods with a reasonable expectation of success.
Conclusion
Claims 1-19 are pending. Claims 1-19 are rejected. No claims are allowed.
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/ALYSSA RAE STONEBRAKER/Examiner, Art Unit 1642
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