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 .
DETAILED ACTION
Claims 1-6 and 11-24 are currently pending and under prosecution.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 1, 6, 11-17 and 24 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 treating chronic graft-versus-host disease (cGVHD)-related bronchiolitis obliterans syndrome in a human subject in need thereof, the method comprising administering to the human subject a therapeutically effective amount of an antibody that binds to colony stimulating factor 1 receptor (CSF-1R). No structure of the antibody that binds to CSF-1R is recited.
The instant specification discloses only 6 examples of the antibody (with their respective sequences) that binds to CSF-1R: [pg 4-9]
Axatilimab
Emactuzumab
Cabiralziumab
IMC-CS4
AMG820
DCB-AB21
The instant specification does not disclose any other examples that functions to treat chronic graft-versus-host disease (cGVHD)-related bronchiolitis obliterans syndrome.
By the time of the filing of the instant application, it was well established in the art that the formation of an intact antigen-binding site in an antibody usually required the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three “complementarity determining regions” (“CDRs”) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro & Fransson, Frontiers in Bioscience 2008; 13:1619-33; (see Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1). Humanized antibodies comprise only the CDRs, or in some cases an abbreviated subset of residues within the CDRs, of a parental rodent antibody in the context of human framework sequences. Id. at Section 4. All of the CDRs of the heavy and light chain, in their proper order of CDR1, then 2, then 3, and in the context of framework sequences which maintain their required conformation are generally required to produce a humanized antibody in which the heavy and light chains associate to form an antigen-binding region that binds the same antigen as the parental rodent antibody. Id. at Section 4.
Antibody binding to the same antigen, or even the same epitope on that antigen, can be accomplished with an impressively wide variety of antibody structures, even when the antibodies are limited to those from a particular source (Gershoni et al., Epitope Mapping, Biodrugs 2007; 21 (3): 145-156 page 146 section 1.1). The skilled artisan therefore understood that antibodies from a variety of different sources may bind the same antigen and even mediate the same functional effects, but differ widely in the details of the structure of their antigen-binding sites, particularly in the amino acid sequence and length of VH-CDR3.
Further, it is not possible to predict the amino acid sequence when an epitope is recited, because there are many different epitope arrangements, such as linear and discontinuous epitopes that is dictated by the unique interaction between an antibody and its cognate epitope (Blythe et al., Benchmarking B cell epitope prediction: Underperformance of existing methods, Protein Science (2005), 14:246–248 pg. 246) . 3D structural analyses of antibody-epitope binding highlighting that the deficiency in the ability to predict the structural features of an antibody when the epitope is disclosed (Schreiber et al.,3D-Epitope-Explorer (3DEX): Localization of Conformational Epitopes within Three-Dimensional Structures of Proteins, Wiley Interscience, 2005 42–44, 60596, page 879).
The structure activity relationship of the CDR antigen binding regions that recognizes CSF-1R is not known and the binding epitopes cannot be predicted based on the antibody sequences. Hume et al (Blood (2012) 119 (8): 1810–1820) teaches the complications of antibodies that target CSF-1 and CSF-1 receptor. Hume et al teaches that there is a question for antibodies on the mechanism of action of the antibody and compared the effects of two anti-CSF-1R antibodies, AFS98 and M279. Hume et al teaches that there are several structural differences between the two antibodies that leads to functional differences. [pg 1816 1st column] Although there are limited number of these antibodies that target this receptor, no two agents are the same, which can in turn affect the function of the antibody. There is not enough guidance in the art or the specification that gives Applicants possession of the broad genus of antibodies that bind to CSF-1R.
To provide adequate written description and evidence of possession of the claimed composition antibody genus, the instant specification can structurally describe representative antibodies or antigen binding fragments, that function to bind to CSF-1R and treating functions as claimed, 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.). A disclosure that does not adequately describe a product itself logically cannot adequately describe a method of using that product.
Although Applicants may argue that it is possible to screen for antibodies that 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 CSF-1R antigen provides no information about the structure of an antibody inhibits it.
Given the lack of representative examples to support the full scope of the claimed antibodies that bind to CSF-1R, and lack of reasonable structure-function correlation with regards to the unknown sequences in the variable domains or CDRs of the antibodies that function as claimed, the present claims lack adequate written description. Thus, the specification does not provide an adequate written description of antibodies that is required to practice the claimed invention. Since the specification fails to adequately describe the product to which the claimed method uses, it also fails to adequately describe the method.
Examiner’s Suggestion: Amend the claims to recite the structure critical to the antibody that binds to CSF-1R, that is the antibody comprising all six heavy and light chain CDR SEQ ID Nos, or comprising both the VH and VL domain sequences (as recited in dependent claims 2-3, respectively).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim(s) 1-4, 6, and 11-24 are rejected under 35 U.S.C. 103 as being unpatentable over NCT04710576; Record History Dated 4/29/2022, in view of Saidu et al (2020) (New Approaches for the Treatment of Chronic Graft-Versus-Host Disease: Current Status and Future Directions. Front. Immunol. 11:578314), Craggs et al (US20160200821 A; Published 7/14/2016), and Haegel et al (US20110081353 A1; Published 4/7/2011).
It is noted that the instant specification discloses the following:
Axatilimab is an example of the antibody that binds to CSF-1R encompassed by claim 1
The sequences of Axatilimab (heavy chain SEQ ID NO: 2, light chain SEQ ID NO: 3, VH SEQ ID NO: 4, VL SEQ ID NO: 5, VH CDR 1-3: SEQ ID NOS: 6-7-8, VL CDR 1-3: SEQ ID NOS: 9-10-11 is disclosed on pages 4-6 of the instant specification, and comparison with sequences demonstrates it includes these CDRs from the claims.
Clinical Trial, NCT04710576, teaches a method of treating chronic graft versus host disease cGVHD comprising administering Axatilimab, an antibody that binds to colony stimulating factor 1 receptor (CSF-1R). [Arms and Interventions]
Regarding claim 6, NCT04710576 teaches that the human subject has received at least two previous cGVHD treatments. [Study Description, Brief Summary]
Regarding claims 11, 12, 15, 18, and 21, NCT04710576 teaches that the antibody is administered intravenously at a dose of 0.3 mg/kg every two weeks. [Arms, Experimental Dose Cohort 1]
Regarding claims 13, 16, 19, and 22, NCT04710576 teaches that the antibody is administered intravenously at a dose of 1 mg/kg every two weeks. [Arms, Experimental Dose Cohort 2]
Regarding claims 14, 17, 20 and 23, NCT04710576 teaches that the antibody is administered intravenously at a dose of 3 mg/kg every four weeks. [Arms, Experimental Dose Cohort 3]
However, does not specifically teach that (1) the method treats cGVHD-related bronchiolitis obliterans syndrome or (2) that cGVHD Is “advanced cGVHD” as recited in claim 24.
Saidu teaches chronic graft-versus host disease (cGvHD) is a severe complication of allogeneic hematopoietic stem cell transplantation. Saidu teaches that GvHD can be acute or chronic and chronic GvHD is present at any time and resembles an autoimmune syndrome and clinical manifestation such as bronchiolitis obliterans (BO) may occur. Saidu teaches that colony stimulating factor-1 is a key cytokine that modulates the differentiation, proliferation and survival of macrophages, and is implicated in cGvHD. Saidu teaches that donor macrophages also infiltrate organs such as the lungs of a HSCT recipient through CSF-1 receptor signaling, and that studies have shown that donor CSF-1R dependent macrophages may contribute to both sclerodermatous-cGvHD and lung cGVHD, otherwise known as bronchiolitis obliterans syndrome (BOS). [pg 3, 1st column] Saidu further teaches that Axatilimab (SNDX-6352) is a humanized IgG4 monoclonal antibody that binds to CSF-1R, and that by binding to this receptor it can disrupt the activities of the donor-derived pro inflammatory macrophages that have been shown to promote cGvHD in the lungs. [pg 12, 1st column, 4th paragraph]
Craggs teaches an anti-CSF-1R antibody comprising the instantly claimed sequences (see sequence alignments below). Craggs teaches that the antibody may be used for treatment of fibrotic diseases and inflammatory disease, such as graft vs host reaction. [0186-0187]
Haegel teaches the use antibodies that bind to CSF-1R. [Abstract] Haegel teaches that the CSF-1 pathway is involved in inflammation, and blockade of macrophage colony stimulating factor reduces macrophage proliferation and accumulation in renal allograft rejection. [0006] Haegel teaches that the antibody can be used to treat bronchiolitis obliterans. [0304]
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat chronic graft-versus-host disease related bronchiolitis obliterans syndrome, including advanced chronic graft-versus-host disease, comprising administering an antibody that binds to colony stimulating factor 1 receptor. One would have been motivated to, and have a reasonable expectation of success, because: (1) Clinical Trial, NCT04710576 and Saidu both teach a method of treating chronic graft versus host disease cGVHD comprising an antibody that binds to colony stimulating factor 1 receptor (CSF-1R), (2) Craggs teaches a method of treating a graft vs host disease reaction comprising administering an anti-CSF-1R antibody, (3) Saidu teaches that cGVHD is a severe complication and may results in autoimmune syndrome and can clinically manifest as bronchiolitis obliterans (BO), (4) Saidu teaches that role of CSF-1 receptor signaling and that CSF-1R dependent macrophages contribute to bronchiolitis obliterans, and (5) Haegel teaches that use of an antibody that binds to CSF-1R for the treatment of bronchiolitis obliterans.
The clinical trial, NCT04710576 recognizes the need in the art to treat chronic graft-versus-host disease. Given the recognized need to treat cGVHD-related bronchiolitis obliterans syndrome including advanced cGVHD, given the known method of using an anti-CSF-1R antibody for both cGVHD and bronchiolitis obliterans, and given the known role of CSF-1R in the manifestations of cGVHD, one of skill in the art in the art could have pursued treating cGVHD-related bronchiolitis obliterans syndrome an anti-CSF-1R antibody, with a reasonable expectation of success.
SEQUENCE ALIGNMENTS
SEQ ID NOS: 6-7-8
RESULT 1
US-14-914-676-23
(NOTE: this sequence has 5 duplicates in the database searched)
Sequence 23, US/14914676
Patent No. 9908939
GENERAL INFORMATION
APPLICANT: UCB Biopharma SPRL
TITLE OF INVENTION: ANTIBODIES
FILE REFERENCE: G0181-PCT
CURRENT APPLICATION NUMBER: US/14/914,676
CURRENT FILING DATE: 2016-02-26
PRIOR APPLICATION NUMBER: GB1315487.7
PRIOR FILING DATE: 2013-08-30
NUMBER OF SEQ ID NOS: 39
SEQ ID NO 23
LENGTH: 125
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: 969 gH2 V-region
Query Match 90.5%; Score 233.4; Length 125;
Best Local Similarity 48.9%;
Matches 44; Conservative 0; Mismatches 0; Indels 46; Gaps 2;
Qy 1 GFSLTTYGMGVG--------------NIWWDDDKYYNPSLKN------------------ 28
|||||||||||| ||||||||||||||||
Db 26 GFSLTTYGMGVGWIRQPPGKALEWLANIWWDDDKYYNPSLKNRLTISKDTSKNQVVLTMT 85
Qy 29 --------------IGPIKYPTAPYRYFDF 44
||||||||||||||||
Db 86 NMDPVDTATYYCARIGPIKYPTAPYRYFDF 115
SEQ ID NOS: 9-10-11
RESULT 1
US-14-914-676-15
(NOTE: this sequence has 5 duplicates in the database searched)
Sequence 15, US/14914676
Patent No. 9908939
GENERAL INFORMATION
APPLICANT: UCB Biopharma SPRL
TITLE OF INVENTION: ANTIBODIES
FILE REFERENCE: G0181-PCT
CURRENT APPLICATION NUMBER: US/14/914,676
CURRENT FILING DATE: 2016-02-26
PRIOR APPLICATION NUMBER: GB1315487.7
PRIOR FILING DATE: 2013-08-30
NUMBER OF SEQ ID NOS: 39
SEQ ID NO 15
LENGTH: 107
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: 969 gL7 V-region
Query Match 82.6%; Score 117.3; Length 107;
Best Local Similarity 36.5%;
Matches 27; Conservative 0; Mismatches 0; Indels 47; Gaps 2;
Qy 1 LASEDIYDNLA---------------YASSLQD--------------------------- 18
||||||||||| |||||||
Db 24 LASEDIYDNLAWYQQKPGKAPKLLIYYASSLQDGVPSRFSGSGSGTDYTLTISSLQPEDF 83
Qy 19 -----LQDSEYPWT 27
|||||||||
Db 84 ATYYCLQDSEYPWT 97
VH DOMAIN: SEQ ID NO: 4
RESULT 1
US-14-914-676-23
(NOTE: this sequence has 5 duplicates in the database searched)
Sequence 23, US/14914676
Patent No. 9908939
GENERAL INFORMATION
APPLICANT: UCB Biopharma SPRL
TITLE OF INVENTION: ANTIBODIES
FILE REFERENCE: G0181-PCT
CURRENT APPLICATION NUMBER: US/14/914,676
CURRENT FILING DATE: 2016-02-26
PRIOR APPLICATION NUMBER: GB1315487.7
PRIOR FILING DATE: 2013-08-30
NUMBER OF SEQ ID NOS: 39
SEQ ID NO 23
LENGTH: 125
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: 969 gH2 V-region
Query Match 100.0%; Score 686; Length 125;
Best Local Similarity 100.0%;
Matches 125; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVTLKESGPALVKPTQTLTLTCTFSGFSLTTYGMGVGWIRQPPGKALEWLANIWWDDDKY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVTLKESGPALVKPTQTLTLTCTFSGFSLTTYGMGVGWIRQPPGKALEWLANIWWDDDKY 60
Qy 61 YNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIGPIKYPTAPYRYFDFWGQGT 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 YNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIGPIKYPTAPYRYFDFWGQGT 120
Qy 121 MVTVS 125
|||||
Db 121 MVTVS 125
VL DOMAIN: SEQ ID NO: 5
RESULT 1
US-14-914-676-15
(NOTE: this sequence has 5 duplicates in the database searched)
Sequence 15, US/14914676
Patent No. 9908939
GENERAL INFORMATION
APPLICANT: UCB Biopharma SPRL
TITLE OF INVENTION: ANTIBODIES
FILE REFERENCE: G0181-PCT
CURRENT APPLICATION NUMBER: US/14/914,676
CURRENT FILING DATE: 2016-02-26
PRIOR APPLICATION NUMBER: GB1315487.7
PRIOR FILING DATE: 2013-08-30
NUMBER OF SEQ ID NOS: 39
SEQ ID NO 15
LENGTH: 107
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: 969 gL7 V-region
Query Match 100.0%; Score 564; Length 107;
Best Local Similarity 100.0%;
Matches 107; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DIQMTQSPSSLSASVGDRVTITCLASEDIYDNLAWYQQKPGKAPKLLIYYASSLQDGVPS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIQMTQSPSSLSASVGDRVTITCLASEDIYDNLAWYQQKPGKAPKLLIYYASSLQDGVPS 60
Qy 61 RFSGSGSGTDYTLTISSLQPEDFATYYCLQDSEYPWTFGGGTKVEIK 107
|||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RFSGSGSGTDYTLTISSLQPEDFATYYCLQDSEYPWTFGGGTKVEIK 107
HEAVY CHAIN: SEQ ID NO: 12
RESULT 1
US-14-914-676-27
(NOTE: this sequence has 9 duplicates in the database searched)
Sequence 27, US/14914676
Patent No. 9908939
GENERAL INFORMATION
APPLICANT: UCB Biopharma SPRL
TITLE OF INVENTION: ANTIBODIES
FILE REFERENCE: G0181-PCT
CURRENT APPLICATION NUMBER: US/14/914,676
CURRENT FILING DATE: 2016-02-26
PRIOR APPLICATION NUMBER: GB1315487.7
PRIOR FILING DATE: 2013-08-30
NUMBER OF SEQ ID NOS: 39
SEQ ID NO 27
LENGTH: 453
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: 969 gH2 heavy chain (V + constant - hu IgG4P)
Query Match 100.0%; Score 2431; Length 453;
Best Local Similarity 100.0%;
Matches 452; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVTLKESGPALVKPTQTLTLTCTFSGFSLTTYGMGVGWIRQPPGKALEWLANIWWDDDKY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVTLKESGPALVKPTQTLTLTCTFSGFSLTTYGMGVGWIRQPPGKALEWLANIWWDDDKY 60
Qy 61 YNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIGPIKYPTAPYRYFDFWGQGT 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 YNPSLKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARIGPIKYPTAPYRYFDFWGQGT 120
Qy 121 MVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 MVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP 180
Qy 181 AVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEF 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 AVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEF 240
Qy 241 LGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREE 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 LGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREE 300
Qy 301 QFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPS 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 QFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPS 360
Qy 361 QEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDK 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 QEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDK 420
Qy 421 SRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG 452
||||||||||||||||||||||||||||||||
Db 421 SRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG 452
LIGHT CHAIN: SEQ ID NO: 3
RESULT 1
US-14-914-676-19
(NOTE: this sequence has 9 duplicates in the database searched)
Sequence 19, US/14914676
Patent No. 9908939
GENERAL INFORMATION
APPLICANT: UCB Biopharma SPRL
TITLE OF INVENTION: ANTIBODIES
FILE REFERENCE: G0181-PCT
CURRENT APPLICATION NUMBER: US/14/914,676
CURRENT FILING DATE: 2016-02-26
PRIOR APPLICATION NUMBER: GB1315487.7
PRIOR FILING DATE: 2013-08-30
NUMBER OF SEQ ID NOS: 39
SEQ ID NO 19
LENGTH: 214
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: 969 gL7 light chain (V + constant)
Query Match 100.0%; Score 1117; Length 214;
Best Local Similarity 100.0%;
Matches 214; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DIQMTQSPSSLSASVGDRVTITCLASEDIYDNLAWYQQKPGKAPKLLIYYASSLQDGVPS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIQMTQSPSSLSASVGDRVTITCLASEDIYDNLAWYQQKPGKAPKLLIYYASSLQDGVPS 60
Qy 61 RFSGSGSGTDYTLTISSLQPEDFATYYCLQDSEYPWTFGGGTKVEIKRTVAAPSVFIFPP 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RFSGSGSGTDYTLTISSLQPEDFATYYCLQDSEYPWTFGGGTKVEIKRTVAAPSVFIFPP 120
Qy 121 SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT 180
Qy 181 LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 214
||||||||||||||||||||||||||||||||||
Db 181 LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 214
Claim(s) 5 is rejected under 35 U.S.C. 103 as being unpatentable over NCT04710576; Record History Dated 4/29/2022, Saidu et al (2020) (New Approaches for the Treatment of Chronic Graft-Versus-Host Disease: Current Status and Future Directions. Front. Immunol. 11:578314), and Craggs et al (US20160200821 A; Published 7/14/2016) (combined references(, as applied to claims 1-4, 6, and 11-24 above, and further in view of Lin CC. (Clinical Development of Colony-Stimulating Factor 1 Receptor (CSF1R) Inhibitors. J Immunother Precis Oncol. 2021 May 14;4(2):105-114).
The teachings of the combined references are above. However, they do not teach the limitation of claim 5, wherein the antibody is emactuzumab, cabiralizumab, AMG820, and IMC-CS4.
Lin et al teaches that CSF1R, also known as macrophage colony-stimulating factor receptor, signaling regulates the differentiation of myeloid cells and plays a role in a few diseases. Lin et al teaches monoclonal antibodies that target CSF1R that are in clinical development, including cabiralizumab, emactuzumab, Axatilimab, IMC-CS4. [pg 109-110; Table 3]
It is noted that claim 5 requires that the antibody of claim 1 is emactuzumab, AMG820, cabiralizumab, or IMC-CS4. This limitation would have been obvious to those of ordinary skill in the art, because: (1) the combined reference all teach the use of an antibody that targets CSF-1R for the treatment cGVHD, (2) Saidu teaches that colony stimulating factor-1 is a key cytokine that modulates the differentiation, proliferation and survival of macrophages, and is implicated in cGvHD, (3) Saidu teaches that donor macrophages also infiltrate organs such as the lungs of a HSCT recipient through CSF-1 receptor signaling, and (4) Lin et al teaches the role of CSF1R with regards to macrophages, and teaches known anti-CSF-1R antibodies, including cabiralizumab, emactuzumab, Axatilimab, IMC-CS4. Thus, given the known role of antibodies that target CSF-1R and the known method of using this antibody for the treatment of cGVHD as taught by the prior art, one of skilled in the art could have substituted one known antibody that binds to CSF-1R for another, and the results of treatment of cHVD would have been predictable.
Claim(s) 1-4, 6, and 11-24 are rejected under 35 U.S.C. 103 as being unpatentable over Ordentlich et al (WO2021119128 A1; Published 6/17/2021), in view of Saidu et al (2020) (New Approaches for the Treatment of Chronic Graft-Versus-Host Disease: Current Status and Future Directions. Front. Immunol. 11:578314), Craggs et al (US20160200821 A; Published 7/14/2016), and Haegel et al (US20110081353 A1; Published 4/7/2011).
It is noted that the instant specification discloses the following:
Axatilimab is an example of the antibody that binds to CSF-1R encompassed by claim 1
The sequences of Axatilimab (heavy chain SEQ ID NO: 2, light chain SEQ ID NO: 3, VH SEQ ID NO: 4, VL SEQ ID NO: 5, VH CDR 1-3: SEQ ID NOS: 6-7-8, VL CDR 1-3: SEQ ID NOS: 9-10-11 is disclosed on pages 4-6 of the instant specification, and comparison with sequences demonstrates it includes these CDRs from the claims.
Ordentlich teaches a method of treating chronic graft versus host disease cGVHD comprising administering Axatilimab, an antibody that binds to colony stimulating factor 1 receptor (CSF-1R). [Abstract, pg 3, 2nd paragraph] Ordentlich teaches that cGVHD is a potentially life-threatening complication of allogeneic hematopoietic stem cell transplantation and it manifests in multiple organ systems. [pg 3, 1st paragraph] Ordentlich teaches that patients with chronic GVHD and lung involvement are often difficult to treat and associated with poor outcomes, thus there is a need to treat these conditions. [pg 4, last paragraph] Ordentlich demonstrates the response of Axatilimab across several organ systems, including the lung. [Figure 12]
Regarding claim 6, Ordentlich teaches that the human subject has received at least two previous cGVHD treatments. [claims 13-14]
Regarding claims 11, 12, 15, 18, and 21, Ordentlich teaches that the antibody is administered intravenously at a dose of 0.3 mg/kg every two weeks. Regarding claims 13, 16, 19, and 22, Ordentlich teaches that the antibody is administered intravenously at a dose of 1 mg/kg every two weeks. Regarding claims 14, 17, 20 and 23, Ordentlich teaches that the antibody is administered intravenously at a dose of 3 mg/kg every four weeks. [pg 6, 4th paragraph; pg 10]
However, Ordentlich does not specifically teach that (1) the method treats bronchiolitis obliterans syndrome or (2) that cGVHD Is “advanced cGVHD” as recited in claim 24.
Saidu teaches chronic graft-versus host disease (cGvHD) is a severe complication of allogeneic hematopoietic stem cell transplantation. Saidu teaches that GvHD can be acute or chronic and chronic GvHD is present at any time and resembles an autoimmune syndrome and clinical manifestation such as bronchiolitis obliterans (BO) may occur. Saidu teaches that colony stimulating factor-1 is a key cytokine that modulates the differentiation, proliferation and survival of macrophages, and is implicated in cGvHD. Saidu teaches that donor macrophages also infiltrate organs such as the lungs of a HSCT recipient through CSF-1 receptor signaling, and that studies have shown that donor CSF-1R dependent macrophages may contribute to both sclerodermatous-cGvHD and lung cGVHD, otherwise known as bronchiolitis obliterans syndrome (BOS). [pg 3, 1st column] Saidu further teaches that Axatilimab (SNDX-6352) is a humanized IgG4 monoclonal antibody that binds to CSF-1R, and that by binding to this receptor it can disrupt the activities of the donor-derived pro inflammatory macrophages that have been shown to promote cGvHD in the lungs. [pg 12, 1st column, 4th paragraph]
Craggs teaches an anti-CSF-1R antibody comprising the instantly claimed sequences (see sequence alignments below). Craggs teaches that the antibody may be used for treatment of fibrotic diseases and inflammatory disease, such as graft vs host reaction. [0186-0187]
Haegel teaches the use antibodies that bind to CSF-1R. [Abstract] Haegel teaches that the CSF-1 pathway is involved in inflammation, and blockade of macrophage colony stimulating factor reduces macrophage proliferation and accumulation in renal allograft rejection. [0006] Haegel teaches that the antibody can be used to treat bronchiolitis obliterans. [0304]
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat chronic graft-versus-host disease related bronchiolitis obliterans syndrome, including advanced chronic graft-versus-host disease, comprising administering an antibody that binds to colony stimulating factor 1 receptor. One would have been motivated to, and have a reasonable expectation of success, because: (1) the prior art all teach a method of treating chronic graft versus host disease cGVHD comprising an antibody that binds to colony stimulating factor 1 receptor (CSF-1R), (2) Craggs teaches a method of treating a graft vs host disease reaction comprising administering an anti-CSF-1R antibody, (3) Saidu teaches that cGVHD is a severe complication and may results in autoimmune syndrome and can clinically manifest as bronchiolitis obliterans (BO), (4) Saidu teaches that role of CSF-1 receptor signaling and that CSF-1R dependent macrophages contribute to bronchiolitis obliterans, and (5) Haegel teaches that use of an antibody that binds to CSF-1R for the treatment of bronchiolitis obliterans.
Ordentlich recognizes the need in the art to treat chronic graft-versus-host disease. Given the recognized need to treat cGVHD-related bronchiolitis obliterans syndrome including advanced cGVHD, given the known method of using an anti-CSF-1R antibody, and given the known role of CSF-1R in the manifestations of cGVHD, one of skill in the art in the art could have pursued treating cGVHD-related bronchiolitis obliterans syndrome an anti-CSF-1R antibody, with a reasonable expectation of success.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 1-4, 6 and 11-24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 9, 14, 16, 17, and 19 of U.S. Patent No. 12,552,869 in view of Saidu et al (2020) (New Approaches for the Treatment of Chronic Graft-Versus-Host Disease: Current Status and Future Directions. Front. Immunol. 11:578314), NCT04710576; Record History Dated 4/29/2022, and Haegel et al (US20110081353 A1; Published 4/7/2011).
The U.S. Patent recites a method of treating chronic graft versus host disease (cGVHD), wherein the method comprises intravenously administering an anti-CSF-1R antibody to a human subject in need thereof at a dose of 0.3 mg/kg every two weeks or 1.0 mg/kg every two weeks, wherein the anti-CSF-1R antibody comprises the sequences of Axatilimab (the sequences listed in the instant claims 2-4). The U.S. Patent recites that the chronic graft versus host disease is selected from lungs chronic graft versus host disease. The U.S. Patent also recites that the human subject has progressed on one or more prior therapies.
However, the U.S. Patent does not recite the method of treating chronic graft-versus host disease bronchiolitis obliterans syndrome or that the antibody is administered at a dose of 3 mg/kg every 4 weeks (as recited in claims 14, 17, 20 and 23).
Saidu teaches chronic graft-versus host disease (cGvHD) is a severe complication of allogeneic hematopoietic stem cell transplantation. Saidu teaches that GvHD can be acute or chronic and chronic GvHD is present at any time and resembles an autoimmune syndrome and clinical manifestation such as bronchiolitis obliterans (BO) may occur. Saidu teaches that colony stimulating factor-1 is a key cytokine that modulates the differentiation, proliferation and survival of macrophages, and is implicated in cGvHD. Saidu teaches that donor macrophages also infiltrate organs such as the lungs of a HSCT recipient through CSF-1 receptor signaling, and that studies have shown that donor CSF-1R dependent macrophages may contribute to both sclerodermatous-cGvHD and lung cGVHD, otherwise known as bronchiolitis obliterans syndrome (BOS). [pg 3, 1st column] Saidu further teaches that Axatilimab (SNDX-6352) is a humanized IgG4 monoclonal antibody that binds to CSF-1R, and that by binding to this receptor it can disrupt the activities of the donor-derived pro inflammatory macrophages that have been shown to promote cGvHD in the lungs. [pg 12, 1st column, 4th paragraph]
Clinical Trial, NCT04710576, teaches a method of treating chronic graft versus host disease cGVHD comprising administering Axatilimab, an antibody that binds to colony stimulating factor 1 receptor (CSF-1R). [Arms and Interventions] NCT04710576 teaches that the human subject has received at least two previous cGVHD treatments. [Study Description, Brief Summary] NCT04710576 teaches that the antibody is administered intravenously at a dose of 0.3 mg/kg every two weeks. [Arms, Experimental Dose Cohort 1] NCT04710576 teaches that the antibody is administered intravenously at a dose of 1 mg/kg every two weeks. [Arms, Experimental Dose Cohort 2] NCT04710576 teaches that the antibody is administered intravenously at a dose of 3 mg/kg every two weeks. [Arms, Experimental Dose Cohort 3]
Haegel teaches the use antibodies that bind to CSF-1R. [Abstract] Haegel teaches that the CSF-1 pathway is involved in inflammation, and blockade of macrophage colony stimulating factor reduces macrophage proliferation and accumulation in renal allograft rejection. [0006] Haegel teaches that the antibody can be used to treat bronchiolitis obliterans. [0304]
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat chronic graft-versus-host disease related bronchiolitis obliterans syndrome, including advanced chronic graft-versus-host disease, comprising administering the antibody of the U.S. Patent. One would have been motivated to, and have a reasonable expectation of success, because: (1) the U.S. Patent recites a method of treating chronic graft versus host disease cGVHD comprising an antibody that binds to colony stimulating factor 1 receptor (CSF-1R), (2) Saidu teaches a method of treating chronic graft versus host disease comprising administering an antibody that binds to CSF-1R, Axatilimab, (3) Saidu teaches that cGVHD is a severe complication and may results in autoimmune syndrome and can clinically manifest as bronchiolitis obliterans (BO), (4) Saidu teaches that role of CSF-1 receptor signaling and that CSF-1R dependent macrophages contribute to bronchiolitis obliterans, and (5) Haegel teaches that use of an antibody that binds to CSF-1R for the treatment of bronchiolitis obliterans.
Given the recognized need to treat cGVHD-related bronchiolitis obliterans syndrome including advanced cGVHD, given the known method of using an anti-CSF-1R antibody, and given the known role of CSF-1R in the manifestations of cGVHD, one of skill in the art in the art could have pursued treating cGVHD-related bronchiolitis obliterans syndrome with the antibody of the U.S. Patent, with a reasonable expectation of success.
It is noted that claims 14, 17, 20 and 23 require that the instantly claimed antibody is administered at dose of 3 mg/kg. This limitation would have been obvious to those of ordinary skill in the art, because: (1) the U.S. Patent recites a method of treating chronic graft versus host disease cGVHD comprising an antibody that binds to colony stimulating factor 1 receptor (CSF-1R), (2) Saidu and the clinical trial both teach the method of treating cGVHD comprising administering an antibody that binds to CSF-1R, and (3) the clinical trial teaches that the antibody is administered intravenously at a dose of 3 mg/kg every four weeks. Given the known function of the antibody that binds to CSF-1R, given the known dose of 3 mg/kg for treatment of cGVHD, one of skill in the art could have pursued administering the antibody intravenously at a dose of 3 mg/kg every 4 weeks, with a reasonable expectation of success.
Conclusion
Conclusion: Claims 1-6, 11-24 are rejected.
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/SARAH A ALSOMAIRY/Examiner, Art Unit 1646
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