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 .
Election/Restrictions
Applicant’s election with traverse of Group I (claims 1-10, 15-16, 19, 31-32, 35, and 38) and the below-listed species in the reply filed on 06/15/2026 is acknowledged.
Elected Species:
A light chain comprising CDRs L1-L3 of SEQ ID NOs: 1-3, respectively;
A heavy chain comprising CDRs H1-H3 of SEQ ID NOs: 4-6, respectively;
A variable heavy chain amino acid sequence of SEQ ID NO: 22;
A variable light chain amino acid sequence of SEQ ID NO: 14;
A full heavy chain amino acid sequence of SEQ ID NO: 23; and
A full light chain amino acid sequence of SEQ ID NO: 15.
With regard to the traversal of the Restriction/Election requirement, it is noted that on Page 10 of Remarks (06/15/2026) Applicant argues that Groups I and II share a special technical feature of light chain CDRs 1-3 of SEQ ID NOs: 1-3, respectively, and therefore a search and evaluation of each of Groups I and II would cover a unified special technical feature and rejoinder is requested.
Applicant’s arguments have been fully considered, but are deemed not persuasive.
It is specifically noted that in the previous Restriction/Election requirement (01/22/2026), it was acknowledged that even though Groups I and II both require the technical feature of an isolated antibody that binds to canine TNFα, wherein the antibody is a caninised antibody comprising a variable light chain comprising (i) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 1; (ii) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 2; (iii) a CDR L3 comprising the amino acid sequence of SEQ ID NO: 3; and (iv) a LC-FR2 comprising a glutamine at position 3 and a lysine at position 8, this technical feature is not a special technical feature as it does not make a contribution over the prior art in view of US 2014/0294815 A1 (previously cited on PTO-892; herein after referred to as "Gearing"). The teachings of Gearing are discussed on Pages 5-6 of the Restriction/Election requirement, and Applicant has not provided any arguments against the Gearing reference with regard to its teachings and the technical feature.
In view of the above, the Restriction/Election requirement is deemed proper and is therefore made FINAL.
Claim Status
Claims 10-14, 17-30, 33-34, 36-37, 40-42, 44-60, and 62 have been cancelled; claims 1-9, 15-16, and 32 have been amended; and, claims 63-64 have been newly added, as requested in the amendment filed on 06/15/2026. Following the amendment, claims 1-9, 15-16, 31-32, 35, 38-39, 43, 61, and 63-64 are pending in the instant application.
Claims 39, 43, and 61 stand as withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention in the Response filed 06/15/2026, there being no allowable generic or linking claim.
It is specifically noted that the elected species recited in claim 7, drawn to the instantly elected species corresponding to an antibody that binds to canine TNFα wherein the antibody comprises a variable light chain comprising the amino acid sequence of SEQ ID NO: 14 and a variable heavy chain sequence comprising the amino acid sequence of SEQ ID NO: 22, is directed to allowable subject matter. As such, the species search has been expanded to include the additionally recited variable light chain sequences of claim 7 corresponding to SEQ ID NOs: 18, 25, 29, 33, 37, 43, and 46. Furthermore, the corresponding full light chain sequences corresponding to SEQ ID NOs: 19, 26, 30, 34, 38, and 44 are also included in the expanded species search. The expanded species search applies to all claims reading on any of the above-recited variable light chain/full light chain sequences, either alone or in combination with the instantly elected variable heavy chain and full heavy chain sequences corresponding to SEQ ID NOs: 22 and 23, respectively.
Claims 1-9, 15-16, 31-32, 35, 38, and 63-64 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.
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Provisional Application No. 63/127,994, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. Specifically, it is noted that Provisional Application No. 63/127,994 does not provide support for an antibody that binds to canine TNFα and canine NGF, a variable light chain comprising the amino acid sequence of any of SEQ ID NOs: 55-56 or 73, nor a variable heavy chain comprising the amino acid sequence of any of SEQ ID NOs: 57-58 or 74.
The disclosure of the prior-filed application, Provisional Application No. 63/128,804, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. Specifically, it is noted that Provisional Application No. 63/128,804 does not provide support for an antibody that binds to canine TNFα and canine NGF, a variable light chain comprising the amino acid sequence of SEQ ID NO: 73, nor a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 74.
Claims 1-9, 15-16, 31, 35, 38, and 63-64 have an effective filing date of December 18, 2020 corresponding to PRO 63/127,994.
Claim 32 has an effective filing date of December 17, 2021 corresponding to PCT/US2021/064223 because the earlier-filed provisional applications fail to provide adequate support for, generally, an antibody that binds to canine TNFα and canine NGF.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 06/16/2023, 11/21/2024, 11/13/2025, and 03/23/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Specification
The specification is objected to for the use of the terms nanobodies, DNASTAR, PURINA Body Condition System, and WSAVA, 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 it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
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.
Art-Free Subject Matter
It is noted that the instant caninized antibody species that bind canine TNFα comprising: (i) a variable light chain sequences comprising the amino acid sequences of SEQ ID NOs: 14, 18, 25, 29, 33, 37, 43, and 46; (ii) a full light chain sequence comprising the amino acid sequences of SEQ ID NOs: 15, 19, 26, 30, 34, 38, and 44; (iii) a variable heavy chain sequence comprising the amino acid sequence of SEQ ID NO: 22; and/or (iv) a full heavy chain sequence comprising the amino acid sequence of SEQ ID NO: 23 have been thoroughly searched and are deemed free of the prior art, as there are no 100% matches to the full-length sequences of the above-recited SEQ ID NOs.
Claim Objections
Claim 1 is objected to because of the following informalities: line 4 currently recites “CDR L3”, but for consistency with the rest of the claim(s) should read “CDR-L3”. Appropriate correction is required.
Claim 2 is objected to because of the following informalities: lines 3-4 currently recite “CDR H3”, but for consistency with the rest of the claim(s) should read “CDR-H3”. Appropriate correction is required.
Claim 32 is objected to because of the following informalities: (i) line 7 currently recites “sequence of SEQ ID NO: SEQ ID NO: 14”, but should read “sequence of SEQ ID NO: 14”; and (ii) line 10 currently recites “SED ID NO: 58”, but should read “SEQ ID NO: 58”. Appropriate correction is required.
Claim Interpretation
With regard to the sequence language of the instant claims, the following are noted:
The recitation of, for example, “comprising the amino acid sequence of SEQ ID NO: 1” is being interpreted such that for a reference sequence to meet the limitation, the reference sequence must comprise an exact match to full-length SEQ ID NO: 1. This interpretation applies to claims 1-9, 15-16, 32, and 63-64.
The recitation of, for example, “comprising at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 43” is being interpreted such that for a reference sequence to meet the limitation, the reference sequence must comprise a sequence having at least 95% identity to full-length SEQ ID NO: 43 wherein the reference sequence may include truncations and/or mutations relative to SEQ ID NO: 43. This interpretation applies to claims 5, 15, 32, and 64.
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, 3-6, 15-16, 31-32, 35, and 38 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 generally drawn to an antibodies that bind to canine TNFα. More specifically, the claims identify the antibodies by the function of binding canine TNFα, and a partial sequence structure that comprises an CDRs L1-3 comprising the amino acid sequences of SEQ ID NOs: 1-3, respectively, and/or a partial sequence structure comprising (i) a variable light chain comprising the amino acid of SEQ ID NO: 14, SEQ ID NO: 18, SEQ ID NO: 25, SEQ ID NO: 29, SEQ ID NO: 33, SEQ ID NO: 37, SEQ ID NO: 43, SEQ ID NO: 46, SEQ ID NO: 55, or SEQ ID NO: 56 or a variant thereof comprising at least 95% sequence identity to the amino acid sequence of SEQ ID NO: SEQ ID NO: 14, SEQ ID NO: 18, SEQ ID NO: 25, SEQ ID NO: 29, SEQ ID NO: 33, SEQ ID NO: 37, SEQ ID NO: 43, SEQ ID NO: 46, SEQ ID NO: 55, or SEQ ID NO: 56 and/or (ii) a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 22, SEQ ID NO: 57, or SED NO: 58 or a variant thereof comprising at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 22, SEQ ID NO: 57, or SEQ ID NO: 58.
It is specifically noted that the definition of “antibody” as provided at Pages 25-26 of the instant specification includes monoclonal, polyclonal, and multispecific antibodies as well as antibody fragments that include Fc, scFv, Fab, Fab’, di-scFv, sdAb, and (Fab’)2 wherein the antibody fragments may include either orientation of single chain scFvs, tandem di-scFv, diabodies, tandem tri-sdcFv, minibodies, etc. and may include nanobodies (sdAb having a single monomeric domain such as a pair of variable domains of heavy chains without a light chain); the definition of “antibody” as provided, wherein said antibodies comprise light chain sequences, are therefore directed to antibodies and fragments thereof that comprise variable light chains and variable heavy chains, therefore requiring six CDRs (three light chain and three heavy chain CDRs). Thus, the claims encompass a vast genus of antibodies and antibody variants that (i) do not necessarily comprise six defined CDRs which are required to bind canine TNFα and/or (ii) comprise variable CDRs in view of the “95% sequence identity” language absent specifically defined CDR sequences. The instant specification discloses in Table 1 of the instant specification (see Pages 13-24): (i) eight structurally similar caninized variable light chain sequences (SEQ ID NOs: 14, 18, 25, 29, 33, 37, 43, and 46) and one caninized variable heavy chain sequence (see SEQ ID NO: 22) wherein said caninized sequences are derived from parental TNFα binding antibody D2E7. Example 4 of the instant specification (see Page 58) discloses eight structurally similar caninized antibodies that bind canine TNFα, each of which comprise one of the above-listed caninized variable light chain sequences and the above listed caninized variable heavy chain sequence; thus, the instant specification discloses eight structurally similar caninized antibodies that function to bind canine TNFα which are sufficiently described by sets of six CDRs (three light chain and three heavy chain).
Thus, the instant specification discloses making eight structurally similar caninized antibodies that bind canine TNFα and describes the complete sets of six CDRs (three light chain and three heavy chain), that function to bind canine TNFα. The specification fails to disclose any antibody species that possess (i) fewer than six CDRs or (ii) mutated CDRs and retain the function of binding to canine TNFα.
To provide adequate written description and evidence of possession of the claimed antibody genus, the instant specification can structurally describe representative antibody species that function to bind canine TNFα, 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, “binds to canine TNFα”, 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 any antibody species that comprise fewer than six CDRs and have the function instantly 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. Other than for the antibodies disclosed in Example 4, the specification fails to provide the structural features (i.e., six CDRs) coupled to the claimed functional characteristics. The instant specification fails to describe a representative number of antibody species 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.
Claim 32, due to the “95% sequence identity” language absent defined CDR sequences broadly encompass any variable light chain and/or variable heavy chain CDR sequence variants that functions to bind canine TNFα, so long as the variable light chain and/or variable heavy chain sequences have at least 95% identity to the recited, full-length sequences. Applicants have not established any reasonable structure-function correlation with regards to the sequences in the CDRs that can be altered and still maintain canine TNFα 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 D2E7 antibody comprising SEQ ID NOs: 1-3 and 4-5 (variable light chain CDRs 1-3 and variable heavy chain CDRs 1-3, respectively) to the structure of any variants required to bind canine TNFα 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 caninized antibodies that bind canine TNFα 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 canine TNFα 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 antibodies, and lack of reasonable structure-function correlation with regards to the claimed canine TNFα-binding function, the present claims lack adequate written description. Thus, the specification does not provide an adequate written description of antibody species that (i) comprise fewer than six CDRs or (ii) comprise mutated CDRs and function to bind canine TNFα as is required to practice the claimed invention.
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.
Claim 15 is 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. Claims 15-16 fail to include all of the limitations of the claim upon which they depend. Claims 15-16 both depend from claim 1, wherein claim 1 is drawn to a caninized antibody that binds to canine TNFα and comprises (i) full-length CDRs L1-3 corresponding to instant SEQ ID NOs: 1-3, respectively, and (ii) a LC-FR2 comprising a glutamine at position 3 and a lysine at position 8. With regard to claim 15, it is noted that instant SEQ ID NO: 34 comprises a CDR-L1 sequence that is not an exact match to instant SEQ ID NO: 1 as required by independent claim 1 (instant SEQ ID NO: 1 corresponds to RASQGIRNYLA, but SEQ ID NO: 34 comprises the sequence QASQGIRNYLA) and SEQ ID NOs: 15, 19, 26, 30, 34, and 38 do not comprise a LC-FR2 comprising a glutamine at position 3 and a lysine at position 8 as required by independent claim 1. Thus, claim 15 fails to include all of the limitations of the claim upon which they depend. 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 63-64 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by US 2014/0294815 A1 (U.S. equivalent of WO 2013/030568 A1; previously cited on PTO-892; herein after referred to as "Gearing").
Gearing discloses caninised or chimeric antibodies or antigen binding fragments thereof which bind specifically to canine tumor necrosis factor (TNF), in particular canine TNF alpha (TNFα) (Paragraph 0022). Gearing further discloses a neutralizing antibody, or an antigen binding fragment thereof, which specifically binds to canine TNF, the antibody or antibody binding fragment comprising, consisting of or consisting essentially of a light chain and a heavy chain wherein the variable region of the light chain (VL) comprises an amino acid sequence of SEQ ID NO: 1 or an amino acid sequence which has a sequence identity of at least 85%, 90%, 95%, or 99% thereto, and wherein the variable region of the heavy chain (VH) comprises, consists or consists essentially of an amino acid sequence which is identical or substantially homologous to the amino acid sequence of SEQ ID NO: 2 or an amino acid sequence which has a sequence identity of at least 85%, 90%, 95%, or 99% thereto (Paragraph 0030; Figure 1). It is particularly noted that Gearing SEQ ID NO: 1 residues 24-34, 50-55, and 89-97 are 100% matches to instant SEQ ID NOs: 1-3, respectively, and Gearing SEQ ID NO: 2 residues 27-35, 50-67, and 97-110 are 100% matches to instant SEQ ID NOs: 4-6, respectively. It is further noted that Gearing SEQ ID NO: 1 is a 96.9% match to instant SEQ ID NO: 43, and Gearing SEQ ID NO: 2 is a 95.4% match to instant SEQ ID NO: 22. Thus, Gearing anticipates a caninised antibody comprising (i) a variable light chain comprising CDRs L1-3 corresponding to instant SEQ ID NOs: 1-3, respectively, and (ii) a variable heavy chain comprising CDRs H1-3 corresponding to instant SEQ ID NOs: 4-6, respectively, and wherein the variable light chain sequence comprises at least 95% sequence identity to instant SEQ ID NO: 43 and the variable heavy chain sequence comprises at least 95% sequence identity to instant SEQ ID NO: 22. Therefore, Gearing anticipates instant claims 63-64.
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 1-5, 15, 31, 35, and 38 are rejected under 35 U.S.C. 103 as being unpatentable over US 2014/0294815 A1 (previously cited on PTO-892; herein after referred to as "Gearing").
Gearing discloses caninised or chimeric antibodies or antigen binding fragments thereof which bind specifically to canine tumor necrosis factor (TNF), in particular canine TNF alpha (TNFα) (Paragraph 0022; emphasis added). Gearing further discloses a neutralizing antibody, or an antigen binding fragment thereof, which specifically binds to canine TNF, the antibody or antibody binding fragment comprising, consisting of or consisting essentially of a light chain and a heavy chain wherein the variable region of the light chain (VL) comprises an amino acid sequence of SEQ ID NO: 1 or an amino acid sequence which has a sequence identity of at least 85%, 90%, 95%, or 99% thereto, and wherein the variable region of the heavy chain (VH) comprises, consists or consists essentially of an amino acid sequence which is identical or substantially homologous to the amino acid sequence of SEQ ID NO: 2 or an amino acid sequence which has a sequence identity of at least 85%, 90%, 95%, or 99% thereto (Paragraph 0030; Figure 1; emphasis added). It is particularly noted that Gearing SEQ ID NO: 1 residues 24-34, 50-55, and 89-97 are 100% matches to instant SEQ ID NOs: 1-3, respectively, and Gearing SEQ ID NO: 2 residues 27-35, 50-67, and 97-110 are 100% matches to instant SEQ ID NOs: 4-6, respectively. It is further noted that Gearing SEQ ID NO: 1 is a 96.9% match to instant SEQ ID NO: 43, and Gearing SEQ ID NO: 2 is a 95.4% match to instant SEQ ID NO: 22. Gearing further teaches embodiments wherein the antibody is a caninised antibody which comprises a light chain which comprises, consists of or consists essentially of the amino acid sequence of SEQ ID NO: 3 and/or a heavy chain which comprises, consists of or consists essentially of an amino acid sequence selected from the group consisting of SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6 and SEQ ID NO: 7, or a sequence having an amino acid identity of at least 85%, more preferably of 95% and most preferably at least 98% identity thereto (Paragraph 0031, emphasis added). It is specifically noted that Gearing SEQ ID NO: 3 is a 99.2% match to instant SEQ ID NO: 30 and Gearing SEQ ID NO: 5 is a 98.7% match to instant SEQ ID NO: 23. Gearing also teaches that: (i) the invention extends to antibody binding fragments that bind canine TNFα which may comprise a heavy chain and light chain sequence of the invention being connected by a flexible linker to form a single chain antibody and/or the antibody binding fragment is selected from a Fab antibody fragment, a Fab' antibody fragment, a F(ab')2 antibody fragment, a Fv antibody fragment, a scFv antibody fragment and the like (Paragraph 0062-0064; emphasis added); (ii) the invention provides a pharmaceutical composition for treating pain, or a condition resulting in or caused by chronic pain in a canine, comprising a pharmaceutically effective amount of an anti-canine TNF caninised antibody according to the present invention, along with at least one pharmaceutically acceptable carrier, excipient or diluent (Paragraph 0088; emphasis added); and (iii) the invention extends to isolated nucleic acid which encodes the antibody or antibody binding fragments of the invention (Paragraph 0090; emphasis added). However, it is noted that Gearing SEQ ID NOs: 1 and 3 do not comprise a lysine at LC-FR2 position 8; however, lysine is the residue at position 8 of the donor antibody (i.e., D2E7 an anti-human TNF antibody) as indicated in Table 2 (see Page 9). It is noted that an exemplary chimeric antibody comprises Gearing SEQ ID NO: 8, which comprises CDRs identical to Gearing SEQ ID NO: 1 (and Gearing SEQ ID NO: 3), wherein said chimeric antibody comprises a LC-FR2 wherein there is a glutamine residue at position 3 and a lysine at LC-FR2 position 8 (Paragraph 0032; Figure 8; emphasis added). It is particularly noted that the above-identified caninised and chimeric antibodies both bind canine TNF and are equipotent (Paragraphs 0194-0195; emphasis added). One of ordinary skill in the art would therefore recognize that LC-FR2 of Gearing SEQ ID NO: 8, wherein residues 35-49 correspond to instant SEQ ID NO: 45 and comprises a glutamine residue at position 3 and a lysine residue at position 8, does not alter/hinder the ability of the chimeric antibody to bind canine TNF, thus one of ordinary skill in the art would recognize that a lysine for glutamine substitution at LC-FR2 position 8 in caninised SEQ ID NO: 1 and/or SEQ ID NO: 3 would likely be compatible and still yield an antibody capable of specifically binding to canine TNF. It is further noted that the lysine for glutamine substitution at LC-FR2 position 8 in caninised SEQ ID NO: 1 and/or 3 would yield a LC-FR2 identical to residues 35-49 of Gearing SEQ ID NO: 8 and a 100% match to instant SEQ ID NO: 45.
Thus, it would have been prima facie obvious to one of ordinary skill in the art to combining the elements of the teachings of Gearing to arrive at a caninised antibody or antibody binding fragment thereof that binds to canine TNFα, an isolated nucleic acid encoding the antibody or antibody binding fragment thereof, and a pharmaceutical composition comprising the antibody or antibody binding fragment thereof, wherein said antibody or antibody binding fragment thereof comprises a variable light chain comprising the instant light chain CDRs corresponding to instant SEQ ID NOs: 1-3 and a variable heavy chain comprising the instant heavy chain CDRs corresponding to SEQ ID NOs: 4-5, further wherein the light chain of said caninised antibody comprises sequences at least 95% identical to instant SEQ ID NOs: 43 (variable light chain) and 30 (full light chain), the heavy chain of said caninised antibody comprises sequences at least 95% identical to instant SEQ ID NOs: 22 (variable heavy chain) and 23 (full heavy chain), LC-FR2 comprises a glutamine at position 3 and a lysine at position 8 such that LC-FR2 comprises instant SEQ ID NO: 45. One of ordinary skill in the art would have recognized, based on the teachings of Gearing, that the modification of the LC-FR2 of the caninised antibody comprising Gearing SEQ ID NO: 1 (variable light chain) and/or 3 (full light chain) to comprise a lysine at position 8 instead of a glutamine would reasonably be expected to yield a functional, caninised antibody that specifically binds to canine TNF because Gearing demonstrated that a chimeric antibody with such a LC-FR2 was specific to canine TNF and equipotent to that of a caninised antibody comprising SEQ ID NO: 1.
Claim 32 is rejected under 35 U.S.C. 103 as being unpatentable over US 2014/0294815 A1 (previously cited on PTO-892; herein after referred to as "Gearing") and in further view of US 2013/0330348 A1 (herein after referred to as “Lacy”) and non-patent literature by Ryan et. al. (Horm. Metab. Res., 2008, 40, 861-868; herein after referred to as “Ryan”) and US 2013/0330348 A1 (herein after referred to as “Lacy”).
Gearing discloses caninised or chimeric antibodies or antigen binding fragments thereof which bind specifically to canine tumor necrosis factor (TNF), in particular canine TNF alpha (TNFα) (Paragraph 0022; emphasis added). Gearing further discloses a neutralizing antibody, or an antigen binding fragment thereof, which specifically binds to canine TNF, the antibody or antibody binding fragment comprising, consisting of or consisting essentially of a light chain and a heavy chain wherein the variable region of the light chain (VL) comprises an amino acid sequence of SEQ ID NO: 1 or an amino acid sequence which has a sequence identity of at least 85%, 90%, 95%, or 99% thereto, and wherein the variable region of the heavy chain (VH) comprises, consists or consists essentially of an amino acid sequence which is identical or substantially homologous to the amino acid sequence of SEQ ID NO: 2 or an amino acid sequence which has a sequence identity of at least 85%, 90%, 95%, or 99% thereto (Paragraph 0030; Figure 1; emphasis added). It is particularly noted that Gearing SEQ ID NO: 1 residues 24-34, 50-55, and 89-97 are 100% matches to instant SEQ ID NOs: 1-3, respectively, and Gearing SEQ ID NO: 2 residues 27-35, 50-67, and 97-110 are 100% matches to instant SEQ ID NOs: 4-6, respectively. It is further noted that Gearing SEQ ID NO: 1 is a 96.9% match to instant SEQ ID NO: 43, and Gearing SEQ ID NO: 2 is a 95.4% match to instant SEQ ID NO: 22. Gearing further teaches embodiments wherein the antibody is a caninised antibody which comprises a light chain which comprises, consists of or consists essentially of the amino acid sequence of SEQ ID NO: 3 and/or a heavy chain which comprises, consists of or consists essentially of an amino acid sequence selected from the group consisting of SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6 and SEQ ID NO: 7, or a sequence having an amino acid identity of at least 85%, more preferably of 95% and most preferably at least 98% identity thereto (Paragraph 0031, emphasis added). It is specifically noted that Gearing SEQ ID NO: 3 is a 99.2% match to instant SEQ ID NO: 30 and Gearing SEQ ID NO: 5 is a 98.7% match to instant SEQ ID NO: 23. Furthermore, it is specifically noted that Gearing defines the term “TNF neutralising antibody” or similar as an antibody that is capable of neutralizing the biological activity and signaling of TNF; the neutralising antibody, which may also be referred to as an antagonistic antibody, or a blocking antibody, specifically and preferably selectively, binds to INF and inhibits one or more biological activities of TNF wherein, for example, the neutralizing antibody may inhibit the binding of a TNF to its target ligand, such as the cell membrane bound TNF Receptor 1
(TNFRl) (Paragraph 0173). Gearing teaches further embodiments wherein the invention extends to a bispecific antibody, wherein an antibody or binding fragment thereof according to the invention is linked to a second antibody or binding fragment thereof which has binding specificity for a secondary target, said target not being TNF and preferably wherein said secondary target assists in preventing TNF mediated signaling through the TNFRl receptor; such multivalent, bispecific or multispecific antibodies can be made by a variety of recombinant methods which would be well known to the person skilled in the art (Paragraph 0065). Gearing also teaches a method for treating or preventing an immune mediated condition in a canine in need thereof, the method comprising the steps of: (i) providing a therapeutically effective amount of an antibody of the invention, or antigen binding fragment thereof, which specifically binds to canine TNFα, and (ii) administering the same to the canine (Paragraphs 0066-0068). In certain embodiments, the immune mediated condition is a chronic inflammatory disease, said chronic inflammatory disease may be selected from the group consisting of, but not limited to, rheumatoid arthritis (RA), osteoarthritis and other polyarthritidies, ankylosing spondylitis (AS), Crohn's disease and ulcerative colitis, psoriasis and psoriatic arthritis (PsA), systemic vasculitis, atopic dermatitis, congestive heart failure (CHF), refractory uveitis, bronchial asthma and allergic conditions; inflammatory mediated conditions may also include sepsis and shock, diabetes mellitus, and neuro-degenerative conditions such as Alzheimer's disease, Parkinson's disease, stroke and amyotrophic lateral sclerosis (Paragraph 0072). Gearing further teaches that methods of the invention (i.e., methods of treatment) further comprise the step of co-administering at least one further agent which may enhance and/or supplement the effectiveness of the anti-TNF antibody of the invention; for example, the antibody or antigen binding fragment of the invention may be co-administered along with one or more additional pharmaceutical compositions, said additional compositions comprising a drug useful for treating a chronic inflammatory condition, in particular a TNF-α related disorder (Paragraph 0083). The additional pharmaceutical composition can be, for example, an antagonist of nerve growth factor, such as an anti-NGF antibody. Thus, Gearing suggests using anti-canine TNFα antibody in combination with an anti-NGF antibody, and further suggests a bispecific antibody, wherein an antibody or binding fragment thereof according to the invention is linked to a second antibody or binding fragment thereof which has binding specificity for a secondary target, said target not being TNF and preferably wherein said secondary target assists in preventing TNF mediated signaling through the TNFRl receptor
However, it is noted that Gearing does not explicitly teach or suggest a connection between NGF and TNFα with regard to TNFα signaling through TNFR1 and thus does not explicitly suggest a bispecific antibody that binds to canine TNFα and canine NGF. This deficiency is remedied by Ryan and Lacy.
Ryan teaches that obesity results from an excessive expansion of white adipose tissue (WAT) mass; globally, the increasing prevalence of obesity in humans is of major public health importance due to comorbidities including type II diabetes and cardiovascular disease (Page 861, Column 1, Introduction, First Paragraph). Obesity in companion animals is also a growing concern, and epidemiological studies on body condition have estimated the prevalence of overweight and obesity in dogs to be between 24 % and 34 %; as in humans, obesity has detrimental effects on canine health, obese dogs having an increased incidence of traumatic and degenerative orthopedic diseases, insulin resistance and diabetes, and a decreased lifespan (Id.). White adipose tissue is now regarded as an active endocrine organ secreting a wide range of protein factors and signals collectively referred to as adipokines, which are highly diverse in terms of structure and function and include a number of proteins involved in inflammatory and stress responses, such as classical cytokines (e.g., TNFα and IL-6), chemokines (e.g., MCP-1 and MIF), and acute-phase proteins (e.g., haptoglobin and serum amyloid A); the inflammatory
response within adipose tissue may provide a connection between obesity, insulin resistance,
and the metabolic syndrome (Page 861, Column 1, Last Paragraph through Column 2, First Paragraph). Studies have demonstrated that the NGF gene is expressed in WAT in mice, humans, and dogs and, furthermore, that NGF itself is secreted from 3T3-L1 and human adipocytes in vitro, thereby establishing this protein as an adipokine in these species; in addition to its neurotrophic role, NGF is involved in inflammation and the inflammatory response; for example, it is synthesized by macrophages and stimulates the production of the proinflammatory cytokine TNFα by these immune cells and TNFα has been shown to have a major stimulatory effect on NGF expression and secretion by both murine and human adipocytes, consistent with the neurotrophin being involved in inflammation in adipose tissue (Page 862, Column 1, First Partial Paragraph). The authors conducted a set of experiments on the regulation of NGF gene expression and secretion in canine adipocytes therefore examined the effects of treatment with three inflammatory agents, namely, LPS, TNFα, and IL-6; cellular NGF mRNA levels and the amount of NGF protein in the medium were both substantially elevated following treatment with TNFα for 24 h wherein NGF mRNA levels were 11-fold higher at 24 h, while there was a 17-fold increase in the amount of NGF in the medium (Page 864, Column 2, Last Paragraph through Page 865 Column 1, First Paragraph; see Figure 4B).The authors conclude that NGF is likely to be important as a target-derived neurotrophin in the development and survival of sympathetic neurones within canine WAT; one of the reported effects of NGF in inflammation is the marked stimulation of TNFα production, via the activation of mitogen-activated protein kinases, in macrophages and given that macrophages infiltrate adipose tissue in obesity and that this appears to be a major factor in the inflammation in the tissue as fat mass expands, NGF may be an important part of the amplification cascade in the inflammatory response (Page 867, Column 1, First Full Paragraph). NGF released from preadipocytes and adipocytes could stimulate TNFα production by the macrophages, the release of which could in turn lead to the synthesis of more NGF by the target cells (Id.). Thus, Ryan teaches a connection between NGF and TNFα, wherein NGF stimulates the production of TNFα which in turn further stimulates the synthesis of NGF, and suggests a connection between white adipose tissue and obesity with higher incidence of diabetes.
Lacy teaches a novel family of binding proteins, CDR grafted antibodies, mammalized (such as bovanized, camelized, caninized, equinized, felinized, humanized etc.) antibodies, and fragments thereof, capable of binding and neutralizing NGF; the disclosure provides a therapeutic means with which to inhibit NGF and provides compositions and methods for treating disease associated with increased levels of NGF, particularly inflammatory disorders (Paragraph 0012; emphasis added). Caninized anti-NGF antibodies are more specifically discussed, and sequences corresponding thereto are provided, at Paragraphs 0336-0337. Lacy also provides a method for reducing NGF activity in a subject, such as a subject suffering from a disease or disorder in which NGF activity is detrimental; the invention provides methods for reducing NGF activity in a subject suffering from such a disease or disorder, which method comprises administering to the subject an antibody or antibody portion of the disclosure such that NGF activity in the subject is reduced (Paragraph 0350). The antibodies and binding proteins
of the invention are useful for treating NGF-related diseases and disorders including or involving acute or chronic pain; non-limiting examples of NGF-related diseases and disorders include general inflammation, surgical and postsurgical pain including pain from amputation, dental pain, pain from trauma, fracture pain, pain from abscess, hyperalgesia and allodynia, neuropathic pain, post-herpetic neuralgia, diabetes, etc. (Paragraph 0354). The invention also provides a method of treating a subject suffering from a disorder in which NGF is detrimental comprising administering a binding protein before, concurrent, or after the administration of a second agent; in another aspect, the additional therapeutic agent that can be co-administered and/or co-formulated with one or more NGF antagonists, (e.g., anti-NGF antibodies or fragments thereof,) includes, for example, TNF antagonists (Paragraph 0355). Combinations of therapeutic agents may interfere at different points in the autoimmune and subsequent inflammatory cascade; examples include TNF antagonists like chimeric, humanized or human TNF antibodies, D2E7, CA2, CDP 571, and soluble p55 or p75 TNF receptors, derivatives, thereof (Paragraph 0392). Thus, Lacy discloses caninized NGF antibodies that bind canine NGF, useful in inflammatory conditions such as diabetes, and useful in combination with TNF antagonists.
In the test of whether it is “obvious to try” there must be:
(1) a finding in the art at the time of filing of the invention that there had been a recognized problem or need in the art;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to make a bispecific antibody that binds to canine TNFα and canine NGF. One would have been motivated to make such a bispecific antibody because (i) Gearing teaches caninized antibodies that bind canine TNFα (said antibodies meeting the claimed sequence limitations) useful in cases of inflammation and/or diabetes, using the canine-TNFα antibodies in combination with anti-NGF antibodies, and suggests bispecific antibodies which bind canine TNFα and target a second antigen implicated in TNFα signaling; (ii) Ryan teaches a connection between NGF and TNFα, wherein NGF stimulates the production of TNFα which in turn further stimulates the synthesis of NGF, and suggests a connection between white adipose tissue and obesity with higher incidence of diabetes; and (iii) Lacy discloses caninized NGF antibodies that bind canine NGF, useful in inflammatory conditions such as diabetes, and useful in combination with TNF antagonists. One of ordinary skill in the art would have a reasonable expectation of success because Gearing and Lacy suggest combination therapies directed at dual targeting of canine TNFα and canine NGF (with separate agents), methods of making bispecific antibodies are well known and established in the art, as supported by Gearing, and a bispecific antibody to canine TNFα and canine NGF would reasonably be expected to neutralize the signaling of both canine TNFα and canine NGF, as supported by Gearing and Lacy, and would subsequently be reasonably expected to reduce inflammation (e.g., inflammation associated with obesity and/or diabetes) in canines, as supported by Ryan.
Conclusion
Claims 1-9, 15-16, 31-32, 35, 38-39, 43, 61, and 63-64 are pending. Claims 39, 43, and 61 are withdrawn. Claims 1-6, 15-16, 31-32, 35, 38, and 63-64 are rejected. Claims 7-9 are allowed.
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/ALYSSA RAE STONEBRAKER/Examiner, Art Unit 1642
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