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 .
Status of Application, Amendments and/or Claims
Claims 36-54 are pending.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 36-52, drawn to a method of purifying a bispecific compound, in the reply filed on 24 February 2026 is acknowledged.
Claims 53 and 54 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 24 February 2026.
Claims 36-52 are under consideration in the instant application.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 10 January 2025 and 12 October 2023 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Claim Objections
1. Claims 36, 49, and 50 are objected to because of the following informalities:
1a. In claim 36, line 19, after the phrase “matrix using”, the word “an” should be amended to recite “a” (i.e., matrix using a sodium acetate buffer).
1b. In claim 49, line 2, the word “positions” in the phrase “positions 234” should recite the singular “position”.
1c. In claim 50, line 1, in the phrase “wherein said the amino acid sequence”, the word “said” should be deleted (i.e., wherein
1d. In claim 50, line 3, before the recitations of “IgG1” and “IgG4”, the word “a” should be deleted and “an” inserted (i.e., an IgG1, an IgG4).
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
2. Claims 39-52 are 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.
2a. Claim 39 recites the limitation "the one or more phosphate buffer compositions" in lines 1-2. There is insufficient antecedent basis for this limitation in the claim. Claim 36, from which claim 39 depends, does not recite “one or more phosphate buffer compositions”.
2b. Claim 40 recites the limitation "the hydroxyapatite elution" in line 1. There is insufficient antecedent basis for this limitation in the claim. Claim 36, from which claim 40 depends, does not recite “the hydroxyapatite elution”.
2c. Claims 41-52 are rejected as being indefinite because claim 41 (subpart C) refers to a heavy chain constant region 2 (CH2) of a conventional antibody while also reciting specific amino acids at specific positions (252, 254, 256). The metes and bounds of the claim cannot be determined because it is not clear what CH2 molecule or sequence these amino acid positions are referring to. Without knowing the reference CH2 molecule or sequence, one skilled in the art would not be apprised of the correct locations of the amino acids.
2d. Claim 49 is rejected as being indefinite because the claim refers to a heavy chain constant region 2 (CH2) of a conventional antibody while also reciting specific amino acids at specific positions (234, 235). The metes and bounds of the claim cannot be determined because it is not clear what CH2 molecule or sequence these amino acid positions are referring to. Without knowing the reference CH2 molecule or sequence, one skilled in the art would not be apprised of the correct locations of the amino acids.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
3. Claims 36-40 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.
Claim 36 is directed to a method of purifying a bispecific compound comprising a first polypeptide and a second polypeptide, which bispecific compounds binds to a first and a second target protein, which target proteins comprise TNF-alpha and IL-23A, wherein:
(A) said first polypeptide of the bispecific compound comprises:
(i) a light chain variable domain of a first immunoglobulin (VL1) specific for a first target protein;
(ii) a heavy chain variable domain of a second immunoglobulin (VH2) specific for a second target protein; and
(iii) a hinge region, a heavy chain constant region 2 (CH2) and a heavy chain constant region 3 (CH3); and
(B) said second polypeptide of the bispecific compound comprises:
(i) a light chain variable domain of a second immunoglobulin (VL2) specific for said second target protein;
(ii) a heavy chain variable domain of a first immunoglobulin (VH1) specific for said first target protein;
Said method comprising the following steps:
(i) applying a composition comprising said bispecific compound to a protein A cross-linked agarose matrix;
(ii) eluting the bispecific compound from the matrix using an sodium acetate buffer;
(iii) neutralizing the resultant sample;
(iv) applying the neutralized sample comprising the bispecific compound to a hydroxyapatite resin; and
(v) recovering the purified bispecific compound by eluting from the hydroxyapatite resin using one or more phosphate buffers.
The instant specification teaches that as of the filing date, there have been no approved compounds that target both TNF-alpha and IL23A (page 13, lines 8-9, 12-13). The specification continues to disclose that there are limited studies with simultaneous neutralization of two/more key inflammatory mediators using biotherapeutics approach (page 13, lines 9-11). The specification states that such bis-specific compounds have been difficult to design, due to issues related to solubility (e.g., aggregation) and stability (e.g., poor pharmacokinetics) (page 13, lines 18-20). The specification teaches that the compounds of the instant invention that bind both TNA-alpha and IL-23A have (i) similar or improved properties compared to individual antibodies targeting either IL-23A or IL-23A; (ii) suitable pharmacokinetics and are soluble at ranges for dosing; and (iii) low aggregation (page 13, lines 21-29). The specification teaches that the compounds of the invention are believed to have one or more advantageous properties, such as decreased side effects, increased ease and safety of administration, increased half-life, increased binding affinity, or increased inhibitory activity as compared to standard antibodies (page 14, lines 1-4).
Regarding the claims, the specification teaches several different configurations of the domains for the first and second polypeptides (page 15). The specification discloses specific sequences for each of the VL1/VL2 (SEQ ID NOs: 2, 4, 6, 8) and VH1/VH2 (SEQ ID NOs: 1, 3, 5, 7) (page 16, Table 1; pages 85-86). However, the specification also discloses that the compound comprises a VH1, VL1, VH2, and/or VL2 that comprises a sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to a sequence disclosed in Table 1 (page 17, lines 12-14). The specification states that the compound comprises a VH1, VL1, VH2, and/or VL2 that comprises a sequence comprising one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) mutations in a sequence described in Table 1 (page 17, lines 25-28 through page 18, lines 1-4). Therefore, in view of the teachings of the instant specification, the limitations in the method claims are broadly interpreted by the Examiner has reading upon any bispecific compound that comprises first and second polypeptides that comprise any VL1, VH2, VL2, and VH2 specific for TNF-alpha and IL-23A, including sequences that encompass variants, fragments, and/or derivatives/mutations. However, the specification does not teach any TNF-alpha and IL-23A VL1, VH2, VL2, and VH2, other than full-length amino acid sequences of VL1/VL2 (SEQ ID NOs: 2, 4, 6, 8) and VH1/VH2 (SEQ ID NOs: 1, 3, 5, 7).
The first paragraph of 35 U.S.C. § 112 "requires a 'written description of the invention' which is separate and distinct from the enablement requirement." Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 1563 (Fed. Cir. 1991). An adequate written description of a chemical invention "requires a precise definition, such as by structure, formula, chemical name, or physical properties." University of Rochester v. G.D. Searle & Co., Inc., 358 F.3d 916, 927 (Fed. Cir. 2004); Regents of the Univ. of Cal. v. Eli Lilly & Co., Inc., 119 F.3d 1559, 1566 (Fed. Cir. 1997); Fiers v. Revel, 984 F.2d 1164, 1171 (Fed. Cir. 1993). "A description of what a material does, rather than of what it is, usually does not suffice." Rochester, 358 F.3d at 923; Eli Lilly, 119 F.3d at 1568. Instead, the "disclosure must allow one skilled in the art to visualize or recognize the identity of the subject matter purportedly described." Id. In addition, possession of a genus "may be achieved by means of a recitation of a representative number of [compounds]... falling within the scope of the genus." Eli Lilly, 119 F.3d at 1569. Possession may not be shown by merely describing how to obtain possession of members of the claimed genus. See Rochester, 358 F.3d at 927.
Thus, case law dictates that to provide evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include actual reduction to practice, disclosure of drawings or structure chemical formulas, sufficient relevant identifying characteristics (such as, complete or partial structure, physical and/or chemical properties, and functional characteristics when coupled with a known or disclosed structure/function correlation), methods of making the claimed product, level of skill and knowledge in the art, predictability in the art, or any combination thereof. In the instant case, the factors present in the method claims for the bispecific compound are (1) structural characteristics of first and second polypeptides that comprise any TNF-alpha and IL-23A VL1, VH2, VL2, and VH2, including sequences that encompass variants, fragments, and/or derivatives/mutations and (2) a functional characteristic of binding to a first and a second target protein (wherein the target proteins comprise TNF-alpha and IL-23A). There is no identification of any particular sequence or structure of the VL1, VH2, VL2, and VH1 that must be conserved in order to provide the required binding function listed. Thus, the claims are drawn to a genus of bispecific compounds that comprise first and second polypeptides that comprise a genus of TNF-alpha and IL-23A VL1, VH2, VL2, and VH2, including sequences that encompass variants, fragments, and/or derivatives/mutations.
The instant specification fails to disclose and there is no art-recognized correlation between the structure of the genus of TNF-alpha and IL-23A VL1, VH2, VL2, and VH2 and the function of binding to a first and a second target protein (TNF-alpha and IL-23A). In other words, the specification does not teach the structure which results in a bispecific compound with the claimed required characteristics. The description of specific sequences for each of the VL1/VL2 (SEQ ID NOs: 2, 4, 6, 8) and VH1/VH2 (SEQ ID NOs: 1, 3, 5, 7) at page 16, Table 1 and pages 85-86 of the instant specification is not adequate written description of an entire genus of bispecific compounds that comprise first and second polypeptides that comprise a genus of TNF-alpha and IL-23A VL1, VH2, VL2, and VH2. The disclosed sequences are not representative of the breadth of the claims.
Furthermore, it is well established in the art that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs which provide the majority of the contact residues for the binding of the antibody to its target epitope (Paul, William E., Fundamental Immunology, 3rd Edition, Raven Press, New York, Chapt. 8, pp. 292-295 (1993), under the heading “Fv Structure and Diversity in Three Dimensions”). The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites (Paul, page 293, first column, lines 3-8 and line 31 to column 2, line 9 and lines 27-30). Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff et al. (Proc Natl Acad Sci USA. Vol 79, page 1979, 1982) and Zhang et al. (mAbs 7(1): 42-52, 2005; page 45, column 2)). Zhang et al. also indicate that minor variations in variable heavy and light chain CDR1s and CDR2s may lead to loss of antigen binding (page 46, column 1). It is noted that numerous other publications also acknowledge that conservative substitutions would in fact change the binding ability of antibodies, if not substantially reduce the affinity (see Vasudevan et al., Blood Cell Mol Dis 32: 176-181, 2004;; Brummell et al, Biochemistry 32: 1180-1187, 1993;; Kobayashi et al., Protein Engineering 12: 879-844, 1999;; Burks et al., PNAS 94: 412-417, 1997;; Jang et al., Mol Immunol 35: 1207-1217, 1998; Brorson et al. J Immunol 163: 6694-6701, 1999;; Colman, Res Immunol 145: 33-36, 1994). Thus, the state of the art recognized that it would be highly unpredictable that polypeptides comprising any VL1, VH2, VL2, or VH1 specific for TNF-alpha and IL-23A (including sequences that encompass variants, fragments, and/or derivatives/mutations) as recited in the instant claims, would maintain their required conformation and would have the requisite antigen binding function.
Applicant is reminded that generally, in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus (Enzo Biochem, Inc. v. Gen-Probe Inc., 323 F.3d 956 (Fed. Cir. 2002); Noelle v. Lederman, 355 F.3d 1343 (Fed. Cir. 2004); Regents of the University of California v. Eli Lilly Co., 119 F.3d 1559 (Fed. Cir. 1997)). A patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017) at page 1358). An adequate written description must contain enough information about the actual makeup of the claimed products – “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361).
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed” (See page 1117). See also, Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017), relying upon Ariad Pharms., Inc. v. Eli Lily & Co., 94 USPQ2d 1161 (Fed Cir. 2010). The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed” (See Vas-Cath at page 1116). A “mere wish or plan” to obtain the claimed invention is not sufficient (Centocor Orth Biotech, Inc. v. Abbott Labs, 636 F.3d 1341 (Fed. Cir. 2011); Regents of the Univ. of California, 119 F.3d at 1566). In the instant application, the skilled artisan cannot envision the detailed chemical structure of the polypeptides comprising any VL1, VH2, VL2, or VH1 specific for TNF-alpha and IL-23A of the encompassed claims, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The VL1, VH2, VL2, and VH1 specific for TNF-alpha and IL-23A are required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
Therefore, only a method of purifying a bispecific compound comprising a first and second polypeptide, wherein the first and second polypeptides comprise
i) a VL1 that comprises the amino acid sequence SEQ ID NO:2, a VH1 that comprises the amino acid sequence of SEQ ID NO:1, a VL2 that comprises the amino acid sequence of SEQ ID NO:8, and a VH2 that comprises the amino acid sequence of SEQ ID NO:7; or
(ii) a VL1 that comprises the amino acid sequence of SEQ ID NO:4 or 6, a VH1 that comprises the amino acid sequence of SEQ ID NO:3 or 5, a VL2 that comprises the amino acid sequence of SEQ ID NO:8, and a VH2 that comprises the amino acid sequence of SEQ ID NO:7; or
(iii) a VL1 that comprises the amino acid sequence of SEQ ID NO:8, a VH1 that comprises the amino acid sequence of SEQ ID NO:7, a VL2 that comprises the amino acid sequence of SEQ ID NO:2, and a VH2 that comprises the amino acid sequence of SEQ ID NO:1; or
(iv) a VL1 that comprises the amino acid sequence of SEQ ID NO:8, a VH1 that comprises the amino acid sequence of SEQ ID NO:7, a VL2 that comprises the amino acid sequence of SEQ ID NO:4 or 6, and a VH2 that comprises the amino acid sequence of SEQ ID NO:3 or 5,
but not the full breadth of the claims meets the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115). See also Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1355 (Fed. Cir. 2010).
4. Claims 36-40 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of purifying a bispecific compound comprising a first and second polypeptide, wherein the first and second polypeptides comprise
i) a VL1 that comprises the amino acid sequence SEQ ID NO:2, a VH1 that comprises the amino acid sequence of SEQ ID NO:1, a VL2 that comprises the amino acid sequence of SEQ ID NO:8, and a VH2 that comprises the amino acid sequence of SEQ ID NO:7; or
(ii) a VL1 that comprises the amino acid sequence of SEQ ID NO:4 or 6, a VH1 that comprises the amino acid sequence of SEQ ID NO:3 or 5, a VL2 that comprises the amino acid sequence of SEQ ID NO:8, and a VH2 that comprises the amino acid sequence of SEQ ID NO:7; or
(iii) a VL1 that comprises the amino acid sequence of SEQ ID NO:8, a VH1 that comprises the amino acid sequence of SEQ ID NO:7, a VL2 that comprises the amino acid sequence of SEQ ID NO:2, and a VH2 that comprises the amino acid sequence of SEQ ID NO:1; or
(iv) a VL1 that comprises the amino acid sequence of SEQ ID NO:8, a VH1 that comprises the amino acid sequence of SEQ ID NO:7, a VL2 that comprises the amino acid sequence of SEQ ID NO:4 or 6, and a VH2 that comprises the amino acid sequence of SEQ ID NO:3 or 5,
does not reasonably provide enablement for a method of purifying a genus of bispecific compounds as broadly claimed. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Claim 36 is directed to a method of purifying a bispecific compound comprising a first polypeptide and a second polypeptide, which bispecific compounds binds to a first and a second target protein, which target proteins comprise TNF-alpha and IL-23A, wherein:
(A) said first polypeptide of the bispecific compound comprises:
(i) a light chain variable domain of a first immunoglobulin (VL1) specific for a first target protein;
(ii) a heavy chain variable domain of a second immunoglobulin (VH2) specific for a second target protein; and
(iii) a hinge region, a heavy chain constant region 2 (CH2) and a heavy chain constant region 3 (CH3); and
(B) said second polypeptide of the bispecific compound comprises:
(i) a light chain variable domain of a second immunoglobulin (VL2) specific for said second target protein;
(ii) a heavy chain variable domain of a first immunoglobulin (VH1) specific for said first target protein;
Said method comprising the following steps:
(i) applying a composition comprising said bispecific compound to a protein A cross-linked agarose matrix;
(ii) eluting the bispecific compound from the matrix using an sodium acetate buffer;
(iii) neutralizing the resultant sample;
(iv) applying the neutralized sample comprising the bispecific compound to a hydroxyapatite resin; and
(v) recovering the purified bispecific compound by eluting from the hydroxyapatite resin using one or more phosphate buffers.
The instant specification teaches that as of the filing date, there have been no approved compounds that target both TNF-alpha and IL23A (page 13, lines 8-9, 12-13). The specification continues to disclose that there are limited studies with simultaneous neutralization of two/more key inflammatory mediators using biotherapeutics approach (page 13, lines 9-11). The specification states that such bis-specific compounds have been difficult to design, due to issues related to solubility (e.g., aggregation) and stability (e.g., poor pharmacokinetics) (page 13, lines 18-20). The specification teaches that the compounds of the instant invention that bind both TNA-alpha and IL-23A have (i) similar or improved properties compared to individual antibodies targeting either IL-23A or IL-23A; (ii) suitable pharmacokinetics and are soluble at ranges for dosing; and (iii) low aggregation (page 13, lines 21-29). The specification teaches that the compounds of the invention are believed to have one or more advantageous properties, such as decreased side effects, increased ease and safety of administration, increased half-life, increased binding affinity, or increased inhibitory activity as compared to standard antibodies (page 14, lines 1-4).
Regarding the claims, the specification teaches several different configurations of the domains for the first and second polypeptides (page 15). The specification discloses specific sequences for each of the VL1/VL2 (SEQ ID NOs: 2, 4, 6, 8) and VH1/VH2 (SEQ ID NOs: 1, 3, 5, 7) (page 16, Table 1; pages 85-86). However, the specification also discloses that the compound comprises a VH1, VL1, VH2, and/or VL2 that comprises a sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to a sequence disclosed in Table 1 (page 17, lines 12-14). The specification states that the compound comprises a VH1, VL1, VH2, and/or VL2 that comprises a sequence comprising one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) mutations in a sequence described in Table 1 (page 17, lines 25-28 through page 18, lines 1-4). Therefore, in view of the teachings of the instant specification, the limitations in the method claims are broadly interpreted by the Examiner has reading upon any bispecific compound that comprises first and second polypeptides that comprise any VL1, VH2, VL2, and VH2 specific for TNF-alpha and IL-23A, including sequences that encompass variants, fragments, and/or derivatives/mutations. However, the specification does not teach any TNF-alpha and IL-23A VL1, VH2, VL2, and VH2, other than full-length amino acid sequences of VL1/VL2 (SEQ ID NOs: 2, 4, 6, 8) and VH1/VH2 (SEQ ID NOs: 1, 3, 5, 7). Undue experimentation is required to generate and screen for all possible bispecific compounds that comprise any combination and sequences of light and heavy chain variable domains (VL1, VH2, VL2, and VH1) that are still capable of binding TNF-alpha and/or IL-23A.
The art recognizes that protein function cannot be predicted from structure alone (Bork, 2000, Genome Research 10:398-400; Skolnick et al., 2000, Trends in Biotech. 18(1):34-39, especially p. 36 at Box 2; Doerks et al., 1998, Trends in Genetics 14:248-250; Smith et al., 1997, Nature Biotechnology 15:1222-1223; Brenner, 1999, Trends in Genetics 15:132-133; Bork et al., 1996, Trends in Genetics 12:425-427). See also Tokuriki et al. (Current Opinion in Structural Biology 19: 596-604, 2009), who teach that mutations are generally destabilizing. For instance, Tokuriki et al. teach at page 596, right column, last paragraph, that “as mutations accumulate, protein fitness declines exponentially...or even more than exponentially...So by the time an average protein accumulates, on average, five mutations, its fitness will decline to <20%.” Further, at page 598, left column, last paragraph, Tokuriki et al. note that 50% of mutations are destabilizing, and >15% of mutations are highly destabilizing, and of the about 5% of mutations that are stabilizing values...many of these mutations result in inactive protein. Indeed, Tokuriki et al. conclude that “a more comprehensive understanding of how mutations affect protein fitness within living cells is needed, including their combined effects on function, thermodynamic and kinetic stability, and clearance through aggregation and degradation” (see page 602, left column, 2nd paragraph). Fenton et al. (Medicinal Chemistry Research 29:1133-1146, 2020) also state that while it is well known that most substitutions at conserved amino acid positions (which they call “toggle” switches) abolish function, it is also true that substitutions at nonconserved positions (which they call “rheostat” positions) are equally capable of affecting protein function. They conclude that substitutions at rheostat positions have highly unpredictable outcomes on the activities and specificities of protein-based drugs. Bhattacharya et al. (PLoS ONE 12(3): e0171355, 2017) state that the range of possible effects of even single nucleotide variations at the protein level are significantly greater than currently assumed by existing software prediction methods, and that correct prediction of consequences remains a significant challenge (p. 18). Furthermore, when multiple mutations are introduced, there is even less predictability. For evidence thereof, see Guo et al. (PNAS USA 101(25):9205-10, 2004), who state that the effects of mutations on protein function are largely additive (page 9207, left column, full paragraph 2). Fenton et al. supra, also acknowledge this (see abstract).
The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites (Paul, page 293, first column, lines 3-8 and line 31 to column 2, line 9 and lines 27-30). Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff et al. (Proc Natl Acad Sci USA. Vol 79, page 1979, 1982) and Zhang et al. (mAbs 7(1): 42-52, 2005; page 45, column 2)). Zhang et al. also indicate that minor variations in variable heavy and light chain CDR1s and CDR2s may lead to loss of antigen binding (page 46, column 1).
Additionally, it is not well established in the art that all variable domains are amenable to modifications much less even conservative. Numerous publications acknowledge that conservative substitutions would in fact change the binding ability of antibodies if not substantially reduce the affinity. Brummell et al. (Biochemistry 32:1180-1187 (1993)) found that mutagenesis of the four HCDR3 contact residues for the carbohydrate antibody (Salmonella B O-polysaccharide) in no instance improved affinity but 60% of the mutants resulted in a 10-fold drop in binding constant (affinity electrophoresis value of 0.85), while still other mutants were lower (Table 1 and p. 1183, Col. 2, ¶2 to p. 1184, Col. 1, ¶1). Brummell demonstrate that no substitution retained antigen binding affinity similar to the wild type antibody despite targeted, conservative substitutions in known contact sites. Kobayashi et al. (Protein Engineering 12:879-844 (1999)) disclose that a scFv for binding a DNA oligomer containing a (6-4) photoproduct with Phe or Tyr substitutions at Trp 33 retained “a large fraction of the wild-type binding affinity, while the Ala substitution diminished antigen binding” (Table 1). However, Kobayashi et al. note “replacing Trp 33 with Phe or Ala alters the local environment of the (6-4) photodimer since binding is accompanied by large fluorescence increases that are not seen with the wild-type scFv” (p. 883, Col. 2, ¶3). Burks et al. (PNAS 94:412-417 (1997)) disclose scanning saturation mutagenesis of the anti-digoxin scFv (26-10) which also binds digitoxin and digoxigenin with high affinity and with 42-fold lower affinity to ouabain. 114 mutant scFvs were characterized for their affinities for digoxin, digitonin, digoxignenin and oubain. Histogram analysis of the mutants (Figure 2) reveals that “not all residues are optimized in even high affinity antibodies such as 26-10, and that the absence of close contact with the hapten confers higher plasticity, i.e., the ability to tolerate a wider range of substitutions without compromising binding (p. 415, Col. 2, ¶4- p. 416, ¶1).
Vasudevan et al. (Blood Cells Mol Diseases 32: 176-181, 2004) indicate that the single amino acid substitution at position 108 in the H3 loop of monoclonal antibody AP7.4 alters the shape of the loop and changes the binding specificity from integrin αIIbβ3 to integrin αvβ3 (page 177, column 1; Table 1; page 180 through page 181, column 1). Jang et al. (Molec. Immunol. 35:1207-1217 (1998)) teach that single amino acid mutations to the CDRH3 of a scFV derived from 2C10, an anti-dsDNA autoantibody, reduced the binding activity about 20-50% compared to the unmutated scFv (Table 4). Brorson et al. (J. Immunol. 163:6694-6701 (1999)) teach that single amino acid substitutions to the CDRs of IgM Abs for the bacterial protein, levan, are ablated. Colman (Research in Immunol. 145:33-36 (1994)) teaches that single amino acid changes within the interface of an antibody-antigen complex are important and that inasmuch as the interaction can tolerate amino acid sequence substitutions, “a very conservative substitution may abolish binding” while “in another, a non-conservative substitution may have very little effect on the binding” (p. 35, Col. 1, ¶1).
Additionally, the relevant art teaches that while CDR3 is important for antigen-binding, the conformations of other CDRs as well as framework residues also influence binding. MacCallum et al. (J Mol Biol. 262: 732-745, 1996) analyzed many different antibodies for interactions with antigen and state that although CDR3 of the heavy and light chain dominate, a number of residues outside the standard CDR definitions make antigen contacts (see page 733, right column) and non-contacting residues within the CDRs coincide with residues as important in defining canonical backbone conformations (see page 735, left col). De Pascalis et al. (The Journal of Immunology. 169: 3076-3084, 2002) demonstrate that grafting of the CDRs into a human framework was performed by grafting CDR residues and maintaining framework residues that were deemed essential for preserving the structural integrity of the antigen binding site (see page 3079, right column). Although abbreviated CDR residues were used in the constructs, some residues in all 6 CDRs were used for the constructs (see page 3080, left column). The fact that not just one CDR is essential for antigen binding or maintaining the conformation of the antigen binding site is underscored by Casset et al. (Biochemical and Biophysical Research Communications 307: 198-205, 2003), who constructed a peptide mimetic of an anti-CD4 monoclonal antibody binding site by rational design and the peptide was designed with 27 residues formed by residues from 5 CDRs (see entire document). Casset et al. also teach that although CDR H3 is at the center of most if not all antigen interactions, clearly other CDRs play an important role in the recognition process (page 199, left column) and this is demonstrated in this work by using all CDRs except L2 and additionally using a framework residue located just before the H3 (see page 202, left column). Vajdos et al. (J Mol Biol. 320: 415-428, 2002) teach that antigen binding is primarily mediated by the CDRs more highly conserved framework segments which connect the CDRs are mainly involved in supporting the CDR loop conformations and in some cases framework residues also contact antigen (page 416, left column). Holm et al. (Mol Immunology. 44: 1075-1084, 2007) describe the mapping of an anti-cytokeratin antibody where although residues in the CDR3 of the heavy chain were involved in antigen binding, unexpectedly a residue in CDR2 of the light chain was also involved (abstract). Chen et al. (J Mol Biol. 293: 865-881, 1999) describe high affinity variant antibodies binding to VEGF wherein the results show that the antigen binding site is almost entirely composed of residues from heavy chain CDRs, CDR-H1, H2, H3 (page 866). Wu et al. (J Mol Biol. 294: 151-162, 1999) state that it is difficult to predict which framework residues serve a critical role in maintaining affinity and specificity due in part to the large conformational change in antibodies that accompany antigen binding (page 152 left col) but certain residues have been identified as important for maintaining conformation. Sela-Culang et al. (Front Immunol 4: 302, 2013) also teach that it is now well-established that some of the framework residues may play an important role in antigen binding (page 7, column 1, last full paragraph through entirety of column 2).
The level of skill required to generate the antibodies (such as bispecific antibodies/compounds) is that of a molecular immunologist, and one of ordinary skill in the art would have been required to identify candidate amino acid residues for mutation/substitution in the heavy/light chain (variable) regions and/or CDR domains, perform the mutagenesis on the heavy/light chain (variable) regions and CDR domains, produce and express the modified antibodies/compounds, and measure binding characteristics (e.g., binding specificity, equilibrium dissociation constant (KD), dissociation and association rates (K off and Kon respectively), and binding affinity and/or avidity compared with the parent antibody). The technology to perform these experiments was available at the time of application filing, but the amount of experimentation required to generate even a single heavy/light chain variable region with the required TNF-alpha and/or IL23A binding specificities encompassed by the instant claims would not have been routine, much less could one of ordinary skill in the art predict that any one or combination of all the heavy/light chain variable region and/or CDR amino acid deletions, substitutions, or additions encompassed by the claims would result in just any heavy/light chain variable region having retained the TNF-alpha and Il-23A binding activity. Because of this lack of guidance in the instant specification, the extended experimentation that would be required to determine which amino acid sequences and modifications would be acceptable to retain occluding structural and functional activity, and the fact that the relationship between the sequence of a protein/peptide and its tertiary structure (i.e. its activity) are not well understood and are not predictable, it would require an undue amount of experimentation for one of skill in the art to arrive at the large number of heavy/light chain variable region polypeptides of the encompassed claims. Applicant has not provided sufficient guidance to enable one of ordinary skill in the art to make and use the genus of anti-TL1A antibodies in the claims in a manner reasonably correlated with the scope of the claims. The scope of the claims must bear a reasonable correlation with the scope of enablement. See In re Fisher, 166 USPQ 19 24 (CCPA 1970).
Due to the large quantity of experimentation necessary to generate and screen for all possible bispecific compounds that comprise any combination and sequences of light and heavy chain variable domains (VL1, VH2, VL2, and VH1) that are still capable of binding TNF-alpha and/or IL-23A; the lack of direction/guidance presented in the specification regarding same; lack of working examples; the teachings of the prior art; the complex nature of the invention; the unpredictability of the effects of CDR and heavy/light chain alterations on antibody/bispecific compound activity; and the breadth of the claims, undue experimentation would be required of the skilled artisan to use the claimed invention.
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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5. Claims 36-38, 40-52 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-27 of U.S. Patent No. 10,793,629 in view of Eon Duval et al. (US 2010/0190961).
Briefly, claim 26 of the ‘629 patent recites a method of producing a compound comprising a first and a second polypeptide, comprising culturing a cell comprising the nucleic acid of claim 1, under conditions whereby said cell expresses the compound encoded thereby.
Claim 27 of the ‘629 patent recites the method according to claim 26, further comprising isolating and purifying said expressed compound.
It is noted at the outset the amino acid sequences recited in the claim set of the ‘629 patent (i.e., SEQ ID NOs: 1-36 and 40) are 100% identical the same sequences recited in the claims of the instant application.
The claims of the ‘629 patent do not recite any specific steps for isolating and purifying the encoded bispecific compound.
Eon-Duval et al. teach a method of purifying an Fc-containing protein, comprising the steps:
a. subjecting a fluid comprising said Fc-containing protein to Protein A affinity chromatography;
b. subjecting the eluate of step (a) to cation exchange chromatography;
c. subjecting the eluate of step (b) to anion exchange chromatography;
d. subjecting the flow-through of step (c) to hydroxyapatite chromatography and collecting the eluate to obtain purified Fc protein (page 3, [0038-0042]; page 4, [0055]; page 7, [0115]).
Eon-Duval et al. teach that step (a) is carried out on a resin comprising cross-linked agarose modified with recombinant Protein A, meeting the limitations of instant claim 36, step (i).
Eon-Duval et al. disclose that the elution in step (a) is carried out in a sodium acetate buffer, meeting the limitations of instant claim 36, step (ii) (page 7, [0127]). Eon Duval et al. indicate that the elution is carried out at pH 3.5, meeting the limitations of instant claim 37 (page 7, [0126]).
Eon-Duval et al. teach that the eluate is neutralized and applied to a hydroxyapatite chromatography resin with a phosphate buffer, meeting the limitations of instant claim 36, steps (iii-v) (page 7, [0128-0135]).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to modify the method of producing a compound comprising a first and a second polypeptide of the claims of the ‘629 patent by specifically subjecting a composition comprising the encoded compound to Protein A affinity chromatography; cation/anion exchange chromatography; and hydroxyapatite chromatography, as taught by Eon-Duval. The person of ordinary skill in the art would have been motivated to make those modifications and would have expected success with purifying the encoded compound-containing compositions of the ‘629 claims because Eon-Duval successfully remove impurities from Fc-containing compositions, with low aggregate levels and high yield (page 3, [0038-0039]; page 15, [0289]).
6. Claims 36-38, 40-52 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6, 7, 9-11, 14, 16, 17, 19-21, 24, 30, 31, 33, 34 of copending Application No. 19/547,752 in view of in view of Eon Duval et al. (US 2010/0190961).
Briefly, claim 34 of the ‘752 application recites a method of producing a compound according to claim 1 comprising obtaining a cell comprising a nucleic acid encoding said compound and expressing said nucleic acid in said cell, and optionally isolating and purifying said compound.
It is noted at the outset the amino acid sequences recited in the claim set of the ‘752 application (i.e., SEQ ID NOs: 1-36 and 40) are 100% identical the same sequences recited in the claims of the instant application.
The claims of the ‘752 application do not recite any specific steps for isolating and purifying the encoded compound.
Eon-Duval et al. teach a method of purifying an Fc-containing protein, comprising the steps:
a. subjecting a fluid comprising said Fc-containing protein to Protein A affinity chromatography;
b. subjecting the eluate of step (a) to cation exchange chromatography;
c. subjecting the eluate of step (b) to anion exchange chromatography;
d. subjecting the flow-through of step (c) to hydroxyapatite chromatography and collecting the eluate to obtain purified Fc protein (page 3, [0038-0042]; page 4, [0055]; page 7, [0115]).
Eon-Duval et al. teach that step (a) is carried out on a resin comprising cross-linked agarose modified with recombinant Protein A, meeting the limitations of instant claim 36, step (i).
Eon-Duval et al. disclose that the elution in step (a) is carried out in a sodium acetate buffer, meeting the limitations of instant claim 36, step (ii) (page 7, [0127]). Eon Duval et al. indicate that the elution is carried out at pH 3.5, meeting the limitations of instant claim 37 (page 7, [0126]).
Eon-Duval et al. teach that the eluate is neutralized and applied to a hydroxyapatite chromatography resin with a phosphate buffer, meeting the limitations of instant claim 36, steps (iii-v) (page 7, [0128-0135]).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to modify the method of producing a compound comprising a first and a second polypeptide of the claims of the ‘752 application by specifically subjecting a composition comprising the encoded compound to Protein A affinity chromatography; cation/anion exchange chromatography; and hydroxyapatite chromatography, as taught by Eon-Duval. The person of ordinary skill in the art would have been motivated to make those modifications and would have expected success with purifying the encoded compound-containing compositions of the ‘752 application claims because Eon-Duval successfully remove impurities from Fc-containing compositions, with low aggregate levels and high yield (page 3, [0038-0039]; page 15, [0289]).
Conclusion
No claims are allowable.
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BEB
Art Unit 1647
20 March 2026
/BRIDGET E BUNNER/Primary Examiner, Art Unit 1647