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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 14 November 2025 has been entered.
Status of Application, Amendments and/or Claims
The amendment of 14 November 2025 has been entered in full. Claims 1, 7, and 13 are amended. Claims 19-21 are cancelled.
Claims 1-18 are under consideration in the instant application.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 14 November 2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Withdrawn Objections and/or Rejections
1. The objections of claims 19-21 are set forth at page 3 of the previous Office Action of 14 August 2025 are withdrawn in view of the cancelled claims (14 November 2025).
2. The rejection of claims 1-21 under 35 U.S.C. 102(a)(1) as being anticipated by Clinical Trial NCT02808429, record history dated 28 May 2019 https://clinicaltrials.gov/study/NCT02808429?term=NCT02808429&rank=1&tab=history&a=23#version-content-panel. (cited on the IDS of 11 March 2025), as evidenced by Lee et al. (J Allergy Clin Immunol 125: 814-820, 2010; cited on the PTO-892 of 23 April 2025) and Del Rio et al. (U.S. Patent 8,637,021; cited on the IDS of 11 March 2025) as set forth at pages 22-27 of the previous Office Action of 14 August 2025 is withdrawn in view of the amended claims and Applicant’s persuasive arguments. Specifically, atacicept comprises the TACI extracellular domain fragment of SEQ ID NO: 1 (see instant specification, bottom of page 159). The amino acid sequence of SEQ ID NO: 1 corresponds to amino acid residues 30 to 110 of SEQ ID NO: 11, which naturally includes amino acids 34-66 within it. Therefore, the instant pending claims, as amended, exclude recitation of a sequence that includes atacicept. Clinical Trial ‘429, in contrast to the instant amended claims, treats IgAN with atacicept.
Maintained 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.
Written Description
3. Claims 1-18 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. The basis for this rejection is set forth for claims 1-21 at pages 4-13 of the previous Office Action of 14 August 2025.
Claim 1, for example, is directed to a method of treating a human patient having IgA nephropathy (IgAN), the method comprising administering to the human patient a therapeutically effective amount of a fusion molecule comprising:
a fragment of a transmembrane activator and calcium modulator and cyclophilin ligand-interactor (TACI) extracellular domain, which binds to BLyS (B Lymphocyte Stimulator) and APRIL (A Proliferation-Inducing Ligand), wherein the fragment comprises amino acid residues 71 to 104 of SEQ ID NO: 11 or a sequence having at least 90% sequence identity thereto, and does not comprise amino acid residues 34 to 66 of SEQ ID NO: 11; and
a human immunoglobulin G1 (IgG1) constant domain (IgG1-Fc), wherein the administration results in an at least 25% reduction in the serum level of galactose deficient immunoglobulin A1 (Gd-IgA1) in the patient, compared to before the administration.
The specification of the instant application teaches that the present disclosure relates to methods for the treatment of IgA nephropathy by administration of a TACI-Ig fusion molecule (page 3, [0012-0013]). The specification discloses that the TACI extracellular domain comprises two cysteine (Cys)-rich repeats (page 20, [0084]). The specification teaches that a splice variant of TACI that comprises only the second, less conserved Cys-rich repeat, is able to bind BLyS (page 20, [0084]). The specification states that the amino acid sequence of the extracellular domain of TACI is provided as SEQ ID NO: 11 (166 total amino acids) (page 20, [0080]). The specification teaches that amino acids 71-104 of SEQ ID NO: 11 correspond to the second Cys-rich repeat (page 21, [0084]). The specification continues to indicate that the amino acids 34-66 of SEQ ID NO: 11 correspond to the first Cys-rich repeat (page 21, [0084]). The specification discloses that the TACI extracellular domain or fragment thereof comprises or consists of amino acid residues 30-110 of SEQ ID NO: 11 (page 21, [0084]). The prior art of Rixon et al. (WO 02/094852 (cited on the IDS of 03/25/2025)) and West et al. (WO 2004/033486) also teach these ligand-binding fragments of TACI.
The specification continues to teach that fragments and variants (e.g. sequence variants of different % of identity) of the TACI extracellular domain can be used in the context of the present invention, as long as the fragment/variant is able to bind BLyS and/or APRIL (page 21, [0085]).
Instant independent claims 1, 7, and 13 recite that the administered fusion molecule comprises (i) a fragment of a TACI extracellular domain which binds BLyS and APRIL, wherein the fragment comprises amino acid residues 71 to 104 of SEQ ID NO: 11 or a sequence having at least 90% sequence identity thereto, and does not comprise amino acid residues 34 to 66 of SEQ ID NO: 11; and (ii) a human IgG1 constant domain. Therefore, the claims are broadly interpreted by the Examiner as reading upon administration of a fusion protein comprising any TACI extracellular domain fragment at least 90% identical to amino acids 71 to 104 of SEQ ID NO: 11 (and that does not comprise amino acids 34-66 of SEQ ID NO: 11), and wherein the fragment retains binding to BLyS and APRIL and treats IgA nephropathy.
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 only factors present in the method claims are (i) a structural characteristic of a fragment of a TACI extracellular domain, wherein the fragment has a sequence at least 90% identical to amino acid residues 71 to 104 of SEQ ID NO: 11 (and that does not comprise amino acids 34-66 of SEQ ID NO: 11), and (ii) functional characteristics of binding BLyS and APRIL and treating IgA nephropathy. There is no identification of any particular sequence or structure of the fragment of the TACI extracellular domain that must be conserved in order to provide the required functions of binding BLyS and APRIL and treating IgA nephropathy. Thus, the claims are drawn to a genus of TACI extracellular domain fragments.
The instant specification fails to disclose and there is no art-recognized correlation between the structure of the genus of fragments of the extracellular domain of TACI and the function of binding BLyS and APRIL. In other words, the specification does not teach the structure which results in a fragment of the extracellular domain of TACI with the claimed required characteristic of binding BLyS and APRIL and treating IgA nephropathy. The description of the full-length TACI extracellular domain of SEQ ID NO: 11; amino acids 71-104 of SEQ ID NO: 11; amino acids 34-66 of SEQ ID NO: 11; and amino acids 30-110 of SEQ ID NO: 11 are not adequate written description of an entire genus of fragments of the extracellular domain of TACI, wherein the wherein the fragment has a sequence at least 90% identical to amino acid residues 71 to 104 of SEQ ID NO: 11. 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. 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). Regarding TACI, Garcia-Carmona et al. (Front Immunol 9: 2125, 2018) even teach that TACI variants with single missense mutations C104R, A181E, and S194X bind APRIL and BLyS (also known as BAFF), but lack signaling function (page 5; Figure 2). Fried et al. (J Allergy Clin Immunol 128(1): 226-228, 2011) also disclose that single TACI mutations Y79C, I87N, C104R, and L171R result in absent or impaired ligand binding (page 227, Table 1).
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 administered fusion molecules that comprise a TACI extracellular domain fragment that binds BLyS and APRIL, wherein the fragment has a sequence at least 90% identical to amino acid residues 71 to 104 of SEQ ID NO: 11 (and that does not comprise amino acids 34-66 of SEQ ID NO: 11), 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 specific fragment is 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 an administered fusion molecule comprising (i) a TACI extracellular domain fragment comprising amino acids 71-104 of SEQ ID NO: 11 (and that does not comprise amino acids 34-66 of SEQ ID NO: 11) and (ii) a human IgG1 constant domain (IgG1-Fc), 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).
(i) At the top of page 7 of the Response of 14 November 2025, Applicant states that without agreeing or acquiescing to the rejection, and solely to expedite prosecution, Applicant submits that the pending independent claims 1, 7, and 13 are amended to refer to one of the four specified sequences, namely, amino acids 71-104 of SEQ ID NO: 11, as well as sequences that have at least 90% sequence identity thereto. Applicant argues that specifying the claimed TACI extracellular fragment to a sequence comprising amino acid residues 71 to 104 of SEQ ID NO: 11, or a sequence having at least 90% sequence identity thereto, sufficiently restricts the scope of the claim to embodiments of the TACI-Ig fusion molecule having common structural that allow skilled artisans to identify members of the genus.
Applicant’s arguments have been fully considered but are not found to be persuasive. The Examiner acknowledges that the instant independent method claims 1, 7, and 13 have been amended to refer to one of the four specified sequences (amino acids 71-104 of SEQ ID NO: 11), and sequences that have at least 90% sequence identity thereto. However, in view of the teachings of the instant specification, the percent identity limitation recited in the claims is broadly interpreted by the Examiner as reading upon any TACI extracellular domain fragment that shares at least 90% sequence identity with amino acids 71-104 of SEQ ID NO: 11 (and that does not comprise amino acids 34-66 of SEQ ID NO: 11), wherein the fragment binds BLyS and APRIL and treats IgA nephropathy.
There is no identification in the instant claims of any particular sequence or structure of the fragment of the TACI extracellular domain of amino acids 71-104 of SEQ ID NO: 11 that must be conserved in order to provide the required functions of binding BLyS and APRIL and treating IgA nephropathy. As discussed above and in the previous Office Actions, the state of the art recognizes that function cannot be predicted from structure alone. Applicant has provided little or no guidance beyond the mere presentation of sequence data to enable one of ordinary skill in the art to determine, without undue experimentation, the positions in the TACI extracellular domain of amino acids 71-104 of SEQ ID NO: 11 which are tolerant to change (e.g. such as by amino acid substitutions or deletions), and the nature and extent of changes that can be made in these positions. Relevant literature teaches that TACI variants with single missense mutations C104R, A181E, and S194X bind APRIL and BLyS (also known as BAFF), but lack signaling function (Garcia-Carmona et al., Front Immunol 9: 2125, 2018 (cited on the PTO-892 of 23 April 2025); page 5; Figure 2). Fried et al. (J Allergy Clin Immunol 128(1): 226-228, 2011; cited on the PTO-892 of 23 April 2025) also disclose that single TACI mutations Y79C, I87N, C104R, and L171R result in absent or impaired ligand binding (page 227, Table 1).
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).
The skilled artisan cannot envision the detailed chemical structure of the administered fusion molecules that comprise a TACI extracellular domain fragment that binds BLyS and APRIL and treats IgA nephropathy, wherein the fragment has a sequence at least 90% identical to amino acid residues 71 to 104 of SEQ ID NO: 11 (and that does not comprise amino acids 34-66 of SEQ ID NO: 11), and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation.
(ii) At the middle of page 7 of the Response, Applicant contends that the Examiner alleges that many mutations result in active protein and that single TACI mutations (Y79C, I87N, C104R, and L171R) result in absent or impaired ligand binding. Applicant asserts that these are likely operability issues which fall under the enablement rejection.
Applicant’s arguments have been fully considered but are not found to be persuasive. Contrary to Applicant’s assertions, the numerous references cited by the Examiner (Bork, Skolnick et al., Doerks et al., Smith et al., Brenner Bork et al., Tokuriki et al., Fenton et al., Bhattacharya et al., Garcia-Carmona et al., Fried et al.) in the written description rejection provide evidence that the prior art recognizes that protein function cannot be predicted from structure alone. In particular, TACI variants with single missense mutations C104R, A181E, and S194X bind APRIL and BLyS (also known as BAFF), but lack signaling function (Garcia-Carmona et al.; page 5; Figure 2). Fried et al. also disclose that single TACI mutations Y79C, I87N, C104R, and L171R result in absent or impaired ligand binding (page 227, Table 1). Thus, it is unpredictable that a TACI extracellular domain fragment that comprises a sequence at least 90% identical to amino acids 71 to 104 of SEQ ID NO: 11 (and does not comprise amino acids 34 to 66) binds BLyS and APRIL and treats IgA nephropathy.
Applicant is again reminded that 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).
In the instant application, the skilled artisan cannot envision the detailed chemical structure of the administered fusion molecules that comprise a TACI extracellular domain fragment that binds BLyS and APRIL, wherein the fragment has a sequence at least 90% identical to amino acid residues 71 to 104 of SEQ ID NO: 11 (and that does not comprise amino acids 34-66 of SEQ ID NO: 11), and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation.
Scope of Enablement
4. Claims 1-18 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 treating a human patient having IgAN, comprising administering to the human patient a therapeutically effective amount of a fusion molecule comprising (i) a TACI extracellular domain comprising the amino acid sequence of SEQ ID NO: 11; amino acids 71-104 of SEQ ID NO: 11; amino acids 34-66 of SEQ ID NO: 11; or amino acids 30-110 of SEQ ID NO: 11 and (ii) a human IgG1 constant domain (IgG1-Fc), does not reasonably provide enablement for a method of treating a human patient having IgAN, comprising administering to the human patient a therapeutically effective amount of a fusion molecule comprising (i) a fragment of a TACI extracellular domain which binds BLyS and APRIL, wherein the fragment comprises a sequence having at least 90% sequence identity to amino acid residues 71 to 104 of SEQ ID NO: 11; and (ii) a human IgG1 constant domain (IgG1-Fc). 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. The basis for this rejection is set forth for claims 1-21 at pages 13-22 of the previous Office Action of 14 August 2025.
Claim 1, for example, is directed to a method of treating a human patient having IgA nephropathy (IgAN), the method comprising administering to the human patient a therapeutically effective amount of a fusion molecule comprising:
a fragment of a transmembrane activator and calcium modulator and cyclophilin ligand-interactor (TACI) extracellular domain, which binds to BLyS (B Lymphocyte Stimulator) and APRIL (A Proliferation-Inducing Ligand), wherein the fragment comprises amino acid residues 71 to 104 of SEQ ID NO: 11 or a sequence having at least 90% sequence identity thereto, and does not comprise amino acid residues 34 to 66 of SEQ ID NO: 11; and
a human immunoglobulin G1 (IgG1) constant domain (IgG1-Fc), wherein the administration results in an at least 25% reduction in the serum level of galactose deficient immunoglobulin A1 (Gd-IgA1) in the patient, compared to before the administration.
The specification of the instant application teaches that the present disclosure relates to methods for the treatment of IgA nephropathy by administration of a TACI-Ig fusion molecule (page 3, [0012-0013]). The specification discloses that the TACI extracellular domain comprises two cysteine (Cys)-rich repeats (page 20, [0084]). The specification teaches that a splice variant of TACI that comprises only the second, less conserved Cys-rich repeat, is able to bind BLyS (page 20, [0084]). The specification states that the amino acid sequence of the extracellular domain of TACI is provided as SEQ ID NO: 11 (166 total amino acids) (page 20, [0080]). The specification teaches that amino acids 71-104 of SEQ ID NO: 11 correspond to the second Cys-rich repeat (page 21, [0084]). The specification continues to indicate that the amino acids 34-66 of SEQ ID NO: 11 correspond to the first Cys-rich repeat (page 21, [0084]). The specification discloses that the TACI extracellular domain or fragment thereof comprises or consists of amino acid residues 30-110 of SEQ ID NO: 11 (page 21, [0084]). The prior art of Rixon et al. (WO 02/094852 (cited on the IDS of 03/25/2025)) and West et al. (WO 2004/033486) also teach these ligand-binding fragments of TACI.
The specification continues to teach that fragments and variants (e.g. sequence variants of different % of identity) of the TACI extracellular domain can be used in the context of the present invention, as long as the fragment/variant is able to bind BLyS and/or APRIL (page 21, [0085]).
Instant independent claims 1, 7, and 13 recite that the administered fusion molecule comprises (i) a fragment of a TACI extracellular domain which binds BLyS and APRIL, wherein the fragment comprises amino acid residues 71 to 104 of SEQ ID NO: 11 or a sequence having at least 90% sequence identity thereto, and does not comprise amino acid residues 34 to 66 of SEQ ID NO: 11; and (ii) a human IgG1 constant domain. Therefore, the claims are broadly interpreted by the Examiner as reading upon administration of a fusion protein comprising any TACI extracellular domain fragment at least 90% identical to amino acids 71 to 104 of SEQ ID NO: 11 (and does not comprise amino acids 34-66), and wherein the fragment retains binding to BLyS and APRIL. However, the specification does not teach all possible TACI extracellular domain fragments at least 90% identical to amino acids 71 to 104 of SEQ ID NO: 11 (and do not comprise amino acids 34-66), other than a TACI extracellular domain comprising the amino acid sequence of SEQ ID NO: 11; amino acids 71-104 of SEQ ID NO: 11; amino acids 34-66 of SEQ ID NO: 11; or amino acids 30-110 of SEQ ID NO: 11.
The problem of predicting protein and DNA structure from sequence data and in turn utilizing predicted structural determinations to ascertain functional aspects of the protein and DNA is extremely complex. While it is known that many amino acid substitutions are generally possible in any given protein the positions within the protein's sequence where such amino acid substitutions can be made with a reasonable expectation of success are limited. Certain positions in the sequence are critical to the protein's structure/function relationship, e.g. such as various sites or regions directly involved in binding, activity and in providing the correct three-dimensional spatial orientation of binding and active sites. These or other regions may also be critical determinants of antigenicity. These regions can tolerate only relatively conservative substitutions or no substitutions (see Wells, 1990, Biochemistry 29:8509-8517; Ngo et al., 1994, The Protein Folding Problem and Tertiary Structure Prediction, pp. 492-495). However, Applicant has provided little or no guidance beyond the mere presentation of sequence data to enable one of ordinary skill in the art to determine, without undue experimentation, the positions in the TACI extracellular domain which are tolerant to change (e.g. such as by amino acid substitutions or deletions), and the nature and extent of changes that can be made in these positions. Even if an active or binding site were identified in the specification, they may not be sufficient, as the ordinary artisan would immediately recognize that an active or binding site must assume the proper three-dimensional configuration to be active, which conformation is dependent upon surrounding residues; therefore substitution of non-essential residues can often destroy activity. The art recognizes that 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). Regarding TACI, Garcia-Carmona et al. (Front Immunol 9: 2125, 2018) even teach that TACI variants with single missense mutations C104R, A181E, and S194X bind APRIL and BLyS (also known as BAFF), but lack signaling function (page 5; Figure 2). Fried et al. (J Allergy Clin Immunol 128(1): 226-228, 2011) also disclose that single TACI mutations Y79C, I87N, C104R, and L171R result in absent or impaired ligand binding (page 227, Table 1).
Therefore, the amount of experimentation required to generate any fragments at least 90% identical to amino acids 71 to 104 of SEQ ID NO: 11 (and that do not comprise amino acids 34-66) would not have been routine, much less could one of ordinary skill in the art predict that any one or combination of all the fragments encompassed by the instant claims would result in a TACI extracellular domain that retains binding to BLyS and APRIL. 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 TACI extracellular domain fragments of the instant claims. Applicant has not provided sufficient guidance to enable one of ordinary skill in the art to make and use the genus of TACI extracellular domain fragments 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 all possible fragments of a TACI extracellular domain, wherein the fragments comprise at least 90% identity to amino acids 71 to 104 of SEQ ID NO: 11 (and do not comprise amino acids 34-66) and screen such for the desired functional activity; the lack of direction/guidance presented in the specification regarding the same; the absence of working examples directed to the same; the complex nature of the invention; the state of the prior art which establishes the unpredictability of the effects of mutation on protein structure and function; and the breadth of the claims, undue experimentation would be required of the skilled artisan to make and/or use the claimed invention.
(i) At page 8 of the Response of 14 November 2025, Applicant indicates that without agreeing or acquiescing to the rejection, and solely to expedite prosecution, independent claims 1, 7, and 13 were amended to refer to one of the specified sequences, namely amino acids 71-104 of SEQ ID NO: 11, as well as sequences that have at least 90% sequence identity thereto. Applicant argues that specifying the claimed TACI extracellular fragment to a sequence comprising amino acid residues 71 to 104 of SEQ ID NO: 11, or a sequence having at least 90% sequence identity thereto, sufficiently restricts the scope of the claim so that one of ordinary skill in the art could make or use the invention from the disclosures in the patent coupled with information known in the art without undue experimentation. Applicant submits that the application as filed, at paragraphs [0170-0132] provides disclosure regarding how to assess ability of any TACI-Ig fusion molecule to bind BLyS and/or APRIL.
Applicant’s arguments have been fully considered but are not found to be persuasive. The Examiner acknowledges that the instant independent method claims 1, 7, and 13 have been amended to refer to one of the four specified sequences (amino acids 71-104 of SEQ ID NO: 11), and sequences that have at least 90% sequence identity thereto. However, in view of the teachings of the instant specification, the percent identity limitation recited in the claims is broadly interpreted by the Examiner as reading upon any TACI extracellular domain fragment that shares at least 90% sequence identity with amino acids 71-104 of SEQ ID NO: 11 (and that does not comprise amino acids 34-66 of SEQ ID NO: 11), wherein the fragment binds BLyS and APRIL and treats IgA nephropathy.
There is no identification in the instant claims of any particular sequence or structure of the fragment of the TACI extracellular domain of amino acids 71-104 of SEQ ID NO: 11 that must be conserved in order to provide the required functions of binding BLyS and APRIL and treating IgA nephropathy. As discussed above and in the previous Office Actions, the state of the art recognizes that function cannot be predicted from structure alone. Applicant has provided little or no guidance beyond the mere presentation of sequence data to enable one of ordinary skill in the art to determine, without undue experimentation, the positions in the TACI extracellular domain of amino acids 71-104 of SEQ ID NO: 11 which are tolerant to change (e.g. such as by amino acid substitutions or deletions), and the nature and extent of changes that can be made in these positions. Relevant literature teaches that TACI variants with single missense mutations C104R, A181E, and S194X bind APRIL and BLyS (also known as BAFF), but lack signaling function (Garcia-Carmona et al., Front Immunol 9: 2125, 2018 (cited on the PTO-892 of 23 April 2025); page 5; Figure 2). Fried et al. (J Allergy Clin Immunol 128(1): 226-228, 2011; cited on the PTO-892 of 23 April 2025) also disclose that single TACI mutations Y79C, I87N, C104R, and L171R result in absent or impaired ligand binding (page 227, Table 1).
Therefore, the amount of experimentation required to generate a TACI extracellular domain fragment that shares at least 90% sequence identity with amino acids 71-104 of SEQ ID NO: 11 (and that does not comprise amino acids 34-66 of SEQ ID NO: 11), wherein the fragment binds BLyS and APRIL and treats IgA nephropathy would not have been routine, much less could one of ordinary skill in the art predict that any one or combination of all the variations encompassed by the instant claims would result in a TACI extracellular domain that retains binding to BLyS and APRIL and treatment of IgA nephropathy. 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 TACI extracellular domain fragments of the instant claims. Applicant has not provided sufficient guidance to enable one of ordinary skill in the art to make and use the genus of fragments of a TACI extracellular domain, wherein the fragments comprise a sequence at least 90% identical to amino acids 71 to 104 of SEQ ID NO: 11 (and do not comprise amino acids 34 to 66 of SEQ ID NO: 11) as recited 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).
Furthermore, although Applicant argues that the specification provides a disclosure regarding how to assess ability of any TACI-Ig fusion molecule to bind BLyS and/or APRIL, such broad brush assertions do not constitute adequate guidance to practice the claimed method. Instead, these teachings constitute an invitation to experiment to first generate a TACI extracellular domain fragment that shares at least 90% sequence identity with amino acids 71-104 of SEQ ID NO: 11 (and that does not comprise amino acids 34-66 of SEQ ID NO: 11), wherein the fragment binds BLyS and APRIL and then determine how to practice the suggested method to obtain the therapeutic results required by the claims. Such trial and error experimentation is considered undue. In other words, a large quantity of experimentation would be required of the skilled artisan to first identify TACI extracellular domain fragments that share at least 90% sequence identity with amino acids 71-104 of SEQ ID NO: 11 (and that do not comprise amino acids 34-66 of SEQ ID NO: 11), wherein the fragments bind BLyS and APRIL and then administer such to treat IgA nephropathy. A single embodiment may provide broad enablement in cases involving predictable factors such as mechanical or electrical elements, but more will be required in cases that involve unpredictable factors such as most chemical reactions and physiological activity. See In re Vickers, 141 F.2d 522, 526-27, 61 USPQ 122, 127 (CCPA 1944); In re Cook, 439 F.2d 730, 734, 169 USPQ 298, 301 (CCPA 1971); In re Soll, 97 F.2d 623, 634, 38 USPQ 189, 191 (CCPA 1938; In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970); In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993); In re Vaeck, 947 F.2d 488, 496, 20 USPQ2d 1438, 1445 (Fed. Cir. 1991).
(ii) At the bottom of page 8 of the Response, Applicant states that the Examiner alleges that many mutations result in inactive protein (page 17) and that single TACI mutations Y79C, I87N, C104R, and L171R result in absent or impaired ligand binding. Applicant argues that even assuming the above allegation for the sake of argument, the enablement requirement merely requires the disclosure allow skilled artisans to practice the invention across its scope without undue experimentation, and not that every embodiment within a claim’s scope is operable.
Applicant’s arguments have been fully considered but are not found to be persuasive. The Examiner acknowledges that a disclosure of every operable species is not required. Applicant is reminded that a single embodiment may provide enablement in cases involving predictable factors, such as mechanical or electrical elements, however, in applications directed to inventions in arts where the results are unpredictable, the disclosure of a single species usually does not provide an adequate basis to support generic claims (See In re Vickers, 141 F.2d 522, 526-27, 61 USPQ 122, 127 (CCPA 1944); In re Cook, 439 F.2d 730, 734, 169 USPQ 298, 301 (CCPA 1971); In re Soll, 97 F.2d 623, 624, 38 USPQ 189, 191 (CCPA 1938)). In cases involving unpredictable factors, such as most chemical reactions and physiological activity, more may be required (see In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) (contrasting mechanical and electrical elements with chemical reactions and physiological activity); see also In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993); In re Vaeck, 947 F.2d 488, 496, 20 USPQ2d 1438, 1445 (Fed. Cir. 1991)). This is because in art areas having a high degree of uncertainty (i.e. the unpredictable arts) it is not reasonably predictable from the disclosure of one species, what other species will work. The Examiner has provided numerous references in the instant rejection to evidence that protein function cannot be predicted from structure alone (see Bork, Skolnick et al., Doerks et al., Smith et al., Brenner Bork et al., Tokuriki et al., Fenton et al., Bhattacharya et al., Guo et al., Garcia-Carmona et al., Fried et al.). In particular, TACI variants with single missense mutations C104R, A181E, and S194X bind APRIL and BLyS (also known as BAFF), but lack signaling function (Garcia-Carmona et al.; page 5; Figure 2). Fried et al. also disclose that single TACI mutations Y79C, I87N, C104R, and L171R result in absent or impaired ligand binding (page 227, Table 1). Thus, it is unpredictable that a TACI extracellular domain fragment that comprises a sequence at least 90% identical to amino acids 71 to 104 of SEQ ID NO: 11 (and does not comprise amino acids 34 to 66) binds BLyS and APRIL and treats IgA nephropathy.
Furthermore, the amount of experimentation required to generate TACI extracellular domain fragments that share at least 90% sequence identity with amino acids 71-104 of SEQ ID NO: 11 (and that do not comprise amino acids 34-66 of SEQ ID NO: 11) wherein the fragments binds BLyS and APRIL, would not have been routine, much less could one of ordinary skill in the art predict that any one or combination of all the fragments encompassed by the instant claims would result in a TACI extracellular domain that retains binding to BLyS and APRIL and treats IgA nephropathy. Applicant has not provided sufficient guidance to enable one of ordinary skill in the art to make and use the genus of TACI extracellular domain fragments that share at least 90% sequence identity with amino acids 71-104 of SEQ ID NO: 11 (and that do not comprise amino acids 34-66 of SEQ ID NO: 11), wherein the fragments bind BLyS and APRIL as recited in the claims in a manner reasonably correlated with the scope of the claims.
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.
5. Claims 1, 2, 7, 8, 13, and 14 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Rixon et al. (WO 2002/094852 or US 2003/0103986; cited on the IDS of 11 March 2025). It is noted that WO 2002/094852 and US 2003/0103986 have the same disclosure. Thus, for brevity, relevant portions of the WO document will be cited below.
Rixon et al. teach TACI-immunoglobulin fusion proteins that comprise (a) a TACI receptor moiety that consists of a fragment of a polypeptide that comprises the cysteine-rich pseudo-repeat region of amino acid residues 71 to 104 (but not amino acids 34 to 66) and (b) a human immunoglobulin (IgG1) constant domain moiety, meeting the limitations of instant claims 1, 7, and 13 (see page 5, lines 1-23, 31-36; pages 16-18; page 20, lines 14-25). It is noted that the TACI extracellular domain fragments of amino acids 71 to 104 of Rixon et al. are 100% identical to amino acids 71 to 104 of instant SEQ ID NO: 11 (see SEQ ID NO: 2 of Rixon et al.). Rixon et al. also state that the TACI receptor moiety binds at least one of ZTNF2 (APRIL) or ZTNF4 (BLyS) (page 2, lines 14-20; page 5, lines 7-8, 35-36).
Rixon et al. disclose that the TACI-immunoglobulin fusion protein may be administered to a treat a subject with IgA nephropathy, meeting the limitations of instant claims 1, 7, and 13 (page 44, lines 20-25). Rixon et al. teach that the subject is a human patient, also meeting the limitations of instant claims 1, 7, and 13 (page 43, lines 22-24).
Rixon et al. indicate that administration of the TACI-immunoglobulin fusion protein to a subject can be intravenous or subcutaneous, meeting the limitations of instant claims 2, 8, and 14 (page 47, lines 1-5).
Therefore, Rixon et al. teach the administration of the same TACI-Ig fusion molecule to the same patient population (patients with IgA nephropathy) as required by the instant claims. Although instant independent claims 1, 7, and 13 recite the additional limitations that administration of a fusion TACI-Ig molecule results in an at least 25% reduction in serum level of Gd-IgA1; results in an increase or a decrease by not more than 10% of eGFR; and results in an at least 25% reduction in urine protein:creatinine ratio, these activities would inherently occur in the prior art of Rixon et al., absent evidence to the contrary (see Ex parte Novitski, 26 USPQ2d 1389 (BPAI 1993); see also Integra LifeSciences I Ltd. V. Merck KGaA, (DC SCalif) 50 USPQ2d 1846; In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977)). Additionally, the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable (In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977); In re May, 574 F.2d 1082, 1090, 197 USPQ 601, 607 (CCPA 1978)).
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.
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.
6. Claims 1-18 are rejected under 35 U.S.C. 103 as being unpatentable over Clinical Trial NCT02808429, record history dated 28 May 2019 https://clinicaltrials.gov/study/NCT02808429?term=NCT02808429&rank=1&tab=history&a=23#version-content-panel (cited on the IDS of 11 March 2025), as evidenced by Lee et al. (J Allergy Clin Immunol 125: 814-820, 2010; cited on the PTO-892 of 23 April 2025); Del Rio et al. (U.S. Patent 8,637,021; cited on the IDS of 11 March 2025); Hymowitz 2005 (J Biol Chem 280(8): 7218-7227, 2005); and Rixon et al. (WO 2002/094852 or US 2003/0103986; cited on the IDS of 11 March 2025).
Clinical Trial NCT02808429 (hereinafter, “Clinical Trial ‘429”) teaches a method of treating a human patient having IgA nephropathy comprising administering to the patient a therapeutically effective amount of atacicept (entirety of page 4). It is noted that as of the effective filing date of the instant application, it was well-known in the art that atacicept is a fusion protein comprised of the extracellular domain of TACI fused with the Fc fragment of human IgG1, as evidenced by Lee et al. (page 818, column 2, 1st full paragraph) and Del Rio et al. (column 2, lines 11-26). The amino acid sequence of atacicept was also well-known at the time of filing the instant application (see for example, SEQ ID NO: 3 of Del Rio et al.; column 2, lines 23-26; column 7, lines 17-18; column 8, lines 2-3).
Atacicept comprises a first Cys-rich repeat and a second Cys-rich repeat (amino acids 34-66 and 71-104 of instant SEQ ID NO: 11), as evidenced by the atacicept amino acid sequence of SEQ ID NO: 3 of Del Rio et al. (see partial sequence alignment, below; amino acids 5-37 and 42-75). The first cys-rich repeat is underlined and the second Cys-rich repeat is bolded and italicized.
Qy= amino acids 30-110 of instant SEQ ID NO: 11
Db= amino acids 1-81 of SEQ ID NO: 3 of Del Rio et al.
Query Match 51.6%; Score 469; DB 1; Length 313;
Best Local Similarity 100.0%;
Matches 81; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 30 AMRSCPEEQYWDPLLGTCMSCKTICNHQSQRTCAAFCRSLSCRKEQGKFYDHLLRDCISC 89
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 AMRSCPEEQYWDPLLGTCMSCKTICNHQSQRTCAAFCRSLSCRKEQGKFYDHLLRDCISC 60
Qy 90 ASICGQHPKQCAYFCENKLRS 110
|||||||||||||||||||||
Db 61 ASICGQHPKQCAYFCENKLRS 81
Furthermore, Clinical Trial ‘429 states that “[t]his study will evaluate the safety, tolerability, dose response and efficacy of atacicept in patients with IgA nephropathy and persistent proteinuria” (page 4, “brief summary”). Clinical Trial ‘429 discloses subcutaneous administration of atacicept (pages 4-5, under “arms and interventions”). Clinical Trial ‘429 indicates that the patient has persistent proteinuria and has been treated with an ACE inhibitor and/or ARB at least 8 weeks prior (page 6, see “eligibility” section, “inclusion criteria”).
Clinical Trial ‘429 does not teach that the administered TACI-IgG fusion protein of atacicept comprises a fragment of the TACI extracellular domain which binds BLyS and APRIL and comprises amino acids 71 to 104 (but does not comprise amino acids 34 to 66).
Hymowitz et al. teach that an alternative splice variant of human TACI lacking the N-terminal cysteine rich domain (CRD), termed “TACI_d2” (amino acids 68-109 of TACI), is still functional for signaling (page 7219, column 1, 1st and 3rd full paragraphs; Figure 1). Hymowitz et al. disclose that the second membrane-proximal CRD of TACI binds both APRIL and BAFF/BLyS with high affinity, whereas the N-terminal first CRD (amino acids 32-67 of TACI) does not (page 7218, column 1; page 7219, column 1, 1st through 3rd full paragraphs; page 7221, column 1, 1st full paragraph; page 7225, column 1, 3rd paragraph). Hymowitz et al. state that “[d]espite the presence of two CRDs in the human TACI sequence, TACI appears to function like a single domain receptor requiring only CRD2 for high affinity interactions with either of its ligands” (page 7226, column 1, last paragraph).
Del Rio et al. teach a TACI-Ig fusion protein wherein the fusion protein comprises a TACI extracellular domain fragment consisting of amino acids 71 to 104 (corresponding to the second cysteine rich domain) (column 8, lines 9-19). Similarly, Rixon et al. teach TACI-immunoglobulin fusion proteins that comprise (a) a TACI receptor moiety that consists of a fragment of a polypeptide that comprises the cysteine-rich pseudo-repeat region of amino acid residues 71 to 104 (but not amino acids 34 to 66) and (b) an immunoglobulin (IgG1) moiety (see WO 02/094852, page 5, lines 1-23, 31-36; page 20, lines 14-25). It is noted that the TACI extracellular domain fragments of amino acids 71 to 104 of Del Rio et al. and Rixon et al. are 100% identical to amino acids 71 to 104 of instant SEQ ID NO: 11 (see SEQ ID NO: 1 of Del Rio et al. and SEQ ID NO: 2 of Rixon et al.).
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 treating a human patient having IgA nephropathy comprising administering to the patient a therapeutically effective amount of the TACI-IgG fusion protein, atacicept, as taught by Clinical Trial ‘429 by substituting atacicept for the TACI-Ig fusion protein comprising a TACI extracellular domain fragment consisting of amino acids 71 to 104 (corresponding to the second cysteine rich domain of TACI) as taught by Del Rio et al. and Rixon et al. The person of ordinary skill in the art would have been motivated to make that modification and would have expected success because (i) human TACI only requires the second cysteine-rich domain, encompassing amino acids 71-104, to bind both APRIL and BAFF/BLyS with high affinity; (ii) the TACI alternative variant encompassing amino acids 71-104 has similar activity as full-length TACI (see Hymowitz et al., page 7219, column 1, 1st through 3rd full paragraphs; Figure 1A-1B; page 7220; Figure 2A-2B; page 7221, column 1, 1st full paragraph; page 7225, column 1, 3rd paragraph); and (iii) Rixon et al. also teach that the TACI-immunoglobulin fusion protein comprising TACI extracellular domain fragment amino acids 71 to 104 may be administered to a treat a subject with IgA nephropathy (page 44, lines 20-25). A person of ordinary skill in the art would have recognized the interchangeability of the TACI alternative variant encompassing amino acids 71-104 for the corresponding extracellular TACI sequence in atacicept that comprises a first Cys-rich repeat and a second Cys-rich repeat (amino acids 34-66 and 71-104 of instant SEQ ID NO: 11) of Clinical Trial ‘429. The substitution of one known element for another yields predictable results (see KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007)). A person of ordinary skill has good reason to pursue the known options within his or her grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense.
Additionally, although instant independent claims 1, 7, and 13 recite the additional limitations that administration of a fusion TACI-Ig molecule results in an at least 25% reduction in serum level of Gd-IgA1; results in an increase or a decrease by not more than 10% of eGFR; and results in an at least 25% reduction in urine protein:creatinine ratio, these activities would inherently occur in the prior art of Clinical Trial ‘429, Del Rio et al., and Rixon et al., absent evidence to the contrary (see Ex parte Novitski, 26 USPQ2d 1389 (BPAI 1993); see also Integra LifeSciences I Ltd. V. Merck KGaA, (DC SCalif) 50 USPQ2d 1846; In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977)). Additionally, the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable (In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977); In re May, 574 F.2d 1082, 1090, 197 USPQ 601, 607 (CCPA 1978)).
Conclusion
No claims are allowable.
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BEB
Art Unit 1647
15 December 2025
/BRIDGET E BUNNER/Primary Examiner, Art Unit 1647