DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Interpretation
The term “antibody” is defined in the specification as describing a type of immunoglobulin molecule, including intact antibodies and antibody fragments ([0022]). “An “immunoglobulin” refers to a class of structurally related proteins generally comprising two pairs of polypeptide chains: one pair of light (L) chains and one pair of heavy (H) chains.” ([0021]). Therefore, it reasonably appears an “antibody as used in the instant claims refers generally to an antigen-binding immunoglobulin or fragment thereof, but does not include antigen-binding molecules comprising the CDR-H1-3 and CDR-L1-3 that are not within respectively a variable heavy (VH) and variable light (VL) region or antigen-binding fragment thereof, i.e., wherein the CDRs are not within non-immunoglobulin-derived framework regions. This is an important under 112(a), written description provision, because claim 1 does not recite that the antibody comprises a VH or VL and does not provide framework region sequences.
Drawings
The drawings were received on 12/10/2025. These drawings are accepted.
Response to Amendment
The rejection of claims 21, 25, 26, 30, 33 are 37 are moot in view of the cancelation of the claims.
The rejection of claims 36-38 under 35 USC 112(b) is withdrawn in view of the amendment deleting the word “conjugate”.
The rejection of claims 33-35 under 35 USC 112(b) is withdrawn in view of the amendment to claim 1 adding “or antibody fragment thereof” in line 1 and amendment to claim 35 to recite an antibody fragment.
The rejections under nonstatutory double patenting over claims of applications 17/608,100 and 17/608,097 are withdrawn in view of the abandonment of the previously copending applications.
The rejection of claims 3, 5, 7, 9, 11, 12, 13, 36 under 35 USC 112(a), written description provision, is withdrawn. Claim 3 depends from claim 2 and should not have been rejected. Claims 5, 7, 9, 11, 12, 13 and 42 had been canceled prior to the previous Office action and should not have been included in the rejection. The rejection of claim 36 depends from claim 1 and is withdrawn because it sets forth antibodies comprising specific heavy and light chain variable region CDR1-3 disclosed as specifically binding BCMA as set forth in Tables 11 and 13. The omission of claims 40-41 in the rejection was an obvious typographical error as acknowledge by Applicant in the response at the bottom of p. 30. The previous inclusion of claim 52 and 54 as being rejected was an obvious typographical error because they represent an invention withdrawn from examination.
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.
Claims 1, 27, 29, 31, 32, 34, 35, 39-41, 51 and 58 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 for the reasons set forth in the previous Office action and recast here to address the amendment to claim 1 further defining the CDR-L1-3 and groups of CDR-H1-3.
Claim 1 is drawn to an antibody that specifically binds BCMA and the structure of which is defined by consensus or variant (consensus) sequences of variable heavy region (VH) and variable light region (VL) CDR1-3. The claim has been amended such that the CDR-L1-3 have the respective sequences of SEQ ID NO:146, 155 and 161. However, there are still a number of variant CDR-H1-3 that may be mixed-and-matched. Consensus sequences of claim 1 for CDR-H3 are SEQ ID NO:248-251 (section 2.9.1 of the specification). Other specific CDR-H3 sequences of claim 1 are selected from SEQ ID NO:116-145. The sequences of SEQ ID NO:116-140 are 13 amino acids long, SEQ ID NO:141-142 are 12 amino acids long, SEQ ID NO:143 is 16 amino acids long, and SEQ ID NO:144-145 are 9 amino acids long. The elected CDRs sequences are CDR-H3 of SEQ ID NO:116, CDR-H2 of SEQ ID NO: 57 or 79, and CDR-H1 of SEQ ID NO:5 or 32, wherein the first of CDR-H2 and -H1 sequences are identified by Chothia numbering and the second by Kabat numbering. These sequences are encompassed by sections (a) and (e) of claim 1. The elected VH and VL are respectively SEQ ID NO:167 and 217. The elected sequences are comprised by the VH of section (i) of claim 36, the VL of section (a) of claim 37, and VH and VL of section (i) of claim 38.
The elected antibody, 2137-C07, was identified by screening a human Fab ribosomal display library first for identification of antibody leads, including of the 2137 family [00349]-[00350]. Antibody 2137-C07 has the VH sequence of SEQ ID NO:167. VH of other antibodies were obtained using this method or by phage display human Fab libraries followed by affinity maturation ([0348]). The libraries used an optimized trastuzumab Fab sequence, of which the VL sequence is SEQ ID NO:217 and which is used in all 29 antibodies identified by the above screenings (VH of SEQ ID NO:167-195, Table 5). Trastuzumab is a humanized antibody. Separately, different chicken and chicken humanized antibodies were made, each of which has a different VH and VL (Table 6 and [00351]-[00352]).
The full genus of antibodies encompassed by the consensus sequences are not supported by the limited disclosure of species, of which 29 antibodies isolated from ribosome and phage-display are disclosed (e.g. Tables 7A-7B and 8A-8B). For claim 1 section (a), which comprises the elected species, there are 96 possible CDR-H3 sequences. The number of possible antibodies with the possible combinations of CDR-H1-3 consensus sequences of claim 1(a) is 19,200. Note the only disclosed antibodies meeting the sequence limitations of claim 1(a) are the first 13 antibodies listed in Tables 11 and 13 (see also Table 7B), but the genus encompassed is much larger. The claimed combinations of amino acids must specifically bind BCMA, defined in [0044] as binding that is “measurably different from a non-specific or non-selective interaction.” It is unknow which antibodies beside those disclosed in Table 10 specifically bind BCMA.
It remains that for an antibody, 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 the 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. 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 Chen et al. (EMBO J. 14 (12): 2784-2794, 1995, cited in the IDS filed 4/17/2024), which teaches that the substitution of a single amino acid in CDR-H2 of an antibody can totally ablate antigen binding and that the same substitution in closely related antibodies can have opposite effects on binding (e.g., see entire document, including Figure 1). The authors compared the effects of identical substitutions in related anti-phosphocholine antibodies DI6 and TI5, and as shown in Figure 3, some substitutions increased antigen binding in one antibody while ablating it in the other. While other amino acid changes in antibodies produced only small or insignificant changes in binding affinity, the complexity of antigen binding and affinity by antibodies is high. Even though there are some publications which acknowledge that CDR-H3 is important, the conformations of other CDRs as well as FRs influence binding. There is no information in the specification about which amino acids of the CDRs and/or FRs are necessary and/or sufficient for specific BCMA binding other than that based on the CDR consensus sequences broadly represented by claim 1 that is based generally on Figs. 2-3 (see also Tables 5 and 6). Fig. 4 shows the VL sequence for trastuzumab (SEQ ID NO:217), which is paired with all VHs identified from the ribosome and phage display libraries ([0365]; this excludes the chicken and humanized chicken VH-VL pairing shown in Table 6). The only disclosed antibodies comprising the consensus sequence of SEQ ID NO:248 are those having a CDR-H3 sequence of SEQ ID NO:116-126, even though there are 96 possible CDR-H3 sequences from the consensus.
Further, it has been shown that the pairing of variable heavy and light chain regions is not random, and only specific pairs of VH and VL bind a designated antigen. Herold et al. (Scientific Reports, 7:12276, DOI:10.1038/s41598-017-12519-9, Sept. 2017, cited in the IDS filed 4/25/2024), showed by mutating conserved regions of VH and VL, almost all VH mutants led to decreased antigen-binding affinity, while the VL was more permissive (p. 4, 2nd and 3rd paragraphs). However, when CDR regions were switched between variable domains, it was found that for the VH binding to antigen not only the CDRs but framework regions were also a determining factor (p 9, 6th paragraph). Also, the interaction between the VH and VL was found to be important as shown by when the VL was absent, the antigen binding loop VH:93-107 showed large fluctuations. “Hence, complex formation of the VL and VH domains appears to lock some of the antigen binding loops into distinct conformations.” (p. 11, first paragraph) It was discussed that (p. 11, start of 3rd paragraph), “The relationship between structure, stability and binding affinity of VH and VL is still unclear. This is an important aspect for understanding antibody architecture both as the basis of our immune system and also in the context of the engineering of antibodies for therapeutic purposes. In this context, it was found that in mutants an increase in affinity is often accompanied by a decrease in stability and vice versa - and these consequences are difficult to predict33–39.” Further (p. 13, start of last paragraph), “It seems that during antibody biogenesis the effect of CDRs on the stability of VH domains is a decisive, so far underappreciated factor…. The grafting constructs revealed that CDRs, in addition to antigen binding, affect variable domain structure strongly.” The reference concludes (p. 14, end of 2nd paragraph and 3rd paragraph), “[B]inding to the antigen is affected by each CDR loop differently and changes in loop mobility can in principle affect antigen binding affinity in an unpredictable way. (¶) Taken together our data indicate that multiple determinants regulate the VH/VL association and the affinity for the antigen. The interplay between interface interactions and CDRs turned out to be complex with mutual influences on VH/VL association and antigen binding.” The limited disclosure of specific functional embodiments encompassed by the claims and evidence in the prior art that the effect of amino acid substitutions in CDRs does not allow the skilled artisan to readily envision a representative number of antibody species to support the broad genus encompassed by the claims, nor does it appear the inventors were in possession of the broadly claimed genus. Even assuming the VL had the sequence of SEQ ID NO:217, the variability encompassed by the claims would not allow the skilled artisan to predict which of the many possible VH would specifically bind BCMA as required by the claims.
This is in line with the teachings of Lamminmaki et al. (J. Biol. Chem. 276:36687, 2001, cited in the IDS filed 4/17/2024) which showed with the crystallographic structure of an anti-estradiol antibody complex that although CDR-H3 played a predominant role in antibody binding, all CDRs in the light chain made direct contact with the antigen, with CDR-L2 also functioning to stabilize CDR-H3 (p. 36693, col. 2, first two paragraphs). MacCallum et al. (J. Mol. Biol 262:732, 1996, cited in the IDS filed 4/17/2024) analyzed a variety of antibodies for their interaction with their antigen and found that although CDR-H3 of the variable heavy chain dominated the interaction, a number of residues outside the CDRs make antigen contact and residues in the CDR which do not contact antigen are important for backbone conformations (e.g., p. 733, section beginning at the end of col. 1, and p. 735, paragraph bridging cols. 1-2). For larger antigens, such as proteins like BCMA, most of CDR-L2 and several residues of CDR-H1 and CDR-L3 typically make contact (p. 733, last paragraph). It is concluded (p. 742, col. 2, middle of second paragraph), “Antigens tend to bind to the antibody residues located at the centre of the combining site where the six CDRs meet….” The heavy chain CDR3 of Claim 1(a) encompasses 96 possible CDR-H3 sequences, and taking into account the encompassed CDR-H1 and -H2 sequences and possible combinations of the different CDR-H1-3, that amounts to 19,200 possible CDR-H1-3 combinations meeting the structural limitations for claim 1, section (a), of which only 13 have been shown to specifically bind BCMA.
Additionally, claim 31 lacks written description for a human antibody. The elected antibody, 2137-C07, was identified by screening a Fab ribosomal display library first for identification of antibody leads, which were then affinity matured to generate further improved derivatives, including of the 2265 family ([00349]-[00350]). These libraries used an optimized trastuzumab Fab sequence, of which the VL of SEQ ID NO:217 was present in all 29 antibodies identified (VH of SEQ ID NO:167-195, Table 5). Trastuzumab is a humanized antibody. Separately, different chicken and chicken humanized antibodies were made, each of which has a different VH and VL (Table 6 and [00351]-[00352]). According to [0040] a “human antibody” has the sequence of an antibody produced by a human or human cell or is derived from a human antibody repertoire…. Human antibodies specifically exclude humanized antibodies.” As discussed in the specification in [00293], there are a variety of techniques known in the art to generate human antibodies; however, being able to make a human antibody is not the same as describing the antibody itself or as showing possession of a human antibody. Affinity maturation necessarily involves making changes in antigen-binding domains to improve their affinity. For ribosomal display, this routinely involves introducing mutations in the antigen-binding domains, e.g., the Fab domains, of a selected antibody lead(s) to display a variety of antigen-binding domains with sequences that are new but highly related to the sequences of the lead(s). Once a mutation is introduced into a human antibody, that antibody is no longer human. As defined by the specification, it is no longer a "human antibody" as defined [0040]. That is, it is not an antibody “which possesses an amino acid sequence corresponding to that of an antibody produced by a human or a human cell, or derived from a non-human source that utilizes a human antibody repertoire or human antibody-encoding sequences (e.g., obtained from human sources or designed de novo).” Even though the original lead antibodies are considered human, affinity maturation involves mutations that transform a “human antibody” into a nonhuman antibodv. The trastuzumab VL is not a human variable region. It does not reasonably appear that any human antibodies are disclosed, nor could the skilled artisan readily envision a human antibody as claimed (see claim 31).
Further, claims 39-41 require the antibodies to have the functional property of having a ka, kd and KD within a specified range (see Tables 7B and 8B). The data in Table 8 B, from which the numbers in amended claims 39-41 come, is for 16 antibodies analyzed by Biacore surface plasmon resonance. Claim 39 specifies the range for ka (1/Ms) is from 1.36x105 to 1.41x106 M-1 for association with human BCMA at 25˚C. This is the range between the highest and lowest ka for the tested antibodies. Claim 40 specifies the range of kd (1/s) is from 2.82x10-5 to 2.83x10-3 sec-1 for dissociation with human BCMA at 25˚C; although, the range between the lowest and highest kd is 9.65x10-5 to 2.83x10-3. Claim 41 specifies the range of kD (M) is from 4.38x10-11 to 2.36x10-9 M for binding with human BCMA at 25˚C; although, the range between the lowest to highest kD is 4.38x10-11 to 2.08x10-9. The values in Table 8B span a wider range than those of Table 7B, the values for 13 antibodies meeting the structural limitations of claim 1(a). Table 8B represents values from antibodies distinct from those of Table 7B. Regardless, it is maintained that one skilled in the art could not readily envisage a representative number of species encompassed by the large genus of antibodies comprising the CDR variant sequences that meet the biophysical properties set forth claims 39-41.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111 (Fed. Cir. 1991), 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.) 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).
With the exception of the antibody sequences identified in Tables 7B and 8B, with those from 7B meeting the structural limitations of claim 1(a), the skilled artisan cannot envision the detailed chemical structure of the encompassed antibodies, 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. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991).
Therefore, only an antibody or antigen-binding fragment thereof that binds BCMA and comprises a variable heavy chain (VH) comprising CDR-H1 of SEQ ID NO:5 or 32, CDR-H2 comprising SEQ ID NO:57 or 79, and CDR-H3 of SEQ ID NO:116, and a variable light chain (VL) comprising CDR-L1-3 comprising SEQ ID NO:146, 155 and 161, respectively, or wherein the VH comprises SEQ ID NO:167 and the VL comprises SEQ ID NO:217, as elected, or wherein the antibody has the CDR-H1-3 sequences of an antibody of Tables 11 and 13 of the specification, including having CDR-L1-3 of SEQ ID NO:217 but not the full breadth of the claim meets the written description provision of 35 U.S.C. § 112, 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).
Applicant argues (section bridging pp. 26-27 of REMARKS) instant claim 1 has been amended to be limited to VH consensus sequences of antibodies 2137, 2265, 2190, 2290, 2213 and 2291 paired with the Trastuzumab VL CDRs. Additionally, specific pairings of CDR sequences have been specified as set forth in SEQ ID NO:248, 258 and 254 in the claim. Therefore, there is no “mixing and matching” of consensus sequences in claim 1. The argument has been fully considered but is not persuasive. Claim 1 now recites 4 different CDR-H1-3 consensus sequence groups. For the first group, section (a) of claim 1, which comprises the elected antibody species with Chothia CDR numbering, this elected VH species having CDR-H3 of SEQ ID NO:116, CDR-H2 of SEQ ID NO:5 and CDR-H1 of SEQ ID NO:57 is one of 19,200 possible VH sequence, looking only at all the combinations of encompassed CDRs. This is mixing and matching with the VH, even if the VL is common. The recited CDR-H3 alone has 96 possible sequences (D-α2-α3- α4-α5-Y-W-T-Y-V-L-D-Y, where α2 is Y or F; α3 is V or I; α4 is Y, L, N, R, Q, or P; and α5 is Q, A, N, or S). Of the disclosed antibodies, only 13 meet the sequence limitations for the three CDR-Hs of claim 1(a) (see Tables 11 and 13, first 13 antibodies). It is not agreed that the skilled artisan would consider this a “representative number" of species sufficient to support the enormous genus of encompassed antibodies, particularly in view of the functional limitation(s) required by the claims. The possible combinations of CDR-H1-3 of claim 1 provides in essence a ‘laundry list’ of species without a disclosure of which would reasonably lead the skilled artisan to any particular species aside from the disclosed 13 which have the required functional limitation. The skilled artisan could not immediately envisage a representative number of those encompassed which specifically bound BCMA.
“Applicant submits that a person of skill would recognize that the consensus sequences in claim 1 do not have significant variability and are sufficiently represented by numerous antibodies species described in the specification as filed.” (p. 27, beginning second full paragraph, through first full paragraph of p. 28 of REMARKS) Ariad Pharms., Inc. v. Eli Lilly & Co. (Fed. Cir. 2020) is cited for the holding that “a sufficient description of a genus instead requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can [']visualize or recognize['] the members of the genus." MPEP 2163(II)(A)(3)(a)(ii) and Regents of the Univ. of Calif. v. Eli Lilly & Co (Fed. Cir. 1997) are also cited as related to written description. The argument has been fully considered but is not persuasive. While the case law is agreed with, it is not agreed that the instant specification has disclosed either a representative number of species having structural features common to the members of the genus so that one skilled in the art can visualize or recognize the members of the genus. Claim 1 is not drawn to a protein without function. It is drawn to an antibody of the IgG class or antibody fragment thereof that specifically binds to BCMA (see [0044]). While applicant has shown a variety of antibodies with a common VL of SEQ ID NO:217, it is not agreed that these are a representative number to support the enormous variety actually encompassed by the claims. For example, the only 13 antibodies are disclosed which comprise one of the possible CDR-H1-3 sequence combinations of section (a) of claim 1, while there are 96 possible sequences (just over 13% of the possible combinations). While one skilled in the art might expect that some or maybe even a majority of these combinations could function in a VH configuration within framework regions (which are not specified in the claim) with the VL to form an antigen-binding region that specifically binds BCMA, it is not agreed the skilled artisan could readily envision which of the 19,200 possible combinations could. There are only 29 antibodies isolated from the ribosome and phage-display libraries (Tables 11 and 13). The consensus sequences of claim 1(a)-(d) (Chothia numbering system) and (e)-(h) (Kabat numbering system) encompass these and thousands more. Kunik et al. (Prot. Eng. Design Selection, 26(10): 599–609, June 10, 2013) examined distinct antibody-antigen-binding pairs to identify how antibodies have specificity for antigen epitopes. They found (p. 607, first paragraph) that “[E]ach ABR [antibody binding region] tends to bind different types of amino acids.” “In summary, we have shown that ABRs different significantly from each other in length, number of Ag [antigen] residues they bind, amino acid compositions, amino acid contact preferences and the energetic contribution of Ag binding. H2, and not only H3, takes on a key role in Ag binding. Moreover, by combining the distinct binding preferences of the ABRs, Abs are capable of recognizing indistinct patches on the surface of Ags.” (p. 608, col.1, second paragraph) Kunik et al. is in agreement with Chen et al. (1995) and Herold et al. (2017), cited in the rejection, discussing the specificity of CDRs in the binding of an antigen. Note in Chen (Fig. 1), even mutants with what instant Table 2 lists as a “conservative substitution” caused a significant change in binding to respectively T15 and D16 (e.g., N53S, M135, decreased binding v. comparable to wildtype; A61G, M107, and V63A, M72, wildtype binding v. increased binding; E58Q, M161, wildtype binding v. no detectable binding; see also Fig. 3 of Chen). This supports the lack of written description for the large genus of antibodies in view of the few disclosed species.
The MPEP citation by Applicant discusses that a representative number of species to support a genus depends on whether the inventor was in possession of the necessary common attributes or features possessed by the members of the genus in view of the disclosed species. In this instance, there are 19,200 species of VH based on possible CDR-H sequences without regard to VH or VL framework sequences. The Regents of the Univ. of Calif. case as state in Applicant’s response (paragraph bridging pp. 27-28) held that description of rat insulin cDNA was not sufficient for broad genus of human or mammalian DNA sequences. “[D]escription of one species of a genus is not necessarily a description of the genus.” (Id. at 1568) Note that this specifically relates to instant claim 31 drawn to an antibody of claim 1 that is human. There are no human antibodies disclosed. For claims 39-41, only 13 species of section (a) of claim 1 and an additional 16 of sections (b)-(d) have been shown to meet the limitations related to association, dissociation and/or affinity. Further, as discussed in the rejection, the prior art has shown that single amino acid changes can significantly change these parameters (see, e.g., Chen et al., EMBO J., 1995). It is additionally noted that the possible amino acids in claim 1(a) CDR-H3 position 4 are not all conservative substitutions as defined in instant Table 2; although, it is not that agreed that such a designation would necessarily mean one “conservative” amino acid could substitute for another while maintaining the necessary binding specificity and/or biophysical property(ies).
Applicant states (p. 28, third paragraph, through p. 29, second paragraph) that for claim 1(a) the CDR-H3 consensus sequence is recited and the four variable amino acids (α2- α5) are limited. The 96 possible combinations are not a significant number and thirteen species are described in the specification and are discernible from the recited consensus sequence. The argument has been fully considered but is not persuasive. The antibody of claim 1(a) is not limited to one in which there is variability only in CDR-H3 (96 encompassed species), but also includes species of CDR-H2 (4 species) and CDR-H1 (50 species), making a total of 19,200 combinations of encompassed antibodies comprising a CDR-H1, CDR-H2 and CDR-H3 variant of claim 1(a). Disclosure of 13 antibody species means that for claim 1(a) 0.6% of possible combinations have been disclosed, and this completely ignores framework regions, which were themselves specific to particular CDR-H1-3 combinations as presented in the Fab phage display and to which there are no limitations specified in the claim ([0348]). Even though there is some overlap between the CDR-H1-3 between the variants of (a)-(d) in claim one, there is enormous variability with relatively few species having been shown to have the required BCMA-binding specificity and for claims 39-41 further biophysical binding properties. It is maintained that the species disclosed are not sufficient to support the written description of the genus.
Applicant argues (p. 29, third paragraph) IgG class antibodies share common sequences and structural features, wherein minor changes would not affect the ability of antibodies to bind to antigens. “As an initial matter, for the reasons discussed above, the consensus sequences of claim 1 do not allow significant variability in the VH CDRs….” Each antibody is composed of a series of immunoglobulin domains with common structural features (citing Janeway, 2001). It was well known that antibodies have 4 polypeptide chains: 2 light and two heavy chains.
The heavy chain has at least 3 constant domains and one variable domain. The light chain has one constant and one variable domain. “The constant domains are so similar they can only be recognized by sequence alignment. In fact, antibodies within a class and species have the same constant domains. Within the variable domains, there are regions of hypervariability, known as the complementarity-determining regions (CDRs), and intervening framework residues. The CDRs form the antigen-binding site of the antibody and vary greatly from antibody to antibody. The framework residues are largely invariant and form about 85% of the variable region.
Therefore, Applicant submits that a person of skill would recognize that antibodies of the IgG class have a conserved structural framework wherein minor changes would not affect the ability of antibodies to bind to antigens. [top of p. 30 of REMARKS]
The argument has been fully considered but is not persuasive. For example, Irani et al. (Mol. Immunol. 67:171-182, 2015) showed the sequence differences in the four IgG subtypes, 1-4 (Fig. 3D), as well as differences between allotypes of different subtypes in Fig. 1A). Different subtypes have different half-lives, with IgG3 having the shortest (p. 175, col. 1, first full paragraph). Further, different subtypes have different binding affinities to Fcγ receptors, for example, IgG3 having the highest affinity for FcγRIIIa (the major receptor involved in antibody-dependent cellular cytotoxicity) (paragraph bridging pp. 172-174). It is also discussed that different allotypes of therapeutic antibodies (ThAb) have been suggested to contribute to therapy resistance associated with anti-ThAb immune and have been associated with enhanced protection against certain diseases (p. 175, last paragraph of col. 1). Note that the claims are drawn to an antibody of the IgG class or antibody fragment thereof. As a result, the recited antibody fragment is not required to have any constant regions, e.g., scFv (see claim 34).
Applicant argues that claims 39-41 have been amended to recite the ranges within Table 8B which encompass the antibodies of claim 1. Therefore, the rejection should be withdrawn. The argument has been fully considered but is not persuasive. For the reasons discussed above the full breadth of antibodies of the claim 1 is not supported by written description. Even though claim 1 has been amended to more specifically claim the encompassed antibodies, the specification still does not satisfy the requirements for written description under 112(a). Claims 39-41 provide further limitations, for which the specification only discloses 29 antibodies meet (13 for section (a) of claim 1). Again, out of the thousands of antibodies or antigen-binding fragments thereof of the claims, the skilled artisan could not readily envision those antibodies which would have these further biophysical properties. It does not appear the inventors were in possession of the full breadth of antibodies or antigen-binding fragments thereof encompassed by the claims.
Allowable Subject Matter
Claims 2, 3, 35 and 38 as they are drawn to the elected species are objected to as being dependent upon a rejected base claim, but would be allowable for the elected species if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Note that as indicate in the previous Office action under Prior Art (p. 17), it remains that US Patent 11,993,658 B2 issued from an application of which the instant application is divisional. It claims what is currently a non-elected species of BCMA antibody (2265-F02). Were this species to be examined in the current application, this would necessitate a rejection under nonstatutory double patenting over the claims of the patent.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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Claire Kaufman
/CLAIRE KAUFMAN/Primary Examiner, Art Unit 1674 March 10, 2026