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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 06/10/2026 has been entered.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
See line 3 of [00357], which recites “(GGGGS)n”.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Response to Amendment
The rejection of claim 31 is moot in view of the cancelation of the claim.
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, 32, 34, 35, 39-41, 51, 58 remain and new claims 59 and 61 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 as recast here to address the amendment to the claims and addition of new claims.
Claims 1, 58 and 61 are drawn to an antibody that specifically binds BCMA and the structure of which is recited as a combination of defined consensus sequences of variable heavy region (VH) CDR sequences and defined variable light region (VL) CDR1-3. The claims recite the CDR-L1-3 have the respective sequences of SEQ ID NO:146, 155 and 161. Consensus sequences of claim 1 for CDR-H3 is SEQ ID NO:248 with CDR-H1 is ζ1-ζ2-G-I-H wherein ζ1 is G, Y A, V or R and ζ2 is S or P (section 2.9.1 of the specification). For claim 59, the CDRs are each defined by a specific sequence except CDR-H1, which has the consensus sequence of the preceding sentence. For claim 61, the CDRs are limited to a specific sequence except CDR-H2, which has the consensus sequence of SEQ ID NO: 264 and CDR-H1 as set forth above. 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. The elected VH and VL are respectively SEQ ID NO:167 and 217.
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 or ribosome display and followed in some cases by affinity maturation ([0348]-[0349]). The libraries used an optimized trastuzumab Fab sequence for the VL sequence of SEQ ID NO:217 and which was 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. There are two disclosed antibodies having the CDR-H3 of SEQ ID NO:116, i.e., 2137-C07 and 2265-E02, and the same two antibodies have the CDR-H2 of SEQ ID NO:79 (Table 10). These antibodies have different CDR-H1 sequences, with 2137-C07 CDR-H1 being SEQ ID NO:32/5, which is not found in any other disclosed antibody. The possible encompassed antibody species are based only on CDRs, completely ignore framework regions, for claim 1 is 106, for claim 59 is 10 antibodies and for claim 61 is 18 possible antibodies based on the consensus sequences of the claims. However, for claim 1 there are only 13 disclosed antibodies meeting the structural limitations. Claim 59 has only 1 disclosed antibody meeting the limitations. Claim 61 has 2 antibodies disclosed meeting the limitations. Additionally, 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. The disclosures does not allow the skilled artisan to immediately envisage which combinations of CDRs would have the functional properties required. Neither the specification nor the prior art taught either a genus or a representative species supporting the full genus meeting the structural and functional limitations of the claims.
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. 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….” US Patent US10,072,088 B2 (‘088) analyzed binding of BCMA to antibody BCMB69. It was found (col. 44, lines 33-34, and Fig. 2B) that “Residues from all CDRs except CDR-L1 contact BCMA.” The structural conformation of the BCMB69 antibody binding BCMA was analyzed and it was found “The heavy chain has twice the number of contacts with BCMA compared to the light chain and CDRs pack into a concave surface of BCMA, which has a chair-like structure, resulting in residues of CDR-L2, CDR-H1 and CDR-H3 contacting the “seat”, while residues of CDR-L3, CDR-H1-H3 contact the back (col. 53, lines 1-13). Note that the inventors of the patent further made 28 mutants based on computational assessment of post-translational modification motifs and aggregation risk of the unbound BCMB69 variable domain and rationally designed the antibody mutants (Example 7, col. 54, lines 24-35, and Table 7). Of these rationally designed antibody mutants, only 7 of the 28 bound BCMA-expressing cells (col. 63, lines 46-51, of Example 7). Chen et al., MacCallum et al. and US ‘088 show that importance of specific CDR sequence for antibody binding and specificity. They do not support the likelihood of mutating a CDR-H of an antibody without significant alteration of BCMA binding. In the instant specification, there is no information about which amino acids of the CDRs and/or FRs are necessary and/or sufficient for specific BCMA binding. The CDR consensus sequences are not based on actual antibody binding, but instead on generally common amino acids in CDRs found in a variety of distinct antibodies that is based generally on Figs. 2-3 (see also Table 5). 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). Further, the only disclosed antibodies comprising the CDR-H3 consensus sequence of SEQ ID NO:248 are those having a CDR-H3 sequence of SEQ ID NO:116-125, even though there are 96 possible CDR-H3 sequences from the consensus.
Additionally, 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. The heavy chain CDR3 of claims 59 and 61, SEQ ID NO:116, is present in only two BCMA-binding antibodies. Also, there is no showing that, for example, the CDR-H2 from one antibody can be substituted into another or support for the ability of amino acids therein to be changed according to the consensus sequence in claim 61 with a reasonable expectation of specific binding to BCMA.
Further, claims 39-41 require the antibodies to have the functional property of having a ka, kd and KD within a specified range (see Table 7B). This is an even more stringent functional requirement than specific binding to BCMA. The data in Table 7B, 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) for association with human BCMA at 25˚C, which represents the range between the one of the highest and lowest ka for the tested antibodies. Claim 40 specifies the range of kd (1/s) for dissociation with human BCMA at 25˚C, representing the range between the lowest and highest kd. Likewise, claim 41 specifies the range of kD (M) for binding with human BCMA at 25˚C, representing the range between the lowest to highest KD. It is maintained that one skilled in the art could not readily envisage a representative number of species encompassed by the genus of antibodies comprising the CDR variant sequences that meet the biophysical properties set forth claims 39-41.
It is stated in AbbVie Deustschland GmbH v. Janssen Biotechnology, Ltd., 111 USPQ 1780, 1789 (759 F.3d 1285, 1298), (Fed. Cir. 2014) discussing Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005) that “When a patent claims a genus using functional language to define a desired result, the specification must demonstrate that the applicant has made a generic invention that achieves the claimed results and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus." Again in AbbVie at 1788, reiterating Enzo Biochem., Inc., 323 F.3d at 964, “It is true that functionally defined claims can meet the written description requirement if a reasonable structure-function correlation is established, whether by the inventor as described in the specification or known in the art at the time of the filing date…” However, no reasonably structure-function correlation has been established. For claim 1 as amended, section (e) is the only remaining section and in it, there are still 96 possible CDR-H3 sequences as well as 10 possible CDR-H1. That results in a total of 106 possible VH antibody sequences. While a variety of distinct antibodies have been disclosed, only 13 meet the limitations of the claim. For claims 59 and 61, only sets of VH CDR1-3 of two antibodies having the required functional characteristics has been disclosed. No further variants thereof that meet the structural limitations of the claims have been shown to specifically bind BCMA as part of an IgG antibody.
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, 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 one of the first 13 antibodies 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 (p. 16, second paragraph of REMARKS) that for written description, possession may be shown in a variety of ways. This includes not only reduction to practice but “by showing the invention was “ready for patenting” such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show the applicant was in possession of the claimed invention.” (case law cited) Possession may also be shown “by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, such as functional characteristics coupled with a known disclosed correction between the function and structure amount others. See M.P.E.P. 2163(l), citing Enzo Biochem, Inc. v. Gen-Probe, Inc….(Fed. Cir. 2002).” The Office alleges that for claim 1(a) alone there are 96 possible CDR-H3 sequences. The argument has been fully considered but is not persuasive. No structure-function correlation has been shown. For claim 1 as amended, section (e) is the only remaining section and in it, there are still 96 possible CDR-H3 sequences as well as 10 possible CDR-H1. That results in a total of 106 possible VH antibody sequences. While a variety of distinct antibodies have been disclosed, only 13 meet the limitations of the claim. For claims 59 and 60, only sets of VH CDR1-3 of two antibodies having the required functional characteristics has been disclosed. No further variants thereof that meet the structural limitations of the claims have been shown to specifically bind BCMA as part of an IgG antibody. Further, the claims are silent with respect to the framework regions, which have been shown to impact antigen binding (see, e.g., MacCallum et al. above). Even looking only at VH CDR regions, Adams et al. (eLife, 5:e23156, 2016) used an experimental approach focusing on antibody regions CDR-H1 (CDR1H) and CDR-H3 (CDR3H) of a well-studied single chain variable fragment (scFv) antibody to determine the effect of amino acid substitutions, noting that these CDRs were known to be important in antigen recognition by this antibody (p. 3, 3rd paragraph). As stated in the beginning of the Abstract, “Despite the central role that antibodies play in the adaptive immune system and in biotechnology, much remains unknown about the quantitative relationship between an antibody’s amino acid sequence and its antigen binding affinity.” Also (p. 15, 3rd full paragraph), “We wish to emphasize, more generally, that changing a protein’s amino acid sequence can be expected to change multiple biochemical properties of that protein. Our work illustrates the importance of designing massively parallel assays that can disentangle these effects.” The work suggested that CDR1H might be evolutionarily optimized to help ensure antibody stability, while CDR3H is more responsible for affinity (p.15, 4th full paragraph). “When a patent claims a genus using functional language to define a desired result, the specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus" (Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005)) (emphasis added). MPEP 2164.03 in discussing enablement states, “The “predictability or lack thereof” in the art refers to the ability of one skilled in the art to extrapolate the disclosed or known results to the claimed invention. If one skilled in the art can readily anticipate the effect of a change within the subject matter to which the claimed invention pertains, then there is predictability in the art.” The prior art of Adams et al., Herold et al., and Chen et al. supports that antibody changes are unpredictable. This supports the difficulty of the skilled artisan to be able to readily envision a representative number of species to support the claimed genus, that is species which are adequately described are representative of the entire genus. Again, in this instant there is a single species that is adequately described. While there are consensus-type sequences disclosed with a limited number of amino acid substitutions, which of these substituted sequences will produce an antibody binding domain that in the context of an IgG antibody can specifically bind BCMA is not disclosed. No structure-function correlation has been established to support the genus of claimed antibodies.
Applicant argues (bottom of p. 16) that the amended claims recite consensus sequences that “do not have significant variability and are sufficiently represented by numerous antibodies species described in the specification as filed.” Ariad Pharms., Inc. c. Eli Lily & Co. is cited to support this. What a “representative number od species” means is discussed, quoting AbbVie Deutschlund GmbH & Co. KG v. Janssen Biothec, Inc. (Fed. Cir. 2014), stating “Thus where there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.” (see also MPEP § 2163(II)(A)(3)(a)(ii)) The argument has been fully considered but is not persuasive. The case law is acknowledged. There are two antibody which have the CDR-H3 of SEQ ID NO:116, which is common to new claims 59-62. Further, they comprise the same CDR-H2 and different CDR-H1, each of which CDR-H1 is not found in any other of the disclosed antibodies. While antibodies that bind BCMA are described, a variety representing the claimed genus is not. 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, only 13 antibodies are disclosed which comprise one of the possible CDR-H1-3 sequence combinations of section of claim 1, while there are 96 possible sequences (just over 13% of the possible combinations). 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). In addition to the teachings of MacCallum et al. discussed above, Kunik et al. (PLoS Computational Biology, 8(2): e1002388, 2012, cited in the PTO-892 mailed 3/12/2026, Abstract) also found “Analyzing the predicted contribution of antigen binding residues to the stability of the antibody-antigen complex, we show that residues that fall outside of the traditionally defined CDRs are at least as important to antigen binding as residues within the CDRs, and in some cases, they are even more important energetically.” It is noted that were the claims limited to wherein the antibody comprised the full VL and VH (e.g., claims 42 and 43), then the antibody would be expected to inherently specifically bind BCMA. The prior art supports the lack of written description for the genus of antibodies in view of the relatively few disclosed species.
Applicant argues in the section bridging pp. 17-18 that the number of possible combinations of CDR-H3, CDR-H2 and CDR-H1 have been substantially limited, particularly in view of the fully defined sequence of CDR-H3. Therefore the consensus sequences in claim 1 do not have significant variability and are sufficiently represented by disclosed antibodies. Applicant points to Tables 7A and 7B sowing thermostabilities, with antibodies having high specific binding affinities for both cynomolgus and human BCMA cells, as well as the ability to internalize when conjugated to drugs. Table 7B shows by BiacoreTM assay the binding to human BCMA is high. The argument has been fully considered but is not persuasive. The results of Tables 7A and 7B are for 13 different antibodies, which, while they do meet the structural and functional limitations of claim 1, are less than 1/3 of the total possible antibodies encompassed by the claims. Even with limited variability of CDR sequences, i) there are no framework sequences recited, which have been shown to contact the antigen and influence antibody confirmation that allow for antigen binding (see, e.g., MacCallum and Herold), and ii) inferring function from structure of an antibody variant is unpredictable. This is shown by US Patent US10,072,088 B2 (‘088, col. 44, lines 33-34, and Fig. 2B) which found that for a BCMA antibody, BCMB69, “Residues from all CDRs except CDR-L1 contact BCMA.” Further analysis of the antibody-antigen interaction showed, “The heavy chain has twice the number of contacts with BCMA compared to the light chain.” Also, CDRs pack into a concave surface of BCMA, which has a chair-like structure, resulting in residues of CDR-L2, CDR-H1 and CDR-H3 contacting the “seat”, while residues of CDR-L3, CDR-H1-H3 contact the back (col. 53, lines 1-13). The inventors of the patent made 28 rationally designed antibody mutants based on computational assessment of post-translational modification motifs and aggregation risk of the unbound BCMB69 variable domain (Example 7, col. 54, lines 24-35, and Table 7). Of these rationally designed antibody mutants, only 7 of the 28 bound BCMA-expressing cells (col. 63, lines 46-51, of Example 7). Again, this shows the unpredictability of CDR modifications and the structural complexity involved in BCMA binding by an antibody. Also, amino acids outside the CDRs have been shown to be important for affinity and stability as supported by the prior art discussed above.
Applicant argues (p. 19 through top of p. 20) that the skilled artisan would recognize species encompassed by the amended claims. As discussed in Lilly, even though the specification disclosed only rat cDNA, there was sufficient written description for the broad genus of human or mammalian DNA. The Court distinguished genetic material from chemical material and that for genes, the function of a gene does not serve to define structural features of the genus of genes. In contrast, for chemical materials, generic formulae usually indicate what specifically the generic claims encompass. In the instant case, “a person of skill in the art would recognize the currently amended claims define structural features commonly possessed by members of the genus that distinguish them from others.” For example, each independent claim comprises at least one fully defined CDR-H, with consensus sequences defining the remaining CDR-H(s). Therefore, the antibodies of these claims have defined structures that satisfy the written description requirement. The argument has been fully considered but is not persuasive. The instant antibodies are not naturally occurring genes, but were isolated from ribosomal and phage display libraries, and are not chemical materials that have a set formula with variances that do not alter the defining function of the chemical. For example, in the situation of Harnish (631 F.2d at 718, 206 USPQ at 302), the common chemical structure was a dye, coumarin, and coumarin derivatives useful as dyes were found to represent a proper Markush group because even though the dyes encompassed different derivatives, they all shared a coumarin group which was sufficient to impart the property of being a dye. However, in the instant case, the different species of antibodies do not all share a particular sequence the provides the particular use. Instead the CDRs work together with the intervening framework regions to bind and stabilize binding to an antigen, and each antibody is structurally different (see Table 11). Similarly, in In re Jones at 481 (CCPA 1947), all the chemicals of the Markush group required a tetralyl nucleus with a methyl side chain at position 6. This describes a very particular structure which itself provides the growth regulating function required by the claims. The common chemical, to which the case law is directed, determined the particular activity; however, the instant specification has not disclosed which amino acids of the VH CDRs are required for specific binding to BCMA and which can be varied within the limitations of the claims while retaining the required function. It is not merely a matter of being able to make and/or list all possible VH CDR sequence combinations encompassed, but to be able to readily envision or identify without making and testing those which meet the function limitation in the claim as well. As discussed above, the nuances of antibody-antigen binding as they relate to changes in CDR sequences are not predictable.
Applicant argues (p. 20 through top of p. 21) IgG antibodies have a conserved structural framework and would be recognized as sharing common sequences and features, where minor changes do not affect the ability of antibodies to bind to antigens. As the claims have been amended, significant structural variability is not allowed in the VH CDRs and minor changes would not affect the ability of the antibodies to bind antigen. Janeway et al. (2001) is cited as showing the general conserved structure of immunoglobulins and the ability to identify variable regions and their parts, e.g., according to numbering systems. Antibody constant domains of the same isotype have the same sequence. Within the variable domains, “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 the antibodies to bind antigen.” (bottom of p. 20 through top of p. 21 of Remarks) The argument has been fully considered but is not persuasive. Even assuming conserved IgG framework regions, the prior art shows the CDRs are critical for antigen binding (e.g., MacCallum et al. and US ‘088). The recited CDR-H3 of claim 1 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 independent claims 1, 59 and 61 (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. Further, there is no requirement that the Fc region and/or framework regions are from the same IgG subtype, only that the antibody is of the IgG class. The skilled artisan could not immediately envisage a representative number of species encompassed which specifically bound BCMA.
Applicant argues that claims 39-41 have been amended to recite the ranges within Tables 7B and 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 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 meeting the functional limitation of these claims (13 of which meeting the structural for section claim 1). Again, out of the about 100 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, 36, 38, 60 and 62 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.
Conclusion
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Claire Kaufman
/CLAIRE KAUFMAN/Primary Examiner, Art Unit 1674 September 10, 2026
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