DETAILED ACTION
Applicant’s amendment and response received on 10/16/25 has been entered. Claim 3 has been canceled. Claims 1, 4, 9, 12-17, 19-20, 22-23, 26-27, 29-31, 33-35, 37-38, and 40-46 are now pending in this application. Of these, claims 22-23, 26-27, 29-31, 33-35, and 40-46 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 3/26/25. Claims 1, 4, 9, 12-17, 19-20, and 37-38 are currently under examination. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . An action on the merits follows.
Those sections of Title 35, US code, not included in this action can be found in a previous office action.
Claim Rejections - 35 USC § 112
Pending claims 1, 4, 12-17, 19-20, and 37-38 remain 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. Note that claim 3, previously rejected, has been canceled. Applicant’s amendment to the claims and arguments have been fully considered but have not been found persuasive in overcoming the rejection for reasons of record as discussed in detail below.
The applicant has amended the claims to add the additional functional limitation that the argues that the antibody which binds to human or mouse TGF-beta3 does not recognize or bind human or mouse TGF-beta1 or TGF-beta2. The applicant argues that the claims as amended meet the written description requirement because the claimed antibodies are not solely defined by their functional activity but required specific heavy and light chain CDR1, 2, and 3 amino acid sequences. The applicant argues that the specification provides sufficient description of the genus of antibodies with these particular CDR sequences which have the recited functional properties of neutralizing the activity of TGF-beta3, and of not recognizing or binding to human or mouse TGF-beta1 or TGF-beta2. The applicant argues that the rejection of record supports their argument that it is well established that characterization and definition of an antibody by their heavy and light chain CDR1, CDR2, and CDR3 sequences is adequate to define a genus of antibodies because the rejection states on page 8 of the previous office action that “the art teaches that antibody specificity and binding to antigen epitopes is largely determined by complementarity determining regions (CDRs). There are 6 CDRs produced by the pairing of heavy and light chain variable regions in an intact antibody”. The applicant also argues that it is a standard practice and approach by Examiners to grant patents to monoclonal antibodies based their 6 CDR sequences only. The applicant further argues that the specification provides “numerous” full length heavy and light chain variable region antibody sequences which meet the limitations of claim 1, pointing to four specific variant antibodies designated 1901-A, B, C, and D, and therefore the claims meet the requirement for written description.
In response, the broadest claim, claim 1, recites an antibody which binds to human or mouse TGF-beta3 and which further has the functional properties of neutralizing the activity of TGF-beta3, and of not recognizing or binding to human or mouse TGF-beta1 or TGF-beta2, where the antibody is limited to a structure which comprises a heavy chain variable region comprising a heavy chain CDR1 sequence of SEQ ID NO:1, a CDR sequence of SEQ ID NO:34, and a CDR sequence of SEQ ID NO:35, and a light chain variable region comprising a light chain CDR1 sequence of SEQ ID NO:4, a CDR2 sequence of SEQ ID NO:5, and a CDR3 sequence of SEQ ID NO:33. Claim 1 as amended thus continues to encompass a genus of antibody defined only by the heavy and light chain CDRs, i.e. encompassing any framework sequences, and by the functional properties of TGF-beta3 binding and neutralization, and of not recognizing or binding to human or mouse TGF-beta1 or TGF-beta2. Claim 4 further limits the structure of the antibody of claim 1 by requiring that the heavy chain variable region comprises one of the sequence of SEQ ID NO:18, 19, or 36, or a variant with at least 90% amino acid identity to one of these sequences, OR one of the light chain variable sequences comprising the sequence of SEQ ID NOS 22 or 23, or a variant with at least 90% amino acid identity to one of these sequences, while retaining TGF-beta3 binding and neutralizing capacity. Thus, claim 4 continues to read broadly on a genus of anti-TGF-beta3 antibodies where the heavy and light chain CDRs are specifically defined and only the heavy chain OR light chain variable region sequence is limited to specific sequence or one with 90% sequence identity to one of those heavy or light chain sequences. Claim 12 further limits the structure of only the heavy chain of the antibody of claim 1, where the heavy chain the heavy chain variable region comprises one of the sequence of SEQ ID NO:18, 19, or 36, or a variant with at least 90% amino acid identity to one of these sequences. The genus of antibodies of claim 12 encompasses one of three specific heavy chains sequences or sequence with 90% sequence identity to one of those three sequences in combination with any light chain comprising the three identified light chain CDRs. Claim 13 depend on claim 12 and further limits the light chain to light chain variable sequences comprising the sequence of SEQ ID NOS 22 or 23, or a variant with at least 90% amino acid identity to one of these sequences. The genus of antibodies encompassed by claim 13 includes any combination of the 3 heavy chain sequences and 2 light chain sequences and any variants of any of these sequences with at least 90% amino acid identity. Thus, even the narrowest of the claims, claim 13, encompasses a large genus of antibodies with certain defined structural features and required functional properties. The broadest claim, claim 1, encompasses an extremely large genus of antibodies with specific functional properties whose heavy and light chains are only defined by their CDR sequences.
As discussed in the rejection of record, it is well established that conception of a chemical compound, in this case is antibody, requires that the inventor be able to define it so as to distinguish it from other materials, and to describe how to obtain it. See Oka, 849 F.2d at 583, 7 USPQ2d at 1171. Conception does not occur unless one has a mental picture of the structure of the chemical, or is able to define it by its method of preparation, its physical or chemical properties, or whatever characteristics sufficiently distinguish it. It is not sufficient to define it solely by its principal biological property, in this case binding to human or mouse TGF-beta3 and neutralizing the activity of TGF-beta3, because an alleged conception having no more specificity than that is simply a wish to know the identity of any material with that biological property. See also Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016, 1021 (Fed. Cir. 1991). While the specification does provide written description for four specific antibodies, each with a specific combination of heavy and light chain variable regions sequences with exhibit these specific properties, the specification does not provide sufficient written description for the genus of antibody heavy and light chain variable region sequences encompassed by the claims as described above which are capable of selective binding to human or mouse TGF-beta3, neutralization of TGF-beta3 activity, and lacking the ability to bind to human or mouse TGF-beta1 or TGF-beta2.
The specification teaches humanization of a specific mouse anti-TGF-beta3 antibody which was previously described in the prior- see WO/2016/201282 (2016), hereafter referred to as Van Snick et al.- and referred to as MTGF-beta3-19 antibody/MTGF-beta3-1901/Ab 1901 in the specification. The parent antibody was described as binding specifically to mouse and human TGF-beta3, which have identical amino acid sequence, without binding to TGF-beta1 or TGF-beta2, and with the further functional ability of neutralizing the activity of TGF beta3. The specification does not identify the antigenic peptide sequence present in mouse or human TGF-beta3 which is recognized by the parent Ab1901 antibody. The specification also does not describe the 3D or crystal structure of the antibody or identify key amino acid residues responsible for or impacting the binding of Ab1901 and TGF-beta3. The specification, in the absence of any structural data regarding key amino acid residues which are involved in and/or affect binding, describes a complicated process of humanization of this mouse antibody which involves both CDR/FR grafting and functional potency assay-driven sequence mutagenesis of both CDR and framework sequences. This process involved the initial identification of human VH and VL framework sequence for CDR grafting of the CDR sequences present in parent antibody Ab1901. The specification discloses that based on the IMGT reference directory of heavy and light chain sequences and further based on a proprietary internal IgM/D sequence database, IGHV1-69*08 and IGKV1-39*-01 was selected as the human base sequence for the murine CDRs. As applicant relied in part on proprietary information and does not describe the specific criteria for selection of these sequences, the specification does not provide sufficient description for alternative human framework sequence. Following the initial grafting, permutation libraries for CDR VH variants and CDR VL variants were constructed, again using proprietary information. These libraries were screened for CDR VH and VL variants. It is not clear whether the heavy and light chains obtained from these initial rounds of screening include the CDR sequences claimed in claim 1. The specification then teaches mutation of certain residues in the framework and in the CDR, including mutation of “human” residues or other “human” residues, and back-mutation of certain “human” residues for “mouse” residues. Based on this process, the specification describes four specific antibodies whose CDR sequences are derived from the CDR sequences present in the heavy and light chain variable regions of Ab1901 and whose framework sequences comprises human and mouse framework sequence. The four antibodies described by the specification are identified as 1901-1A, 1901-1B, 1901-1C, and 1901-1D. 1901-1A comprises a heavy chain variable region sequence as set forth in SEQ ID NO:18, and a light chain variable region sequence as set forth in SEQ ID NO:23. 1901-1B comprises a heavy chain variable region sequence as set forth in SEQ ID NO:19, and a light chain variable region sequence as set forth in SEQ ID NO:23. 1901-1C comprises a heavy chain variable region sequence as set forth in SEQ ID NO:18, and a light chain variable region sequence as set forth in SEQ ID NO:22. 1901-1D comprises a heavy chain variable region sequence as set forth in SEQ ID NO:19, and a light chain variable region sequence as set forth in SEQ ID NO:22. Note that SEQ ID NOS 18 and 19 differ in 3 framework amino acids at positions 38, 40, and 43, and SEQ ID NOS 22 and 23 differ in 2 framework amino acids at positions 42 and 43. All four of these antibodies share less than 90% amino acid identity to parental antibody Ab-1901. While the specification discloses that generation of several clonal libraries of heavy chain and light chains which were screened at different points of the humanization process, the specification does not describe any antibody comprising heavy or light chains comprising the modified CDRs recited in claim 1 other than the four antibodies discussed above, although it is noted that the specification does disclose on page 88 an additional variant antibody and VH sequence of SEQ ID NO:36, paired with the VL sequence of SEQ ID NO:22. The specification does not name this antibody or provide any data regarding its activity, but does state that this variant was tested for TGFb3 silencing in MLEC cells and found to be effective in neutralizing. While the specification does not clarify what has been neutralized, it would appear to be TGFb3. SEQ ID NO:36 differ by one mismatch at position 43 with SEQ ID NO:18 and by 2 positions, 38 and 40 with SEQ ID NO:19. Aside from these specific disclosures, the specification does not provide any data or any additional specific description of residues which can be modified in the framework sequences of any of the cloned heavy or light chain variable regions of the 5 antibodies without substantially affecting antibody structure and function, including antigen specificity for TGF-beta3 versus TGF-beta1 or TGF-beta2, or ability to neutralize TGF-beta3 activity. In the absence of any information as to the exact epitope bound by any of the 5 disclosed antibodies such as a defined epitope amino acid sequence or the location/positioning of the epitope residues within the TGF-beta3 protein, the specification fails to provide the requisite description of the genus of antibodies with the claimed functions of binding to TGF-beta3.
Applicant’s argument that the disclosure of the four antibodies 1901-1A, 1901-1B, 1901-1C, and 1901-1D, which exhibit the claimed functional properties and comprise the CDRs recited in the claims is sufficient to describe the entire genus of antibodies encompassed by the claims as discussed above is not found persuasive. It is first noted that applicant contention that it is the practice of the U.S. Patent and Trademark Office to issue claims to monoclonal antibodies defined solely by their six CDR sequences because there are examples of US Patents with such claims is not a compelling argument. There is no USPTO policy stating that any antibody which recites six heavy and light chain CDRs meets the written description requirement. It is USPTO policy, however, that each case is decided on its own merits. Furthermore, it is not agreed that it is well established in the prior art that characterization and definition of an antibody by their heavy and light chain CDR1, CDR2, and CDR3 sequences is adequate to define a genus of antibodies. The applicant points to page 8 of the previous office action which states that “the art teaches that antibody specificity and binding to antigen epitopes is largely determined by complementarity determining regions (CDRs). There are 6 CDRs produced by the pairing of heavy and light chain variable regions in an intact antibody” as alleged evidence that the examiner agrees with their assessment of the state of the prior art. However, this quote was taken out of context. The full text of rejection of record clearly shows that the examiner does not agree with applicant that the recitation of six CDR is sufficient to provide written description of a genus of antibodies, particularly antibodies with specific functional activities. The rejection of record actually stated that the prior art teaches that combinatorial diversity and somatic mutation during B cell development and maturation into antibody secreting cells contribute to the diversity of antibodies which are capable of recognizing a particular antigen epitope such that it is unlikely that any two antibodies which recognize the same antigen, or even the same antigen epitope would share the same amino acid or nucleic acid sequence. This is reflected in applicant’s sequence data of clones which bind to the TGF-beta3 capsid protein. At the time of filing, the art teaches that antibody specificity and binding to antigen epitopes is largely determined by complementarity determining regions (CDRs). Note that this sentence says “largely” not completely. The rejection then continues by stating, “[w]hile the heavy chain CDR3 region has been implicated as being crucial for defining antigen specificity of an antibody, the art teaches that both CDRs and framework regions (FRs) in the heavy and light chain also contribute to and affect antigen specificity and affinity. The prior art at the time of filing does not teach any specific TGF-beta3 binding motif or domain shared among all antibodies which bind to TGF-beta3, or any one particular epitope within TGF-beta3, nor does the prior art at the time of filing teach which specific residues at specific positions in the antibody heavy chain or light chain are either essential or non-essential to the binding of any and all antibodies. Instead, the prior art at the time of filing is replete with teachings that while the overall structure between antibodies is shared, the structure of the antigen binding region of an antibody and the residues involved in binding to its cognate antigen are unique to each antibody and can involve residues both within any one or all of the heavy and light chain CDRs and framework regions (see for example, Vajdos et al. (2002) J. Mol. Biol., Vol. 320, 415-428, Chen et al. (1992) J. Exp. Med., Vol. 176, 855-866, and Sela-Culang et al. (2013) Frontiers in Immunology, Vol. 4, pages 1-13). Vajdos et al. teaches that residues in both the CDRs and framework regions of antibodies can be important for antigen recognition and binding, and discloses attempts to identify key residues in the antigen binding site of the Fab2C4 antibody for its peptide epitope derived from the extracellular domain of the human oncogene ErbB2 (Vajdos et al., pages 416-418). Vajdos et al. teaches that two different mutagenesis strategies were used to identify key residues in peptide binding- shotgun alanine scanning mutagenesis and shotgun homolog-scanning mutagenesis- and report that the results of the two methods in combination three dimensional crystal structure of the Fab2C4 antibody provided distinct yet complementary view of key residues in binding between the antibody and antigen (Vajdos et al., page 417, Figure 1 and Table 2). As can be seen in Figure 1 of Vajdos, each method identified different key residues, with some overlap. Vajdos et al. states that key residues for binding are present in both the heavy and light chain and include both solvent exposed and buried residues, where the buried residues may act as essential scaffolding residues that maintain the structural integrity of the antigen binding site (Vajdos et al, page 423). Thus, Vajdos demonstrates that identification of key residues in an antibody that affect antigen binding and are not tolerant of modification, or which may only tolerate certain modifications, is a labor intensive process which cannot be predicted a priori. Chen et al. provides the results of random point mutation mutagenesis of the heavy chain CDR2 in the PC-specific T15 antibody and demonstrates that mutations in this CDR alone can abrogate binding and further that increasing the number of mutations within this one CDR results in a significant increase in non-binding mutants, from approximately 7% nonbinding mutants with 1 mutation to 58% nonbinding mutants with 2 mutations in HCDR2 (Chen et al., pages 855-859, Table 2). Chen et al. also demonstrated that mutations in at least 5 residues in this CDR2 were important in antigen binding (Chen et al., page 855). Thus, Chen et al., like Vajdos et al. demonstrates that mutations affecting antigen binding in antibody chains cannot be determined a priori, and further teaches that increasing the number of mutations within a CDR substantially increases the chances of generating a non-binding mutant. Sela-Culang et al., in a recent review of the structural basis of antibody-antigen recognition teaches that some off-CDR residues can contribute critically to the interaction of the antibody with antigen (Sela-Culang et al. (2013) Frontiers in Immunology, Vol. 4, pages 1-13, page 1). Sela-Culang et al. teaches that in some antibodies, framework residues contribute to the antigen binding site, and in other antibodies, the frame work residues affect the antigen binding site indirectly by shaping the antigen binding site (Sela-Culang et al., page 7). In fact, Sela-Culang et al. teaches that constructing an antibody using only the CDRs from an known antigen-specific antibody usually results in a significant drop or a complete loss of binding of the antibody to its antigen (Sela-Culang et al., page 7). Sela-Culang et al. further teaches that different CDR identification methods may often identify radically different stretches as “CDRs”, indicating that CDRs are not well defined and thus are not necessarily a good proxy for the binding site (Sela-Culang et al., page 8). Thus, Sela-Culang et al. provides additional evidence that the generation of mutants of a known antibody with known heavy and light chain sequences cannot be predicted a priori, including mutations within the framework regions of the antibody. Kim et al. further teaches that while humanization of therapeutic murine antibodies by CDR grafting is desired in order to limit human anti-mouse antibody (HAMA) responses, that such CDR grafting often decreases the binding affinity and specificity of the antibody because some framework residues directly contact with the antigen and/or support the conformation of the CDR loops (Kim et al. “Humanization by CDR Grafting and Specificity-Determining Residue Grafting” (2012) Patrick Chames (ed.), Antibody Engineering: Methods and Protocols, Second Edition, Methods in Molecular Biology, vol. 907, Chapter 13DOI 10.1007/978-1-61779-974-7_13, pages 237-245, see pages 237-238). Kim et al. further teaches that if the crystal structure of the antibody is known that specificity determining residues (SDRs) can be identified; but that ultimately, testing of modifications to the sequence is required to determine the affects of the modifications (Kim et al., pages 240-241). Kim et al. teaches that if the structure of the antibody is not available, panels of mutant antibodies must be screened to identify SDRs (Kim et al., page 241). Thus, Kim et al. teaches that even if the crystal structure of antibody and it cognate antigen are available, mutations must be screened for functional effects, as such functional effects cannot be reliably predicted. Therefore, the prior art at time of filing clearly teaches that the sequence of the heavy and light chain variable region of an antibody which binds to a specific protein or protein epitope cannot be predicted a priori, and further that even starting from a known antibody with binding for a particular antigen, the effects of the introduction of any one or more mutations into any one of the six CDR or the framework region of the antibody cannot be predicted from the sequence of the antibody alone. Applicant’s own working examples support the art-recognized need to for substantial amounts of screening to identify variant antibodies which retain the desired binding specificity and affinity. As discussed above, the applicant relied in part on proprietary information and screening to select base sequences which were then further modified and screened through multiple rounds, including following the initial grafting, the construction and screening of permutation libraries using proprietary information followed by the mutation of certain residues in the framework and in the CDR, including mutation of “human” residues or other “human” residues, and back-mutation of certain “human” residues for “mouse” residues. Based on this process, the specification describes four specific antibodies whose CDR sequences are derived from the CDR sequences present in the heavy and light chain variable regions of Ab1901 and whose framework sequences comprises human and mouse framework sequence. The four antibodies described by the specification are identified as 1901-1A, 1901-1B, 1901-1C, and 1901-1D. Thus, both the prior art and the working examples show that even where the six CDRs of an antibody with a desired specificity are known, the introduction of mutations in the framework can effect antigen binding specificity which cannot be predicted, particularly in the absence of a crystal structure or knowledge of all the residues both within the CDR and framework which contribute to antigen binding and specification. For this reason, both the prior art of record and the working examples teach the necessity of screening mutations to identify those which do not affect antigen binding and specificity. Applicant’s response does not acknowledge the evidence of record in the form of the teachings of Vajdos et al., Chen et al., Sela-Culang et al., and Kim et al. that residues outside of the CDRs are clearly important in antigen binding and specificity of an antibody and that the effects of mutations in the framework sequence of an antibody cannot be known a priori. As such, applicant’s argument that all that is required to define antibody binding and specificity to an antigen is the sequence of the six CDRs is not found persuasive.
As to the argument that the disclosure of 4 specific antibody variants, 1901-1A, 1901-1B, 1901-1C, and 1901-1D, is sufficient to describe the genus of antibodies claimed, this is not agreed. Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, clearly states that "applicant must convey with reasonable clarity to those skilled 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 claimed." (See page 1117). The instant 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). An applicant shows possession of the claimed invention by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention. Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997). Possession may also be shown in a variety of ways including description of an actual reduction to practice, or by showing that 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 that the applicant was in possession of the claimed invention. See, e.g., Pfaff v. Wells Elecs., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641, 1647 (1998); Regents of the University of California v. Eli Lilly, 119 F.3d 1559, 1568, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997); Amgen, Inc. v. Chugai Pharmaceutical, 927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991) (one must define a compound by "whatever characteristics sufficiently distinguish it"). The applicant has not provided any description or reduction to practice of the large genus of antibodies claimed which is capable of binding to human or mouse TGF-beta3 outside of 4 specific antibodies with specific heavy and light chain variable sequences. Note that the broadest claims as written read on thousands of antibodies. The specification further does not provide any description or reduction of practice for additional specific mutations within any of the 4 disclosed antibodies which can be effected without changing the binding specificity and/or affinity of the antibody to its epitope, particularly as no specific TGF-beta3 epitopes recognized by any of the antibody clones are disclosed in the specification. Therefore, conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. See Fiers v. Revel, 25 USPQ2d 1602 at 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. Thus, for the reasons outlined above, it is maintained that the claims do not meet the requirements for written description under 35 U.S.C. 112, first paragraph.
Pending claims 1, 4, 12-17, 19-20, and 37-38 remain rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, for scope of enablement. Note that claim 3, previously rejected, has been canceled. Applicant’s amendment to the claims and arguments have been fully considered but have not been found persuasive in overcoming the rejection for reasons of record as discussed in detail below.
The applicant argues that the specification provides ample guidance for making antibodies comprising the recited six CDRS which have the claimed functional properties and further provides four specific examples of antibodies, 1901-1A, 1901-1B, 1901-1C, and 1901-1D, which meet the claims limitations and have the functional properties of neutralizing the activity of TGF-beta3, and of not recognizing or binding to human or mouse TGF-beta1 or TGF-beta2. The applicant also argues that the experimentation to identify other antibodies which meet the claim requirements would not be undue and that therefore the claimed genus of antibodies is enabled.
In response, the rejection of record identified the following scope of enablement: the specification, while being enabling for the following antibodies: 1) 1901-1A which comprises a heavy chain variable region sequence as set forth in SEQ ID NO:18, and a light chain variable region sequence as set forth in SEQ ID NO:23, 2) 1901-1B which comprises a heavy chain variable region sequence as set forth in SEQ ID NO:19, and a light chain variable region sequence as set forth in SEQ ID NO:23, 3) 1901-1C which comprises a heavy chain variable region sequence as set forth in SEQ ID NO:18, and a light chain variable region sequence as set forth in SEQ ID NO:22, 4) 1901-1D which comprises a heavy chain variable region sequence as set forth in SEQ ID NO:19, and a light chain variable region sequence as set forth in SEQ ID NO:22, and 5) an unnamed antibody which comprises a heavy chain variable region sequence as set forth in SEQ ID NO:36, and a light chain variable region sequence as set forth in SEQ ID NO:22, does not reasonably provide enablement for the genus of antibodies whose heavy and light chain comprise the specific CDR sequences set forth in claim 1, or for any of the five antibodies identified above where the sequence of the heavy and/or light chain is less than 100% identical to the SEQ ID NOS set forth above. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to the invention commensurate in scope with these claims.
The Office has analyzed the specification in direct accordance to the factors outlined in In re Wands, namely 1) the nature of the invention, 2) the state of the prior art, 3) the predictability of the art, 4) the amount of direction or guidance present, and 5) the presence or absence of working examples, and presented detailed scientific reasons supported by publications from the prior art for the finding of a lack of enablement for the scope of the instant methods. Note that the amount of experimentation required to make and use an invention and whether such experimentation is “undue” is based on the analysis of all of these factors.
The broadest amended claim, claim 1, recites an antibody which binds to human or mouse TGF-beta3 and which further has the functional property of neutralizing the activity of TGF-beta3, and does not recognize or bind to TGF-beta1 or TGF-beta2, where the antibody is limited to a structure which comprises a heavy chain variable region comprising a heavy chain CDR1 sequence of SEQ ID NO:1, a CDR sequence of SEQ ID NO:34, and a CDR sequence of SEQ ID NO:35, and a light chain variable region comprising a light chain CDR1 sequence of SEQ ID NO:4, a CDR2 sequence of SEQ ID NO:5, and a CDR3 sequence of SEQ ID NO:33. Claim 1 as amended thus continues to encompass a genus of antibody defined only by the heavy and light chain CDRs, i.e. encompassing any framework sequences, and by the functional properties of TGF-beta3 binding and neutralization and of not recognizing or binding to TGF-beta1 or TGF-beta2. Claim 4 further limits the structure of the antibody of claim 1 by requiring that the heavy chain variable region comprises one of the sequence of SEQ ID NO:18, 19, or 36, or a variant with at least 90% amino acid identity to one of these sequences, OR one of the light chain variable sequences comprising the sequence of SEQ ID NOS 22 or 23, or a variant with at least 90% amino acid identity to one of these sequences, while retaining TGF-beta3 binding and neutralizing capacity. Thus, claim 4 reads broadly on a genus of anti-TGF-beta3 antibodies where the heavy and light chain CDRs are specifically defined and only the heavy chain OR light chain variable region sequence is limited to specific sequence or one with 90% sequence identity to one of those heavy or light chain sequences. Claim 12 further limits the structure of only the heavy chain of the antibody of claim 1, where the heavy chain the heavy chain variable region comprises one of the sequence of SEQ ID NO:18, 19, or 36, or a variant with at least 90% amino acid identity to one of these sequences. The genus of antibodies of claim 12 encompasses one of three specific heavy chains sequences or sequence with 90% sequence identity to one of those three sequences in combination with any light chain comprising the three identified light chain CDRs. Claim 13 depend on claim 12 and further limits the light chain to light chain variable sequences comprising the sequence of SEQ ID NOS 22 or 23, or a variant with at least 90% amino acid identity to one of these sequences. The genus of antibodies encompassed by claim 13 includes any combination of the 3 heavy chain sequences and 2 light chain sequences and any variants of any of these sequences with at least 90% amino acid identity. Thus, even the narrowest of the claims, claim 13, encompasses a large genus of antibodies with certain defined structural features and required functional properties. The broadest claim, claim 1, encompasses an extremely large genus of antibodies with specific functional properties whose heavy and light chains are only defined by their CDR sequences.
The specification teaches humanization of a specific mouse anti-TGF-beta3 antibody which was previously described in the prior- see WO/2016/201282 (2016), hereafter referred to as Van Snick et al.- and referred to as MTGF-beta3-19 antibody/MTGF-beta3-1901/Ab 1901 in the specification. The parent antibody was described as binding specifically to mouse and human TGF-beta3, which have identical amino acid sequence, without binding to TGF-beta1 or TGF-beta2, and with the further functional ability of neutralizing the activity of TGF beta3. The specification does not identify the antigenic peptide sequence present in mouse or human TGF-beta3 which is recognized by the parent Ab1901 antibody. The specification also does not disclose the 3D or crystal structure of the antibody or identify key amino acid residues responsible for or impacting the binding of Ab1901 and TGF-beta3. The specification, in the absence of any structural data, teaches a complicated process of humanization of this mouse antibody which involves both CDR/FR grafting and functional potency assay-driven sequence mutagenesis of both CDR and framework sequences. As set forth in the working examples, this process involved the initial identification of human VH and VL framework sequence for CDR grafting of the CDR sequences present in parent antibody Ab1901. The specification discloses based on the IMGT reference directory of heavy and light chain sequences and further based on a proprietary internal IgM/D sequence database, IGHV1-69*08 and IGKV1-39*-01 was selected as the human base sequence for the murine CDRs. As applicant relied in part on proprietary information and does not provide guidance for the specific criteria for selection of these sequences, the specification does not provide sufficient guidance for alternative human framework sequence useful as forming the base of the humanized antibody with CDRs as claimed. Following the initial grafting, the working examples show that permutation libraries for CDR VH variants and CDR VL variants were constructed, again using proprietary information. These libraries were screened for CDR VH and VL variants. It is not clear whether the heavy and light chains obtained from these initial rounds of screening include the CDR sequences claimed in claim 1. The specification then teaches mutation of certain residues in the framework and in the CDR, including mutation of “human” residues or other “human” residues, and back-mutation of certain “human” residues for “mouse” residues. Based on this process, the specification describes four specific antibodies whose CDR sequences are derived from the CDR sequences present in the heavy and light chain variable regions of Ab1901 and whose framework sequences comprises human and mouse framework sequence. The four antibodies described by the specification are identified as 1901-1A, 1901-1B, 1901-1C, and 1901-1D. 1901-1A comprises a heavy chain variable region sequence as set forth in SEQ ID NO:18, and a light chain variable region sequence as set forth in SEQ ID NO:23. 1901-1B comprises a heavy chain variable region sequence as set forth in SEQ ID NO:19, and a light chain variable region sequence as set forth in SEQ ID NO:23. 1901-1C comprises a heavy chain variable region sequence as set forth in SEQ ID NO:18, and a light chain variable region sequence as set forth in SEQ ID NO:22. 1901-1D comprises a heavy chain variable region sequence as set forth in SEQ ID NO:19, and a light chain variable region sequence as set forth in SEQ ID NO:22. Note that SEQ ID NOS 18 and 19 differ in 3 framework amino acids at positions 38, 40, and 43, and SEQ ID NOS 22 and 23 differ in 2 framework amino acids at positions 42 and 43. All four of these antibodies share less than 90% amino acid identity to parental antibody Ab-1901. While the specification discloses that generation of several clonal libraries of heavy chain and light chains which were screened at different point of the humanization process, the specification does not provide guidance for any antibody comprising heavy or light chains comprising the modified CDRs recited in claim 1 other than the four antibodies discussed above, although it is noted that the specification does disclose on page 88 an additional variant antibody and VH sequence of SEQ ID NO:36, paired with the VL sequence of SEQ ID NO:22. The specification does not name this antibody or provide any data regarding its activity, but does state that this variant was tested for TGFb3 silencing in MLEC cells and found to be effective in neutralizing. While the specification does not clarify what has been neutralized, it would appear to be TGFb3. SEQ ID NO:36 differ by one mismatch at position 43 with SEQ ID NO:18 and by 2 positions, 38 and 40 with SEQ ID NO:19. Aside from these specific disclosures, the specification does not provide any data or any additional specific guidance for residues which can be modified in the framework sequences of any of the cloned heavy or light chain variable regions of the 5 disclosed antibodies without substantially affecting antibody structure and function, including antigen specificity for TGF-beta3 versus TGF-beta1 or TGF-beta2, or ability to neutralize TGF-beta3 activity. In the absence of any information as to the exact epitope bound by any of the 5 disclosed antibodies such as a defined epitope amino acid sequence or the location/positioning of the epitope residues within the TGF-beta3 protein, the specification fails to provide the requisite guidance for predictably making a genus of antibodies with the claimed functions of binding to TGF-beta3, and neutralizing TGF-beta3 activity.
Turning to the state of the art at the time of filing, the art teaches that combinatorial diversity and somatic mutation during B cell development and maturation into antibody secreting cells contribute to the diversity of antibodies which are capable of recognizing a particular antigen epitope such that it is unlikely that any two antibodies which recognize the same antigen, or even the same antigen epitope would share the same amino acid or nucleic acid sequence. This is reflected in applicant’s sequence data of clones which bind to the TGF-beta3 capsid protein. At the time of filing, the art teaches that antibody specificity and binding to antigen epitopes is largely determined by complementarity determining regions (CDRs). There are 6 CDRs produced by the pairing of heavy and light chain variable regions in an intact antibody. While the heavy chain CDR3 region has been implicated as being crucial for defining antigen specificity of an antibody, the art teaches that both CDRs and framework regions (FRs) in the heavy and light chain also contribute to and affect antigen specificity and affinity. The prior art at the time of filing does not teach any specific TGF-beta3 binding motif or domain shared among all antibodies which bind to TGF-beta3, or any one particular epitope within TGF-beta3, nor does the prior art at the time of filing teach which specific residues at specific positions in the antibody heavy chain or light chain are either essential or non-essential to the binding of any and all antibodies. Instead, the prior art at the time of filing is replete with teachings that while the overall structure between antibodies is shared, the structure of the antigen binding region of an antibody and the residues involved in binding to its cognate antigen are unique to each antibody and can involve residues both within any one or all of the heavy and light chain CDRs and framework regions (see for example, Vajdos et al. (2002) J. Mol. Biol., Vol. 320, 415-428, Chen et al. (1992) J. Exp. Med., Vol. 176, 855-866, and Sela-Culang et al. (2013) Frontiers in Immunology, Vol. 4, pages 1-13). Vajdos et al. teaches that residues in both the CDRs and framework regions of antibodies can be important for antigen recognition and binding, and discloses attempts to identify key residues in the antigen binding site of the Fab2C4 antibody for its peptide epitope derived from the extracellular domain of the human oncogene ErbB2 (Vajdos et al., pages 416-418). Vajdos et al. teaches that two different mutagenesis strategies were used to identify key residues in peptide binding- shotgun alanine scanning mutagenesis and shotgun homolog-scanning mutagenesis- and report that the results of the two methods in combination three dimensional crystal structure of the Fab2C4 antibody provided distinct yet complementary view of key residues in binding between the antibody and antigen (Vajdos et al., page 417, Figure 1 and Table 2). As can be seen in Figure 1 of Vajdos, each method identified different key residues, with some overlap. Vajdos et al. states that key residues for binding are present in both the heavy and light chain and include both solvent exposed and buried residues, where the buried residues may act as essential scaffolding residues that maintain the structural integrity of the antigen binding site (Vajdos et al, page 423). Thus, Vajdos demonstrates that identification of key residues in an antibody that affect antigen binding and are not tolerant of modification, or which may only tolerate certain modifications, is a labor intensive process which cannot be predicted a priori. Chen et al. provides the results of random point mutation mutagenesis of the heavy chain CDR2 in the PC-specific T15 antibody and demonstrates that mutations in this CDR alone can abrogate binding and further that increasing the number of mutations within this one CDR results in a significant increase in non-binding mutants, from approximately 7% nonbinding mutants with 1 mutation to 58% nonbinding mutants with 2 mutations in HCDR2 (Chen et al., pages 855-859, Table 2). Chen et al. also demonstrated that mutations in at least 5 residues in this CDR2 were important in antigen binding (Chen et al., page 855). Thus, Chen et al., like Vajdos et al. demonstrates that mutations affecting antigen binding in antibody chains cannot be determined a priori, and further teaches that increasing the number of mutations within a CDR substantially increases the chances of generating a non-binding mutant. Sela-Culang et al., in a recent review of the structural basis of antibody-antigen recognition teaches that some off-CDR residues can contribute critically to the interaction of the antibody with antigen (Sela-Culang et al. (2013) Frontiers in Immunology, Vol. 4, pages 1-13, page 1). Sela-Culang et al. teaches that in some antibodies, framework residues contribute to the antigen binding site, and in other antibodies, the frame work residues affect the antigen binding site indirectly by shaping the antigen binding site (Sela-Culang et al., page 7). In fact, Sela-Culang et al. teaches that constructing an antibody using only the CDRs from an known antigen-specific antibody usually results in a significant drop or a complete loss of binding of the antibody to its antigen (Sela-Culang et al., page 7). Sela-Culang et al. further teaches that different CDR identification methods may often identify radically different stretches as “CDRs”, indicating that CDRs are not well defined and thus are not necessarily a good proxy for the binding site (Sela-Culang et al., page 8). Thus, Sela-Culang et al. provides additional evidence that the generation of mutants of a known antibody with known heavy and light chain sequences cannot be predicted a priori, including mutations within the framework regions of the antibody. Kim et al. further teaches that while humanization of therapeutic murine antibodies by CDR grafting is desired in order to limit human anti-mouse antibody (HAMA) responses, that such CDR grafting often decreases the binding affinity and specificity of the antibody because some framework residues directly contact with the antigen and/or support the conformation of the CDR loops (Kim et al. “Humanization by CDR Grafting and Specificity-Determining Residue Grafting” (2012) Patrick Chames (ed.), Antibody Engineering: Methods and Protocols, Second Edition, Methods in Molecular Biology, vol. 907, Chapter 13DOI 10.1007/978-1-61779-974-7_13, pages 237-245, see pages 237-238). Kim et al. further teaches that if the crystal structure of the antibody is known that specificity determining residues (SDRs) can be identified; but that ultimately, testing of modifications to the sequence is required to determine the affects of the modifications (Kim et al., pages 240-241). Kim et al. teaches that if the structure of the antibody is not available, panels of mutant antibodies must be screened to identify SDRs (Kim et al., page 241). Thus, Kim et al. teaches that even if the crystal structure of antibody and it cognate antigen are available, mutations must be screened for functional effects, as such functional effects cannot be reliably predicted. Therefore, the prior art at time of filing clearly teaches that the sequence of the heavy and light chain variable region of an antibody which binds to a specific protein or protein epitope cannot be predicted a priori, and further that even starting from a known antibody with binding for a particular antigen, the effects of the introduction of any one or more mutations into any one of the six CDR or the framework region of the antibody cannot be predicted from the sequence of the antibody alone. Applicant’s own working examples support the art-recognized need to for substantial amounts of screening to identify variant antibodies which retain the desired binding specificity and affinity. As discussed above, the applicant relied in part on proprietary information and screening to select base sequences which were then further modified and screened through multiple rounds, including following the initial grafting, the construction and screening of permutation libraries using proprietary information followed by the mutation of certain residues in the framework and in the CDR, including mutation of “human” residues or other “human” residues, and back-mutation of certain “human” residues for “mouse” residues. Based on this process, the specification describes four specific antibodies whose CDR sequences are derived from the CDR sequences present in the heavy and light chain variable regions of Ab1901 and whose framework sequences comprises human and mouse framework sequence. The four antibodies described by the specification are identified as 1901-1A, 1901-1B, 1901-1C, and 1901-1D. Thus, applicant’s own screening, using proprietary guidelines, only identified four specific antibody variants that meet the claim limitations. As such, both the prior art and the working examples show that even where the six CDRs of an antibody with a desired specificity are known, the introduction of mutations in the framework can effect antigen binding specificity which cannot be predicted, particularly in the absence of a crystal structure or knowledge of all the residues both within the CDR and framework which contribute to antigen binding and specification. For this reason, both the prior art of record and the working examples teach the necessity of screening mutations to identify those which do not affect antigen binding and specificity, with no predictable expectation regarding the number of antibodies which may meet the required functional properties or sequences of any such antibodies which may meet the required functional properties. It is also noted that applicant’s response does not acknowledge the evidence of record in the form of the teachings of Vajdos et al., Chen et al., Sela-Culang et al., and Kim et al. that residues outside of the CDRs are clearly important in antigen binding and specificity of an antibody and that the effects of mutations in the framework sequence of an antibody cannot be known a priori.
Therefore, it is maintained that in view of the nature of the invention which is humanized antibodies, the art recognized unpredictability in identifying mutations within both the CDR and framework of an antibody which do not diminish, change, or abrogate binding and other functional activities a priori, the lack of guidance in the specification and limitation of the working examples to a disclosure of 4 specific humanized antibodies with shared heavy and light chains obtained using in part proprietary information, and the breadth of the claims, that it would have required undue experimentation to make and use the full scope of anti-TGFbeta3 antibodies encompassed by the claims as written.
Claim Objections
Claim 9 remains objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
No claims are allowed.
THIS ACTION IS MADE FINAL. 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.
Any inquiry concerning this communication from the examiner should be directed to Anne Marie S. Wehbé, Ph.D., whose telephone number is (571) 272-0737. If the examiner is not available, the examiner’s supervisor, Maria Leavitt, can be reached at (571) 272-1085. For all official communications, the technology center fax number is (571) 273-8300. Please note that all official communications and responses sent by fax must be directed to the technology center fax number. For informal, non-official communications only, the examiner’s direct fax number is (571) 273-0737. For any inquiry of a general nature, please call (571) 272-0547.
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Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634