Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 March 13, 2026 has been entered.
Claims 33-37, 39-46, and 48-51 are pending and being acted upon in this Office Action.
Priority
Applicant’ claim priority to provisional applications 61/776,724, filed March 11, 2013, 61/776,715 filed March 11, 2013 and 61/776,710 filed March 11, 2013 is acknowledged.
Rejection Withdrawn
The rejection of claims 33-50 on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1, 5, 11-25 of U.S. Patent No. 9,701,753 is withdrawn in view of the terminal disclaimer filed on April 22, 2026.
The rejection of claims 33-50 on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-2, 6, 11-16, 27, 32, 35-38, 45 and 46 of U.S. Patent No. 9,580,511 is withdrawn in view of the terminal disclaimer filed on April 22, 2026.
Claim rejections under - 35 U.S.C. 112
The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
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 35-36 and 51 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the Application. These include: (1) Actual reduction to practice, (2) Disclosure of drawings or structural chemical formulas, (3) Sufficient relevant identifying characteristics (such as: i. Complete structure, ii. Partial structure, iii. Physical and/or chemical properties, iv. Functional characteristics when coupled with a known or disclosed, and correlation between function and structure), (4) Method of making the claimed invention, (5) Level of skill and knowledge in the art, and (6) Predictability in the art. “Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient.” MPEP § 2163 (II)(A)(3)(a)(ii)).
The U.S. Court of Appeals for the Federal Circuit recently reaffirmed, in an en banc decision, that the written description requirement for a genus may be satisfied either by (i) the disclosure of a representative number of species falling within the scope of the genus or (ii) 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. Ariad Pharmaceuticals', Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1350, 94 U.S.P.Q.2d 1161, 1171 (en banc) (Fed. Cir. 2010), citing Regents" of the University of California v. Eli Lilly & Co., 119 F.3d 1559, 1568-69, 43 U.S.P.Q.2d 1398, 1406 (Fed. Cir. 1997) and AbbVie v. Janssen Biotech and Centocor Biologics (Fed. Cir. 2014).
Claim 33 encompasses claim 33 encompasses any antibody or antigen-binding fragment thereof comprising a CH1 domain, wherein the CH1 domain comprises an asparagine residue at amino acid position 114, according to Kabat numbering, and wherein a side chain of said asparagine residue is linked to a glycan, wherein the antibody or an antigen-binding fragment thereof is linked to a drug effector moiety to form an antibody drug conjugate (ADC), and wherein the drug effector moiety comprises Monomethyl Auristatin E (MMAE) or Dolastatin 10 (Dol10).
Claim 34 encompasses the antibody or antigen-binding fragment thereof of claim 33, wherein the CH1 domain further comprises: any amino acid residue except proline at position 115, according to Kabat numbering; and a serine or threonine residue at position 116, according to Kabat numbering.
Claim 35 encompasses the antibody or antigen-binding fragment thereof of claim 33, wherein the CH1 domain is an IgG1 CH1 domain, or any variant thereof.
Claim 36 encompasses the antibody or antigen-binding fragment thereof of claim 35, wherein the CH1 domain is a human IgG1 CH1 domain, or any variant thereof.
Claim 37 encompasses the antibody or antigen-binding fragment thereof of claim 33, wherein the side chain of the asparagine residue is linked to the glycan though β-glycosylamide linkage.
Claim 39 encompasses the antibody or antigen-binding fragment thereof of claim 38, wherein the glycan is a biantennary glycan.
Claim 40 encompasses the antibody or antigen-binding fragment thereof of claim 39, wherein the glycan is a naturally occurring mammalian glycoform.
Claim 41 encompasses the antibody or antigen-binding fragment thereof of claim 37, wherein the glycan comprises a reactive aldehyde group.
Claim 42 encompasses the antibody or antigen-binding fragment thereof of claim 37, wherein the glycan comprises an oxidized saccharide residue comprising a reactive aldehyde group.
Claim 43 encompasses the antibody or antigen-binding fragment thereof of claim 42, wherein the oxidized saccharide residue is a terminal sialic acid or galactose.
Claim 44 encompasses the antibody or antigen-binding fragment thereof of claim 33, wherein the drug effector moiety is linked through an oxime or hydrazone linkage to a saccharide residue of the glycan.
Claim 45 encompasses the antibody or antigen-binding fragment thereof of claim 44, wherein the saccharide residue is a terminal sialic acid or galactose residue of the glycan.
Claim 46 encompasses the antibody or antigen-binding fragment thereof of claim 44, wherein the drug effector moiety comprises a pH-sensitive linker, disulfide linker, enzyme- sensitive linker or other cleavable linker moiety.
Claim 48 encompasses the antibody or antigen-binding fragment thereof of claim 44, wherein the drug effector moiety is linked through the side chain of the asparagine residue to the saccharide residue of the glycan.
Claim 49 encompasses the antibody or antigen-binding fragment thereof of claim 33, wherein the antibody or antigen-binding fragment specifically binds an antigen selected from the group consisting of tumor endothelial marker 1 (TEM1), any CD52, human epidermal growth factor receptor 2 (HER2), and any fibroblast activation protein (FAP).
Claim 50 encompasses a composition comprising the antibody or antigen-binding fragment thereof of claim 33 and a pharmaceutically acceptable carrier or excipient.
Claim 51 encompasses any IgG antibody or antigen-binding fragment thereof comprising a CH1 domain, wherein the CH1 domain comprises an asparagine residue at amino acid position 114, according to Kabat numbering, and wherein a side chain of the asparagine residue is linked to a glycan, wherein the glycan is linked to a drug effector moiety to form an antibody drug conjugate (ADC), and wherein the drug effector moiety comprises Monomethyl Auristatin E (MMAE) or Dolastatin (Dol10) wherein the antibody or antigen-binding fragment thereof binds any tumor-associated antigen.
Regarding IgG antibody or antigen-binding fragment thereof comprising a CH1 domain wherein the CH1 domain comprises an asparagine residue at position 114, according to Kabat numbering that binds to any tumor-associated antigen (claim 51), the specification discloses just human IgG1 antibody that binds to CD52 wherein the position 114 is substituted for N comprising the amino acid sequence of SEQ ID NO: 3, p. 63, anti-TEM1 (SEQ ID NO: 11), anti-FAP, and anti-HER2 (SEQ ID NO: 14 and 16). The specification discloses glycoconjugate comprising any one of the IgG1 antibodies above conjugated to monomethyl auristatin E (MMAE) or Dolastatin 10 (Dol10) via aminoxy-cys-Mc-Vc-PABC or aminooxy (AO) or AO-PEG8 linker through hydrazide or oxime linkage.
However, the specification does not describe i. Complete structure, e.g., amino acid sequence of heavy chain variable region and light chain variable region, ii. Partial structure, e.g., six CDRs of any and all IgG that correlated with binding to any and all possible tumor-associated antigen encompassed by the claimed IgG antibody or antigen binding fragment thereof conjugated to drug moiety comprising monomethyl auristatin E (MMAE) or Dolastatin 10 (Dol10) at position 114 of CH1 domain or variant thereof numbering according to Kabat numbering. There is no limitation on the structure correlated with the tumor associated antigen of the antibody to which it binds (claim 51). The specification does not describe a representative number of species falling within the scope of the genus or structural features common to the members of the genus so the one of skill in the art can visualize or recognize the member of the genus of the actual claimed IgG antibody or antigen-binding fragment thereof that bind to any and all possible tumor-associated antigens. The disclosure of a limited species of human IgG1 antibodies that bind to CD52, HER2, TEM1 and FAP is not representative of the vast genus of IgG antibody or antigen binding fragment thereof comprising 114A substitution that bind to any and all possible tumor-associated antigen at the time of filing.
An adequate written description must contain enough information about the actual makeup of the claimed products – “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361).
At the time the invention was made, it was known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope.
For example, Lloyd et al. taught that hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences (Lloyd et al. of record, Protein Engineering, Design & Selection 22:159-168, 2009; PTO 892; see, e.g., Discussion).
Similarly, Edwards et al., (of record, J Mol Biol. 334(1): 103-118, 2003; PTO 892) found that over 1000 antibodies, all different in amino acid sequence, were generated to a single protein; 568 different amino acid sequences identified for the V(H) CDR3 domains of these antibodies (Abstract).
Further, even minor changes in the amino acid sequence of a heavy or light variable region, particularly the CDRs, may dramatically affect antigen-binding function and IgG binding to the neonatal Fc receptor (FcRn) and pharmacokinetics.
For example, Piche-Nicholas et al (of record, MABS 10(1): 81-94, 2018; PTO 892) teaches altering complementary-determining region (CDRs) by 1-5 mutations significantly alter binding affinity to FcRn in vitro, see entire document, abstract, p. 95, right col, in particular. Engineering CDRs by modify local charge and thus maintain affinity to FcRn at 400 nM or weaker in vitro while retaining antigen binding may have far-reaching implications in the half-life optimization efforts of IgG therapeutics with respect to in vivo pharmacokinetics, see p. 90, in particular.
Poosarla et al (newly cited, Biotechn. Bioeng., 114(6): 1331-1342, 2017; PTO 892) teach substantial diversity in designed mAbs (sharing less than 75% sequence similarity to all existing natural antibody sequences) that bind to the same 12-mer peptide, binding to different epitopes on the same peptide. Said reference further teaches “most B-cell epitopes... in nature consist of residues from different regions of the sequence and are discontinuous...de novo antibody designs against discontinuous epitopes present additional challenges...". (See entire reference.)
Given that hundreds of unique antibody structures may bind a single antigen, the structure of an antibody cannot be predicted from the structure of the antigen (as held in Amgen), and a single species, or small group of species, cannot define a structure-function relationship so as to be representative of all the IgG antibodies that bind to that tumor-associated antigen (as held in Abbvie).
Regarding “IgG1 CH1 variant” (claim 35) and “human IgG1 CH1 domain variant” (claim 36), the specification discloses:
[0065] As used herein, the term “CH1 domain” includes the first (most amino terminal) constant region domain of an immunoglobulin heavy chain that extends, e.g., from about positions 114-223 in the Kabat numbering system (EU positions 118-215). The CH1 domain is adjacent to the VH domain and amino terminal to the hinge region of an immunoglobulin heavy chain molecule, and does not form a part of the Fc region of an immunoglobulin heavy chain.
[0087] CH1 domains from any immunoglobulin class (e.g., IgM, IgG, IgD, IgA and IgE) and species can be used in the binding polypeptides disclosed herein. Chimeric CH1 domains comprising portions of CH1 domains from different species or Ig classes can also be employed. In certain embodiments, the CH1 domain is a human IgG1 CH1 domain. In the case of a human IgG1 domain, mutation of the wild type amino acid at position 114 to an asparagine results in the formation of an N-linked glycosylation consensus site (i.e, the N-X-T/S sequon, where X is any amino acid except proline). However, in the case of other CH1 domains of other species and/or Ig classes or isotypes, the skilled artisan will appreciate that it may be necessary to mutate positions 115 and/or 116 of the CH1 domain to create an N-X-T/S sequon.
However, the term “variant” encompasses any substitution, deletion, addition or a combination thereof. Other than N-linked glycosylation consensus site N-X-T/S at positions 114-116 within the CH1 domain of IgG or human IgG1 CH1 domain, the specification does not teach where and what amino acid within the full-length sequence of CH1 domain to be substituted, deleted, added or a combination thereof such that the drug effector moiety is site-specifically conjugated to CH1 domain.
It is well-established that target therapies such as ADCs is highly unpredictable even when using the same or similar linker-payload but different antibody.
For example, Nejadmoghaddam (Avicenna Journal of Medical Biotechnology 2(1): 3-23, 2019; PTO 892) discusses major obstacles of antibody-drug conjugates include off-target toxicity, tumor marker selection, antibody specificity, adequately affinity and receptor-mediated internalization are major aspects of choice, cytotoxic payload (e.g., up to 7 drugs per antibody), cytotoxic payload linkage strategy, aqueous solubility, non-immunogenic and stability in storage and bloodstream, see entire document, abstract, p. 15, in particular.
Gogia et al (Cancers 15: 3886, 2023; PTO 892) teaches the challenges of antibody drug conjugates (ADCs); these include the antibody specificity, the cytotoxic payload, linker chemistry, e.g., chemically labile (hydrazone bond and disulfide bond) or enzymatically labile, stability of the ADCs. Gogia et al teach that various Tumor-specific antigens have been discovered, However, despite the discovery of these tumor-specific antigens, difficulties persist. Firstly, high antigen affinity does not necessarily have high tumor penetration. Secondly, the distribution of cell surface target antigen expression defines the therapeutic window and a high antigen expression level in a tumor does not necessarily guarantee an ADC will be highly effective, see p. 23, in particular. ADCs have complex pharmacokinetic and pharmacodynamic profiles, which poses a challenge in designing them. Another challenge for ADC development is drug resistance, see p. 24, in particular.
As such, there is a high level of unpredictability in the art of ADCs such that the antibody in one ADC cannot simply be exchanged with another antibody directed against a different antigen with the expectation that the same result will be achieved.
A patent specification must set forth enough detail to allow a person of ordinary skill in the art to understand what is claimed and to recognize that the inventor invented what is claimed. In the case of DNA, an adequate written description requires a precise definition, such as by structure, formula, chemical name, or physical properties, not a mere wish or plan for obtaining the claimed chemical invention (see Lilly, 119 F.3d at 1566 (quoting Fiers, 984 F.2d 15 1171 ).
One of skill in the art would reasonably conclude that the disclosure does not provide a representative number of species of all IgG antibody or antigen binding fragment thereof that specifically bind any and all possible tumor-associated antigen wherein the CH1 domain or variant thereof comprises an asparagine residue at amino acid position 114, according to Kabat numbering wherein the side chain of the asparagine residue is linked to any glycan wherein the glycan is linked to Monomethyl Auristatin E (MMAE) or Dolastatin 10 (Dol 10) that would be sufficient to describe the claimed genus. Thus, Applicant is not in possession of the genus of IgG antibody or antigen-binding fragment thereof that bins any and all possible tumor-associated antigen wherein the IgG antibody or antigen-binding fragment thereof comprises a CH1 domain or variable thereof comprises an asparagine residue at amino acid position 114, according to Kabat numbering, and wherein a side chain of the asparagine residue is linked to a glycan, wherein the glycan is linked to a drug effector moiety to form an antibody drug conjugate (ADC), and wherein the drug effector moiety comprises Monomethyl Auristatin E (MMAE) or Dolastatin (Dol10) at the time of filing as broadly as claimed.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear 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).
Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddles v. Baird, 30 USPQ2d 1481, 1483. In Fiddles v. Baird, claims directed to mammalian FGF’s were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
Therefore, only IgG antibody or antigen-binding fragment thereof as set forth in claims 33-34, 37, 39-46, 48-50 meet the written description requirement, but not the breadth of CH1 variants in claims 35-36 and the breadth of IgG antibody or antigen-binding fragment thereof that that binds any and all possible tumor-associated antigen as set forth in claim 51 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).
Applicants’ arguments filed March 13, 2026 have been fully considered but are not found persuasive.
Applicant’s position is that new claim 51 is added that specifies:
IgG antibody or antigen-binding fragment thereof comprising a CH1 domain, wherein the CH1 domain comprises an asparagine residue at amino acid position 114, according to Kabat numbering, and wherein a side chain of the asparagine residue is linked to a glycan, wherein the glycan is linked to a drug effector moiety to form an antibody drug conjugate (ADC), and wherein the drug effector moiety comprises Monomethyl Auristatin E (MMAE) or Dolastatin (Dol10) wherein the antibody or antigen-binding fragment thereof binds any tumor-associated antigen.
The Specification expressly describes antibodies having a CH1 domain engineered to contain an asparagine at Kabat position 114, the resulting N-linked glycan at that position, and conjugation of that glycan to MMAE or Dol10 to form antibody-drug conjugates. The disclosure includes detailed descriptions of the CH1 Al14N mutation, the glycan structures, oxidation and oxime/hydrazone chemistries, and direct conjugation of MMAE or Dol10 (e.g., FIGS. 25-31). These passages provide explicit structural support for the claimed antibody format and ADC configuration.
Further, the Specification discloses four representative antibodies-anti-CD52, anti-TEM1, anti-HER2, and anti-FAP-each incorporating the CH1 A114N substitution. For all four, the Specification confirms successful introduction of the engineered glycosylation site, additional glycan mass at A114N, and compatibility with conjugation chemistry used for MMAE and Dol10. These four structurally diverse antibodies demonstrate possession of the genus of IgG antibodies comprising the Al14N CH1 modification and capable of glycan-mediated drug attachment.
Further, the Specification discloses four representative antibodies-anti-CD52, anti-TEM1, anti-HER2, and anti-FAP-each incorporating the CH1 A114N substitution. For all four, the Specification confirms successful introduction of the engineered glycosylation site, additional glycan mass at A114N, and compatibility with conjugation chemistry used for MMAE and Dol10. These four structurally diverse antibodies demonstrate possession of the genus of IgG antibodies comprising the Al14N CH1 modification and capable of glycan-mediated drug attachment.
The Specification also establishes that the A114N modification does not impair antigen binding. Examples 1 and 2 show that each antibody-despite having unrelated VH/VL sequences retains full binding to its respective antigen following introduction of A114N. Because the mutation resides in the CH1 constant region rather than the antigen-determining variable region, a skilled artisan would understand that this modification is broadly applicable to IgG antibodies without altering antigen specificity. This provides the required structure-function correlation demonstrating possession of the claimed genus.
As for new claim 51, reciting tumor-associated antigens, the Specification again provides direct support. The four disclosed antibodies bind four distinct tumor-associated antigens CD52, TEM1, HER2, and FAP-and each of these antibodies incorporates the Al14N CH1 substitution while maintaining antigen recognition. These embodiments constitute multiple representative species across unrelated antigen classes, demonstrating possession of the genus of IgG antibodies that bind tumor-associated antigens and include the A114N CH1 engineering.
Accordingly, the Specification provides structural support, multiple representative embodiments, establishing that the inventors were in possession of the full scope of the present claims.
Accordingly, Applicant respectfully requests that the rejection of the present claims as lacking written description be reconsidered and withdrawn.
In response, the added new claim 51 is acknowledged.
Upon reconsideration in light of the argument that A114N modification in the CH1 domain does not impair antigen binding, the rejection to claims 33-34, 37, 39-46, 48-50 is hereby withdrawn.
Claim 51 encompasses any IgG antibody or antigen-binding fragment thereof comprising a CH1 domain, wherein the CH1 domain comprises an asparagine residue at amino acid position 114, according to Kabat numbering, and wherein a side chain of the asparagine residue is linked to a glycan, wherein the glycan is linked to a drug effector moiety to form an antibody drug conjugate (ADC), and wherein the drug effector moiety comprises Monomethyl Auristatin E (MMAE) or Dolastatin (Dol10) wherein the antibody or antigen-binding fragment thereof binds any and all possible tumor-associated antigen.
The specification discloses just human IgG1 antibody that binds to CD52 wherein the position 114 is substituted for N comprising the amino acid sequence of SEQ ID NO: 3, p. 63, anti-TEM1 (SEQ ID NO: 11), anti-FAP, and anti-HER2 (SEQ ID NO: 14 and 16). The specification discloses glycoconjugate comprising any one of the IgG1 antibodies above conjugated to monomethyl auristatin E (MMAE) or Dolastatin 10 (Dol10) via aminoxy-cys-Mc-Vc-PABC or aminooxy (AO) or AO-PEG8 linker through hydrazide or oxime linkage.
However, the specification does not describe i. Complete structure, e.g., amino acid sequence of heavy chain variable region and light chain variable region, ii. Partial structure, e.g., six CDRs of any and all IgG that correlated with binding to any and all possible tumor-associated antigen encompassed by the claimed IgG antibody or antigen binding fragment thereof conjugated to drug moiety comprising monomethyl auristatin E (MMAE) or Dolastatin 10 (Dol10) at position 114 of CH1 domain or variant thereof numbering according to Kabat numbering. There is no limitation on the structure correlated with the tumor associated antigen of the antibody to which it binds (claim 51).
The specification does not describe a representative number of species falling within the scope of the genus or structural features common to the members of the genus so the one of skill in the art can visualize or recognize the member of the genus of the actual claimed IgG antibody or antigen-binding fragment thereof that bind to any and all possible tumor-associated antigens. The disclosure of a limited species of human IgG1 antibodies that bind to CD52, HER2, TEM1 and FAP is not representative of the vast genus of IgG antibody or antigen binding fragment thereof comprising CH1 A114N substitution or variant thereof that bind to any and all possible tumor-associated antigen at the time of filing.
An adequate written description must contain enough information about the actual makeup of the claimed products – “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361).
At the time the invention was made, it was known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope.
For example, Lloyd et al. taught that hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences (Lloyd et al. of record, Protein Engineering, Design & Selection 22:159-168, 2009; PTO 892; see, e.g., Discussion).
Similarly, Edwards et al., (of record, J Mol Biol. 334(1): 103-118, 2003; PTO 892) found that over 1000 antibodies, all different in amino acid sequence, were generated to a single protein; 568 different amino acid sequences identified for the V(H) CDR3 domains of these antibodies (Abstract).
Further, even minor changes in the amino acid sequence of a heavy or light variable region, particularly the CDRs, may dramatically affect antigen-binding function and IgG binding to the neonatal Fc receptor (FcRn) and pharmacokinetics.
For example, Piche-Nicholas et al (of record, MABS 10(1): 81-94, 2018; PTO 892) teaches altering complementary-determining region (CDRs) by 1-5 mutations significantly alter binding affinity to FcRn in vitro, see entire document, abstract, p. 95, right col, in particular. Engineering CDRs by modify local charge and thus maintain affinity to FcRn at 400 nM or weaker in vitro while retaining antigen binding may have far-reaching implications in the half-life optimization efforts of IgG therapeutics with respect to in vivo pharmacokinetics, see p. 90, in particular.
Poosarla et al (newly cited, Biotechn. Bioeng., 114(6): 1331-1342, 2017; PTO 892) teach substantial diversity in designed mAbs (sharing less than 75% sequence similarity to all existing natural antibody sequences) that bind to the same 12-mer peptide, binding to different epitopes on the same peptide. Said reference further teaches “most B-cell epitopes... in nature consist of residues from different regions of the sequence and are discontinuous...de novo antibody designs against discontinuous epitopes present additional challenges...". (See entire reference.)
Given that hundreds of unique antibody structures may bind a single antigen, the structure of an antibody cannot be predicted from the structure of the antigen (as held in Amgen), and a single species, or small group of species, cannot define a structure-function relationship so as to be representative of all the antibodies that bind to that antigen (as held in Abbvie).
In AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014), the Court held that a disclosure of many different antibodies (in that case neutralizing antibodies to IL-12 with a particular binding affinity) was not enough to support the genus of all IL-12 neutralizing antibodies because the disclosed antibodies were very closely related to each other in structure and were not representative of the full diversity of the genus. The Court further noted that functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support especially in technology fields that are highly unpredictable where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus.
In the instant case, Applicant has not provided enough information such as identification of the CDRs, or heavy and light chain variable regions known to be responsible for binding to any and all possible tumor-associated antigen, such that one of ordinary skill in the art would recognize applicant as being in possession of the extremely diverse repertoire of IgG which might or might not meet the functional limitations of the claims.
While Abbvie states that one does not need to disclose every species in a genus in order to meet the written description requirement, the specification must at least describe some species representative of the entire genus (see p. 25 of Abbvie). Further, Abbvie as noted above states that such functional defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus, (see p. 26 of Abbvie).
Although the specification discloses four IgG1 antibodies that bind to four distinct tumor-associated antigens CD52, TEM1, HER2, and FAP-and each of these antibodies incorporates the Al14N CH1 substitution, a "representative number of species" means that those species that are adequately described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech. Ill USPQ2d 1780, 1790 (Fed. Cir. 2014).
When there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. The "structural features common to the members of the genus" needed for one of skill in the art to 'visualize or recognize' the members of the genus takes into account the state of the art at the time of the invention. For example, the Federal Circuit has found that possession of a mouse antibody heavy and light chain variable regions provides a structural "stepping stone" to the corresponding chimeric antibody, but not to human antibodies. Centocor Ortho Biotech Inc, v. Abbott Labs.. 97 USPQ2d 1870, 1875 (Fed. Cir. 2011).
In short, applicant appears to be trying to do what Abbvie cautions against which is to achieve a result without defining what means will do so (see Abbvie at pp. 25-26, citing Fiers v. Revel, 984 F.2d 1164, 1171 (Fed. Cir. 1993) “claiming all DNA[s] that achieve a result without defining what means will do so is not in compliance with the description requirement; it is an attempt to preempt the future before it has arrived.”). Such claim (claim 51) is known as “reach-through” claims, where an applicant attempts to obtain patent protection on an invention not yet discovered.
Regarding “IgG1 CH1 variant” (claim 35) and “human IgG1 CH1 domain variant” (claim 36), the specification discloses:
[0065] As used herein, the term “CH1 domain” includes the first (most amino terminal) constant region domain of an immunoglobulin heavy chain that extends, e.g., from about positions 114-223 in the Kabat numbering system (EU positions 118-215). The CH1 domain is adjacent to the VH domain and amino terminal to the hinge region of an immunoglobulin heavy chain molecule, and does not form a part of the Fc region of an immunoglobulin heavy chain.
[0087] CH1 domains from any immunoglobulin class (e.g., IgM, IgG, IgD, IgA and IgE) and species can be used in the binding polypeptides disclosed herein. Chimeric CH1 domains comprising portions of CH1 domains from different species or Ig classes can also be employed. In certain embodiments, the CH1 domain is a human IgG1 CH1 domain. In the case of a human IgG1 domain, mutation of the wild type amino acid at position 114 to an asparagine results in the formation of an N-linked glycosylation consensus site (i.e, the N-X-T/S sequon, where X is any amino acid except proline). However, in the case of other CH1 domains of other species and/or Ig classes or isotypes, the skilled artisan will appreciate that it may be necessary to mutate positions 115 and/or 116 of the CH1 domain to create an N-X-T/S sequon.
However, the term “variant” encompasses any substitution, deletion, addition or a combination thereof.
Other than N-linked glycosylation consensus site N-X-T/S at positions 114-116 within the CH1 domain of IgG or human IgG1 CH1 domain, the specification does not teach where and what amino acid within the full-length sequence of CH1 domain to be substituted, deleted, added or a combination thereof such that the drug effector moiety is site-specifically conjugated to CH1 domain.
Regarding antibody drug conjugate, it is well-established that target therapies such as ADCs is highly unpredictable even when using the same or similar linker-payload but different antibody.
For example, Nejadmoghaddam (Avicenna Journal of Medical Biotechnology 2(1): 3-23, 2019; PTO 892) discusses major obstacles of antibody-drug conjugates include off-target toxicity, tumor marker selection, antibody specificity, adequately affinity and receptor-mediated internalization are major aspects of choice, cytotoxic payload (e.g., up to 7 drugs per antibody), cytotoxic payload linkage strategy, aqueous solubility, non-immunogenic and stability in storage and bloodstream, see entire document, abstract, p. 15, in particular.
Gogia et al (Cancers 15: 3886, 2023; PTO 892) teaches the challenges of antibody drug conjugates (ADCs); these include the antibody specificity, the cytotoxic payload, linker chemistry, e.g., chemically labile (hydrazone bond and disulfide bond) or enzymatically labile, stability of the ADCs. Gogia et al teach that various Tumor-specific antigens have been discovered, However, despite the discovery of these tumor-specific antigens, difficulties persist. Firstly, high antigen affinity does not necessarily have high tumor penetration. Secondly, the distribution of cell surface target antigen expression defines the therapeutic window and a high antigen expression level in a tumor does not necessarily guarantee an ADC will be highly effective, see p. 23, in particular. ADCs have complex pharmacokinetic and pharmacodynamic profiles, which poses a challenge in designing them. Another challenge for ADC development is drug resistance, see p. 24, in particular.
As such, there is a high level of unpredictability in the art of ADCs such that the antibody in one ADC cannot simply be exchanged with another antibody directed against a different antigen with the expectation that the same result will be achieved.
For these reasons, the rejection is maintained.
Claims 35-36 and 51 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for IgG antibody or antigen-binding fragment thereof comprising as set forth in claims 33-34, 37, 39-46, 48-50, does not reasonably provide enablement for any IgG antibody or antigen-binding fragment as set forth in claims 35-36 and 51. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). These factors include, but are not limited to: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. . In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
Claim 33 encompasses claim 33 encompasses any antibody or antigen-binding fragment thereof comprising a CH1 domain, wherein the CH1 domain comprises an asparagine residue at amino acid position 114, according to Kabat numbering, and wherein a side chain of said asparagine residue is linked to a glycan, wherein the antibody or an antigen-binding fragment thereof is linked to a drug effector moiety to form an antibody drug conjugate (ADC), and wherein the drug effector moiety comprises Monomethyl Auristatin E (MMAE) or Dolastatin 10 (Dol10).
Claim 34 encompasses the antibody or antigen-binding fragment thereof of claim 33, wherein the CH1 domain further comprises: any amino acid residue except proline at position 115, according to Kabat numbering; and a serine or threonine residue at position 116, according to Kabat numbering.
Claim 35 encompasses the antibody or antigen-binding fragment thereof of claim 33, wherein the CH1 domain is an IgG1 CH1 domain, or any variant thereof.
Claim 36 encompasses the antibody or antigen-binding fragment thereof of claim 35, wherein the CH1 domain is a human IgG1 CH1 domain, or any variant thereof.
Claim 37 encompasses the antibody or antigen-binding fragment thereof of claim 33, wherein the side chain of the asparagine residue is linked to the glycan though β-glycosylamide linkage.
Claim 39 encompasses the antibody or antigen-binding fragment thereof of claim 38, wherein the glycan is a biantennary glycan.
Claim 40 encompasses the antibody or antigen-binding fragment thereof of claim 39, wherein the glycan is a naturally occurring mammalian glycoform.
Claim 41 encompasses the antibody or antigen-binding fragment thereof of claim 37, wherein the glycan comprises a reactive aldehyde group.
Claim 42 encompasses the antibody or antigen-binding fragment thereof of claim 37, wherein the glycan comprises an oxidized saccharide residue comprising a reactive aldehyde group.
Claim 43 encompasses the antibody or antigen-binding fragment thereof of claim 42, wherein the oxidized saccharide residue is a terminal sialic acid or galactose.
Claim 44 encompasses the antibody or antigen-binding fragment thereof of claim 33, wherein the drug effector moiety is linked through an oxime or hydrazone linkage to a saccharide residue of the glycan.
Claim 45 encompasses the antibody or antigen-binding fragment thereof of claim 44, wherein the saccharide residue is a terminal sialic acid or galactose residue of the glycan.
Claim 46 encompasses the antibody or antigen-binding fragment thereof of claim 44, wherein the drug effector moiety comprises a pH-sensitive linker, disulfide linker, enzyme- sensitive linker or other cleavable linker moiety.
Claim 48 encompasses the antibody or antigen-binding fragment thereof of claim 44, wherein the drug effector moiety is linked through the side chain of the asparagine residue to the saccharide residue of the glycan.
Claim 49 encompasses the antibody or antigen-binding fragment thereof of claim 33, wherein the antibody or antigen-binding fragment specifically binds an antigen selected from the group consisting of tumor endothelial marker 1 (TEM1), any CD52, human epidermal growth factor receptor 2 (HER2), and any fibroblast activation protein (FAP).
Claim 50 encompasses a composition comprising the antibody or antigen-binding fragment thereof of claim 33 and a pharmaceutically acceptable carrier or excipient.
Claim 51 encompasses any IgG antibody or antigen-binding fragment thereof comprising a CH1 domain, wherein the CH1 domain comprises an asparagine residue at amino acid position 114, according to Kabat numbering, and wherein a side chain of the asparagine residue is linked to a glycan, wherein the glycan is linked to a drug effector moiety to form an antibody drug conjugate (ADC), and wherein the drug effector moiety comprises Monomethyl Auristatin E (MMAE) or Dolastatin (Dol10) wherein the antibody or antigen-binding fragment thereof binds any tumor-associated antigen.
Enablement is not commensurate in scope with how to make and use the claimed IgG antibody or antigen-binding fragment thereof comprising a CH1 domain or any variant thereof, wherein the CH1 domain comprises an asparagine residue at amino acid position 114, according to Kabat numbering, and wherein the side chain of the asparagine residue is linked to a glycan, wherein the glycan is linked to a drug effector moiety to form an antigen drug conjugate (ADC), and wherein the effector moiety comprises Monomethyl Auristatin E (MMAE) or dolastatin (Dol10) wherein the IgG antibody or antigen binding fragment thereof binds to any and all possible tumor-associated antigen for treating any cancer.
The specification discloses just human IgG1 antibody that binds to CD52 wherein the position 114 is substituted for N (A114N) comprising the amino acid sequence of SEQ ID NO: 3, p. 63, anti-TEM1 (SEQ ID NO: 11), anti-FAP, and anti-HER2 (SEQ ID NO: 14 and 16). The specification discloses glycoconjugate comprising any one of the IgG1 antibodies above conjugated to monomethyl auristatin E (MMAE) or Dolastatin 10 (Dol10) via aminoxy-cys-Mc-Vc-PABC or aminooxy (AO) or AO-PEG8 linker through hydrazide or oxime linkage.
However, the specification does not teach i. Complete structure, e.g., amino acid sequence of heavy chain variable region and light chain variable region, ii. Partial structure, e.g., six CDRs of any and all IgG that correlated with binding to any and all possible tumor-associated antigen (claim 51) encompassed by the claimed IgG antibody or antigen binding fragment thereof conjugated to drug moiety comprising monomethyl auristatin E (MMAE) or Dolastatin 10 (Dol10) at position 114 of CH1 domain or variant thereof numbering according to Kabat numbering. There is no limitation on the structure that correlated with binding specificity of the antibody to which tumor associated antigen it binds (claim 51). The specification does not teach a representative number of species falling within the scope of the genus or structural features common to the members of the genus so the one of skill in the art can make and use member of the genus of the actual claimed IgG antibody or antigen-binding fragment thereof that bind to any and all possible tumor-associated antigens. The disclosure of a limited species of human IgG1 antibodies that bind to CD52, HER2, TEM1 and FAP is not representative of the vast genus of IgG antibody or antigen binding fragment thereof comprising 114A substitution in the CH1 domain or any variant thereof.
At the time the invention was made, it was known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope.
For example, Lloyd et al. taught that hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences (Lloyd et al. of record, Protein Engineering, Design & Selection 22:159-168, 2009; PTO 892; see, e.g., Discussion).
Similarly, Edwards et al., (of record, J Mol Biol. 334(1): 103-118, 2003; PTO 892) found that over 1000 antibodies, all different in amino acid sequence, were generated to a single protein; 568 different amino acid sequences identified for the V(H) CDR3 domains of these antibodies (Abstract).
Further, even minor changes in the amino acid sequence of a heavy or light variable region, particularly the CDRs, may dramatically affect antigen-binding function and IgG binding to the neonatal Fc receptor (FcRn) and pharmacokinetics.
For example, Piche-Nicholas et al (of record, MABS 10(1): 81-94, 2018; PTO 892) teaches altering complementary-determining region (CDRs) by 1-5 mutations significantly alter binding affinity to FcRn in vitro, see entire document, abstract, p. 95, right col, in particular. Engineering CDRs by modify local charge and thus maintain affinity to FcRn at 400 nM or weaker in vitro while retaining antigen binding may have far-reaching implications in the half-life optimization efforts of IgG therapeutics with respect to in vivo pharmacokinetics, see p. 90, in particular.
Poosarla et al (newly cited, Biotechn. Bioeng., 114(6): 1331-1342, 2017; PTO 892) teach substantial diversity in designed mAbs (sharing less than 75% sequence similarity to all existing natural antibody sequences) that bind to the same 12-mer peptide, binding to different epitopes on the same peptide. Said reference further teaches “most B-cell epitopes... in nature consist of residues from different regions of the sequence and are discontinuous...de novo antibody designs against discontinuous epitopes present additional challenges...". (See entire reference.)
Given that hundreds of unique antibody structures may bind a single antigen, the structure of an antibody cannot be predicted from the structure of the antigen, and a single species, or small group of species, cannot define a structure-function relationship so as to be representative of all the antibodies that bind to that antigen.
Regarding “IgG1 CH1 variant” (claim 35) and “human IgG1 CH1 domain variant” (claim 36), the specification discloses:
[0065] As used herein, the term “CH1 domain” includes the first (most amino terminal) constant region domain of an immunoglobulin heavy chain that extends, e.g., from about positions 114-223 in the Kabat numbering system (EU positions 118-215). The CH1 domain is adjacent to the VH domain and amino terminal to the hinge region of an immunoglobulin heavy chain molecule, and does not form a part of the Fc region of an immunoglobulin heavy chain.
[0087] CH1 domains from any immunoglobulin class (e.g., IgM, IgG, IgD, IgA and IgE) and species can be used in the binding polypeptides disclosed herein. Chimeric CH1 domains comprising portions of CH1 domains from different species or Ig classes can also be employed. In certain embodiments, the CH1 domain is a human IgG1 CH1 domain. In the case of a human IgG1 domain, mutation of the wild type amino acid at position 114 to an asparagine results in the formation of an N-linked glycosylation consensus site (i.e, the N-X-T/S sequon, where X is any amino acid except proline). However, in the case of other CH1 domains of other species and/or Ig classes or isotypes, the skilled artisan will appreciate that it may be necessary to mutate positions 115 and/or 116 of the CH1 domain to create an N-X-T/S sequon.
However, the term “variant” encompasses any substitution, deletion, addition or a combination thereof. Other than N-linked glycosylation consensus site N-X-T/S at positions 114-116 within the CH1 domain of IgG or human IgG1 CH1 domain, the specification does not teach where and what amino acid within the full-length sequence of CH1 domain to be substituted, deleted, added or a combination thereof such that the drug effector moiety is site-specifically conjugated to CH1 domain.
Regarding antibody drug conjugate (ADCs), it is well-established that target therapies such as ADCs is highly unpredictable even when using the same or similar linker-payload but different antibody.
For example, Nejadmoghaddam (Avicenna Journal of Medical Biotechnology 2(1): 3-23, 2019; PTO 892) discusses major obstacles of antibody-drug conjugates include off-target toxicity, tumor marker selection, antibody specificity, adequately affinity and receptor-mediated internalization are major aspects of choice, cytotoxic payload (e.g., up to 7 drugs per antibody), cytotoxic payload linkage strategy, aqueous solubility, non-immunogenic and stability in storage and bloodstream, see entire document, abstract, p. 15, in particular.
Gogia et al (Cancers 15: 3886, 2023; PTO 892) teaches the challenges of antibody drug conjugates (ADCs); these include the antibody specificity, the cytotoxic payload, linker chemistry, e.g., chemically labile (hydrazone bond and disulfide bond) or enzymatically labile, stability of the ADCs. Gogia et al teach that various Tumor-specific antigens have been discovered, However, despite the discovery of these tumor-specific antigens, difficulties persist. Firstly, high antigen affinity does not necessarily have high tumor penetration. Secondly, the distribution of cell surface target antigen expression defines the therapeutic window and a high antigen expression level in a tumor does not necessarily guarantee an ADC will be highly effective, see p. 23, in particular. ADCs have complex pharmacokinetic and pharmacodynamic profiles, which poses a challenge in designing them. Another challenge for ADC development is drug resistance, see p. 24, in particular. Thus, there is a high level of unpredictability in the art of ADCs such that the antibody in one ADC cannot simply be exchanged with another antibody directed against a different antigen with the expectation that the same result will be achieved.
There are insufficient in vivo working examples. It is unpredictable which undisclosed IgG antibody or antigen-binding fragment thereof that bind to any and all possible tumor associated antigen comprising a CH1 domain or any variant thereof, wherein the CH1 domain comprises an asparagine residue at position 114, according to Kabat numbering, wherein the side chain of the asparagine residue is linked to a glycan, wherein the glycan is linked to either Monomethyl Auristatin E (MMAE) or Dolastatin 10 (Dol10) is effective for treating which cancer.
In Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 2023 USPQ2d 602 (2023), the Supreme Court, held that claims drawn to a genus of monoclonal antibodies, which were functionally claimed by their ability to bind to a specific protein, PCSK9, were invalid due to lack of enablement. The claims at issue were functional, in that they defined the genus by its function (the ability to bind to specific residues of PCSK9) as opposed to reciting a specific structure (the amino acid sequence of the antibodies in the genus). The Supreme Court concluded that the patents at issue failed to adequately enable the full scope of the genus of antibodies that performed the function of binding to specific amino acid residues on PCSK9 and blocking the binding of PCSK9 to a particular cholesterol receptor, LDLR.
For these reasons, one skilled in the art would need to resort to undue experimentation in a complex and unpredictable field in order to determine how to perform the invention as claimed.
Applicants’ arguments filed March 13, 2026 have been fully considered but are not found persuasive.
Applicant’s position is that [T]he specification teaches the introduction of the Al14N substitution into the CH1 domain and describes its functional consequence, see, e.g., Applicant's Figure 1, namely the creation of an N-linked glycosylation site that supports site-specific conjugation across four antibodies directed to distinct tumor-associated antigens (CD52, TEM1, HER2, and FAP). See Applicant's Tables 4 and 5. The breadth of the amended claims is commensurate with what the specification enables (Wands A) because the claims recite a structurally defined genus tied to a single, mutation in the IgG CH1 region and further define the target class as tumor-associated antigens.
The claimed invention likewise supports enablement (Wands B), because the A114N mutation resides in a constant-region framework that behaves independently of the antibody's variable-region sequence binding any one specific tumor-associated antigen, as demonstrated in Examples 1 and 2.
At the time of filing, antibody mutagenesis, antibody-drug conjugation, and tumor- associated binding targets were well-established techniques and knowledge. As described in Applicant's Background and Summary, the novel Al14N site provided a more consistent and efficient attachment point for drug effector moieties (Wands C). Further, the level of ordinary skill in the art was high, and a practitioner versed in IgG engineering and ADC preparation would readily understand and perform the disclosed steps without requiring any specialized or uncommon expertise (Wands D).
The outcomes reported in the Specification provide reliable, experimentally supported evidence that a skilled artisan would be able to practice the claimed invention without undue experimentation, (Wands E). The Al14N mutation does not impair antigen recognition across four different tumor-associated antibodies (Examples 1-2), and ADCs generated using the engineered glycan exhibit potency in an in vitro cellular proliferation assay (Example 14) and therapeutic efficacy in an in vivo tumor-regression murine model (Example 15) enabling one skilled in the art to carry out the claimed invention.
Accordingly, Applicant respectfully requests that the rejection of the present claims as lacking enablement be reconsidered and withdrawn.
In response, enablement is not commensurate in scope with how to make and use the claimed IgG antibody or antigen-binding fragment thereof comprising a CH1 domain or any variant thereof, wherein the CH1 domain comprises an asparagine residue at amino acid position 114, according to Kabat numbering, and wherein the side chain of the asparagine residue is linked to a glycan, wherein the glycan is linked to a drug effector moiety to form an antigen drug conjugate (ADC), and wherein the effector moiety comprises Monomethyl Auristatin E (MMAE) or dolastatin (Dol10) wherein the IgG antibody or antigen binding fragment thereof binds to any and all possible tumor-associated antigen for treating any cancer for the following reasons.
The specification discloses just human IgG1 antibody that binds to CD52 wherein the position 114 is substituted for N (A114N) comprising the amino acid sequence of SEQ ID NO: 3, p. 63, anti-TEM1 (SEQ ID NO: 11), anti-FAP, and anti-HER2 (SEQ ID NO: 14 and 16). The specification discloses glycoconjugate comprising any one of the IgG1 antibodies above conjugated to monomethyl auristatin E (MMAE) or Dolastatin 10 (Dol10) via aminoxy-cys-Mc-Vc-PABC or aminooxy (AO) or AO-PEG8 linker through hydrazide or oxime linkage.
However, the specification does not teach i. Complete structure, e.g., amino acid sequence of heavy chain variable region and light chain variable region, ii. Partial structure, e.g., six CDRs of any and all IgG that correlated with binding to any and all possible tumor-associated antigen (claim 51) encompassed by the claimed IgG antibody or antigen binding fragment thereof conjugated to drug moiety comprising monomethyl auristatin E (MMAE) or Dolastatin 10 (Dol10) at position 114 of CH1 domain or variant thereof numbering according to Kabat numbering. There is no limitation on the structure that correlated with binding specificity of the antibody to which tumor associated antigen it binds (claim 51). The specification does not teach a representative number of species falling within the scope of the genus or structural features common to the members of the genus so the one of skill in the art can make and use member of the genus of the actual claimed IgG antibody or antigen-binding fragment thereof that bind to any and all possible tumor-associated antigens. The disclosure of a limited species of human IgG1 antibodies that bind to CD52, HER2, TEM1 and FAP is not representative of the vast genus of IgG antibody or antigen binding fragment thereof that bind to any and all possible tumor associated antigen and wherein the IgG antibody or antigen binding fragment thereof comprising 114A substitution in the CH1 domain or any variant thereof linked to a glycan wherein the glycan is linked to a drug moiety such as Monomethyl Auristatin (MMAE) or Dolastatin 10 (Dol10).
At the time the invention was made, it was known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope.
For example, Lloyd et al. taught that hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences (Lloyd et al. of record, Protein Engineering, Design & Selection 22:159-168, 2009; PTO 892; see, e.g., Discussion).
Similarly, Edwards et al., (of record, J Mol Biol. 334(1): 103-118, 2003; PTO 892) found that over 1000 antibodies, all different in amino acid sequence, were generated to a single protein; 568 different amino acid sequences identified for the V(H) CDR3 domains of these antibodies (Abstract).
Further, even minor changes in the amino acid sequence of a heavy or light variable region, particularly the CDRs, may dramatically affect antigen-binding function and IgG binding to the neonatal Fc receptor (FcRn) and pharmacokinetics.
For example, Piche-Nicholas et al (of record, MABS 10(1): 81-94, 2018; PTO 892) teaches altering complementary-determining region (CDRs) by 1-5 mutations significantly alter binding affinity to FcRn in vitro, see entire document, abstract, p. 95, right col, in particular. Engineering CDRs by modify local charge and thus maintain affinity to FcRn at 400 nM or weaker in vitro while retaining antigen binding may have far-reaching implications in the half-life optimization efforts of IgG therapeutics with respect to in vivo pharmacokinetics, see p. 90, in particular.
Poosarla et al (newly cited, Biotechn. Bioeng., 114(6): 1331-1342, 2017; PTO 892) teach substantial diversity in designed mAbs (sharing less than 75% sequence similarity to all existing natural antibody sequences) that bind to the same 12-mer peptide, binding to different epitopes on the same peptide. Said reference further teaches “most B-cell epitopes... in nature consist of residues from different regions of the sequence and are discontinuous...de novo antibody designs against discontinuous epitopes present additional challenges...". (See entire reference.)
Given that hundreds of unique antibody structures may bind a single antigen, the structure of an antibody cannot be predicted from the structure of the antigen, and a single species, or small group of species, cannot define a structure-function relationship so as to be representative of all the antibodies that bind to that antigen.
Regarding “IgG1 CH1 variant” (claim 35) and “human IgG1 CH1 domain variant” (claim 36), the specification discloses:
[0065] As used herein, the term “CH1 domain” includes the first (most amino terminal) constant region domain of an immunoglobulin heavy chain that extends, e.g., from about positions 114-223 in the Kabat numbering system (EU positions 118-215). The CH1 domain is adjacent to the VH domain and amino terminal to the hinge region of an immunoglobulin heavy chain molecule, and does not form a part of the Fc region of an immunoglobulin heavy chain.
[0087] CH1 domains from any immunoglobulin class (e.g., IgM, IgG, IgD, IgA and IgE) and species can be used in the binding polypeptides disclosed herein. Chimeric CH1 domains comprising portions of CH1 domains from different species or Ig classes can also be employed. In certain embodiments, the CH1 domain is a human IgG1 CH1 domain. In the case of a human IgG1 domain, mutation of the wild type amino acid at position 114 to an asparagine results in the formation of an N-linked glycosylation consensus site (i.e, the N-X-T/S sequon, where X is any amino acid except proline). However, in the case of other CH1 domains of other species and/or Ig classes or isotypes, the skilled artisan will appreciate that it may be necessary to mutate positions 115 and/or 116 of the CH1 domain to create an N-X-T/S sequon.
However, the term “variant” encompasses any substitution, deletion, addition or a combination thereof. Other than N-linked glycosylation consensus site N-X-T/S at positions 114-116 within the CH1 domain of IgG or human IgG1 CH1 domain, the specification does not teach where and what amino acid within the full-length sequence of CH1 domain to be substituted, deleted, added or a combination thereof such that the drug effector moiety is site-specifically conjugated to CH1 domain.
In response to the argument that the specification discloses method of making glycoconjugate using A114N mutation in the CH1 domain does not impair antigen recognition, the enablement requirement refers to the requirement of 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph that the specification describe how to make and how to use the invention, not just how to make the invention. See MPEP 2164.
Regarding antibody drug conjugate (ADCs), it is well-established that target therapies such as ADCs is highly unpredictable even when using the same or similar linker-payload but different antibody.
For example, Nejadmoghaddam (Avicenna Journal of Medical Biotechnology 2(1): 3-23, 2019; PTO 892) discusses major obstacles of antibody-drug conjugates include off-target toxicity, tumor marker selection, antibody specificity, adequately affinity and receptor-mediated internalization are major aspects of choice, cytotoxic payload (e.g., up to 7 drugs per antibody), cytotoxic payload linkage strategy, aqueous solubility, non-immunogenic and stability in storage and bloodstream, see entire document, abstract, p. 15, in particular.
Gogia et al (Cancers 15: 3886, 2023; PTO 892) teaches the challenges of antibody drug conjugates (ADCs); these include the antibody specificity, the cytotoxic payload, linker chemistry, e.g., chemically labile (hydrazone bond and disulfide bond) or enzymatically labile, stability of the ADCs. Gogia et al teach that various Tumor-specific antigens have been discovered, However, despite the discovery of these tumor-specific antigens, difficulties persist. Firstly, high antigen affinity does not necessarily have high tumor penetration. Secondly, the distribution of cell surface target antigen expression defines the therapeutic window and a high antigen expression level in a tumor does not necessarily guarantee an ADC will be highly effective, see p. 23, in particular. ADCs have complex pharmacokinetic and pharmacodynamic profiles, which poses a challenge in designing them. Another challenge for ADC development is drug resistance, see p. 24, in particular. Thus, there is a high level of unpredictability in the art of ADCs such that the antibody in one ADC cannot simply be exchanged with another antibody directed against a different antigen with the expectation that the same result will be achieved.
There are insufficient in vivo working examples. It is unpredictable which undisclosed IgG antibody or antigen-binding fragment thereof that bind to any and all possible tumor associated antigen comprising a CH1 domain or any variant thereof, wherein the CH1 domain comprises an asparagine residue at position 114, according to Kabat numbering, wherein the side chain of the asparagine residue is linked to a glycan, wherein the glycan is linked to either Monomethyl Auristatin E (MMAE) or Dolastatin 10 (Dol10) is effective for treating which cancer.
As such, it would require undue experimentation of one skilled in the art to make and use the claimed invention, commensurate in scope with the claims.
For these reasons, the rejection is maintained.
Conclusion
Claims 33-34, 37, 39-46, 48-50 are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PHUONG HUYNH whose telephone number is (571)272-0846. The examiner can normally be reached on 9:00 a.m. to 6:30 p.m. The examiner can also be reached on alternate alternative Friday from 9:00 a.m. to 5:30 p.m.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Misook Yu, can be reached at 571-270-3497. The fax phone number for the organization where this application or proceeding is assigned is 571-272-0839.
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/PHUONG HUYNH/ Primary Examiner, Art Unit 1641
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