DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
1. 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 April 8, 2026 has been entered. Claims 1, 8, 20, 29, 32, 36, 37, 39, 41-49, 51, 54-64 are pending. Claims 36, 37, 44, 54, 56-58, 60, 61, 63, and 64 are amended. Claims 29, 39, 41-43, 45 remain withdrawn. Claims 1, 8, 20, 32, 36, 37, 44, 46-49, 51, 54-64 are currently being examined as drawn to the elected species of:
A. effector protein (E) CD63;
B. VH CDRs SEQ ID NOs:2, 12, 14 and VL CDRs SEQ ID NOs:6, 7, 8 (claim 32(d));
C. Not conjugated to a moiety (withdraw claims 42-43); and
D. full length bispecific IgG1.
Claim Objections
2. Claim 32 is free of the art but is 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.
Maintained Rejections
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
3. Claims 1, 8, 20, 36-37, 44, 46-49, 51, and 54-64 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a WRITTEN DESCRIPTION rejection.
The claims are now drawn to a multispecific antibody comprising a first antigen-binding domain and a second antigen-binding domain, wherein the first antigen-binding domain specifically binds a cell surface-expressed tumor associated antigen (TAA), and wherein the second antigen-binding domain specifically binds to CD63, and wherein the second antigen-binding domain has a dissociation constant KD value with CD63 of between 2.0 x 10-9 and 7.3 x 10-9 M; wherein the multispecific antibody is induces internalization into a cell by way of binding CD63 only in the presence of the cell surface-expressed TAA; wherein the multispecific antibody has an EC50 value for binding to tumor-associated target (T)-expressing cells of lower than 5.0 ug/ml, as determined by flow cytometry; wherein binding of T and E by the multispecific antigen-binding molecule induces internalization of the multispecific antibody to a greater extent than the binding of T alone; wherein the second antigen-binding domain binds to the human CD63 second extracellular domain (Ala 103-Val 203); and treating cancer or targeting a tumor by administration of the multispecific antibody to a subject. Thus, the claims identify the second antigen-binding domain and multispecific antibody by function only, where the function is to:
bind CD63;
have a dissociation constant KD value with CD63 of between 2.0 x 10-9 and 7.3 x 10-9 M;
internalize into a cell by way of binding to CD63 only in the presence of the cell surface-expressed TAA;
have an EC50 value for binding to tumor-associated target (T)-expressing cells of lower than 5.0 ug/ml, as determined by flow cytometry;
induce internalization of the multispecific antibody to a greater extent than the binding of TAA alone;
bind to the human CD63 second extracellular domain (Ala 103-Val 203); and
treat cancer or target a tumor in a subject.
Thus, the claims identify the second antigen-binding domain and multispecific antibody by function only.
Claim 55 recites that the variable heavy domain (VH) of the second antigen binding domain comprises one or more substitutions in the amino acid sequence set forth in SEQ ID NO:1, which broadly encompasses any sequence having all amino acid residues of SEQ ID NO:1 substituted with any amino acid residues, and does not require the VH to have any conserved, identifying sequence structure. Claim 55 does not provide any identifying sequence for the variable light domain (VL) of the second antigen binding domain.
Similarly, claims 59 and 62 recite the VL of the second antigen binding domain comprises one or more substitutions in the amino acid sequence set forth in SEQ ID NO:5, which broadly encompasses any sequence having all amino acid residues of SEQ ID NO:5 substituted with any amino acid residues, and does not require the VL to have any conserved, identifying sequence structure. Claims 59 and 62 do not provide any conserved, identifying sequence for the VH domain of the second antigen binding domain.
Claims 56 and 57 recite there can be an amino acid substitution at position 71, 72, and/or 74 of the amino acid sequence set forth in SEQ ID NO:1, but do not identify what substitution occurs at which residue or require the claimed VH of the second antigen-binding domain to comprise any of SEQ ID NO:1 itself, and do not identify the sequences of the VL.
Claim 58 recites the VH comprises N74H substitution of SEQ ID NO:1, but does not require the VH of the second antigen-binding domain to comprise any of SEQ ID NO:1 itself, or identify the sequences of the VL critical to perform the claimed functions.
Similarly, claims 60 and 63 recite there can be an amino acid substitution at position 54 of the amino acid sequence set forth in SEQ ID NO:5, but do not identify what substitution occurs at position 54 or require the VL of the second antigen-binding domain to comprise any of SEQ ID NO:5 itself, and do not identify the sequences of the VH.
Claims 61 and 64 recite the VL of the second antigen binding domain comprises N54H substitution of SEQ ID NO:5, but does not require the VL to comprise any of SEQ ID NO:5 itself, or identify the sequences of the VH critical to perform the claimed functions.
Claims 55-64 recite that the VH or VL of the second antigen binding domain comprise an amino acid substitution in the amino acid sequence set forth in SEQ ID NO:1 or 5, or recite the VH or VL comprise one or more amino acid substitutions at positions found in SEQ ID NO:1 or 5, but never recite that the VH and VL are required to actually comprise the sequences of SEQ ID NO:1 and 5 and comprising the recited substitutions.
The instant specification discloses:
[0094] In a preferred embodiment said second domain, preferably as part of said second binding arm, comprises:
a) VH CDRs 1, 2, and 3 as provided in SEQ ID Nos: 2, 3, and 4, respectively, and VL CDRs 1, 2, and 3 as provided in SEQ ID Nos: 9, 7, and 8, respectively, or
b) VH CDRs 1, 2, and 3 as provided in SEQ ID Nos: 2, 10, and 4, respectively, and VL CDRs 1, 2, and 3 as provided in SEQ ID Nos: 6, 7, and 8, respectively, or
c) VH CDRs 1, 2, and 3 as provided in SEQ ID Nos: 2, 11, and 4, respectively, and VL CDRs 1, 2, and 3 as provided in SEQ ID Nos: 6, 7, and 8, respectively, or
d) VH CDRs 1, 2, and 3 as provided in SEQ ID Nos: 2, 12, and 4, respectively, and VL CDRs 1, 2, and 3 as provided in SEQ ID Nos: 6, 7, and 8, respectively.
[0099] In a particularly preferred embodiment, said second domain, preferably as part of said second binding domain, comprises VH CDRs 1, 2, and 3 as provided in SEQ ID Nos: 2, 12, and 4, respectively, and VL CDRs 1, 2, and 3 as provided in SEQ ID Nos: 6, 7, and 8, respectively.
[0100] According to another embodiment, said multispecific antigen-binding molecule comprises a mutated Fab region of a CD63-specific monoclonal antibody. According to another embodiment, said multispecific antigen-binding molecule comprises a mutated Fab region of CD63-specific monoclonal Ab 2192. According to another embodiment, said multispecific antigen-binding molecule comprises an antigen-binding region specific for CD63 selected from a hybridoma or phage-display library.
[0101] According to another embodiment, said first and second antigen-binding domains are each a pair of an antibody heavy chain variable domain and an antibody light chain variable domain.
[0102] The bispecific antigen-binding molecule may preferably further comprise antibody constant regions.
[0103] According to another embodiment, the antigen-binding molecule is a tumor-associated target (T)xCD63 bispecific antibody. In a preferred embodiment, the (T)xCD63 bispecific antibody is conjugated to a cytotoxic drug. In one embodiment the (T)xCD63 bispecific antibody is conjugated to duostatin-3. In one embodiment the (T)xCD63 bispecific antibody is conjugated to duostatin-3 and the anti-CD63 binding domain, which is the second binding domain, comprises VH CDRs 1, 2, and 3 as provided in SEQ ID Nos: 2, 12, and 4, respectively, and VL CDRs 1, 2, and 3 as provided in SEQ ID Nos: 6, 7, and 8, respectively.
Example 1: Antibody Generation, Site-Directed Mutagenesis and Duostatin-3 Conjugation
[0142] Cloning and production of the human HER2 antibody IgG1-153 has been described elsewhere; de Goeij B. E. C. G. MAbs, 2014. 6(2): p. 392-402. The variable domain heavy and light chain regions of the mouse monoclonal CD63 antibody 2192 (see Table 1 below, SEQ ID Nos. 1 and 5) were obtained from hybridoma 2.19 (Metzelaar M. J. Virchows Arch B Cell Pathol Incl Mol Pathol, 1991. 61(4): p. 269-77), by 5′-RACE of the variable regions from hybridoma-derived RNA and sequencing. Variable regions were cloned in the mammalian expression vector pcDNA3.3 (Invitrogen) containing the relevant human light chain constant domains (codon optimized, Invitrogen) with the relevant human heavy chain constant domain mutations (K409R or F405L). The human-mouse chimeric CD63 antibody was referred to as wild type IgG1-CD63. IgG1-CD63 antibody mutations were introduced in the variable domains either by site directed mutagenesis or direct gene synthesis, with the aim to generate a panel of IgG1-CD63 affinity variants. The amino acid mutations were indicated in the antibody names (i.e. anti-CD63-N74H has an asparagine to histidine mutation at amino acid position 74 of the heavy chain (SEQ ID No. 1, Table 1), anti-CD63-LN54H has a asparagine to histidine mutation at position 54 of the light chain, as numbered in SEQ ID No. 5, Table 1. Antibodies were produced by co-transfection of heavy chain and light chain vectors and transient expression in HEK-293 freestyle cells (Invitrogen) as described by Vink T. Methods, 2014. 65(1): p. 5-10. Bispecific antibodies (Duobody) were made by controlled Fab-arm exchange as described by Labrijn A. F. Nat Protoc, 2014. 9(10): p. 2450-63. The HIV gp120-specific human antibody IgG1-b12 was included as isotype control, see; Parren P. W. H. I. AIDS, 1995. 9(6): p. F1-6.
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The instant specification provides the sequence structure of CD63 antibody 2192 in Table 1, and paragraphs [94] and [103] critical to the claimed CD63 binding functions. The specification discloses that the CD63 antibody is a mouse monoclonal antibody 2192 (wild type) and discloses producing histidine amino acid substitutions at various residues and testing for alterations in CD63 affinity (Example 3; Table 2; Figures 2-5). The various histidine substitutions resulted in antibodies that either had greater, similar, or weaker affinity for CD63 than wild type, wherein N74H mutant, N54H mutant, T71H mutant, and P72H mutant all had a middle range of affinity (falling in the 2.0 x 10-9 and 7.3 x 10-9 M range) compared to all the mutants, and they had decreased affinity for CD63 compared to wild type (WT) (Figure 2). The four histidine substitution variants, N54H, T71H, P72H, and N74H, demonstrated a dissociation constant with CD63 of between 2.0 x 10-9 and 7.3 x 10-9 M and all share identical heavy and light chain variable domain sequences (SEQ ID NOs:1 and 5), except for the single substitutions N54H, T71H, P72H, and N74H.
With regard to the effect of histidine mutations on bispecific antibody internalization, the specification demonstrated:
Example 5 Lysosomal Co-Localization of Affinity Variants of Monovalent bsCD63xb12 ADCs
[0154] A confocal microscopy experiment was performed to confirm that CD63xb12 bispecific antibodies with reduced affinity for CD63 show less internalization and lysosomal transport. SK-OV-3 cells were cultured on glass coverslips (Thermo Fisher Scientific) at 37° C. for 16 hours. Antibody (2 and 10 μg/mL) was added and cells were incubated for 16 hours at 37° C. Cells were fixed, permeabilized and incubated 45 min with goat anti-human IgG1-FITC (Jackson) to stain for human IgG and mouse anti-human CD107a-APC (BD) to stain for lysosomes. Coverslips were mounted (Calbiochem) on microscope slides and imaged with a Leica SPE-II confocal microscope (Leica Microsystems) equipped with LAS-AF software. 12-bit grayscale TIFF images were analyzed for co-localization using MetaMorph® software (Molecular Devices). Co-localization was depicted as arbitrary units [AU] representing the total pixel intensity of antibody overlapping with the lysosomal marker LAMP1. This value was divided by the total pixel intensity of LAMP1, to correct for differences in cell density between different images.
[0155] As seen in FIG. 6 , wild type IgG1-CD63 showed the highest co-localization values, followed by its monovalent counterpart (bsCD63WTxb12) and bsCD63-Y79Hxb12. Lysosomal co-localization values for bsP72Hxb12, bsY121Hxb12, bsLN54Hxb12 and bsN74Hxb12 were ~10 fold lower compared to bsY79Hxb12 and wild type bsCD63xb12. Values for bsV52Hxb12, bsG76Hxb12, bsLV49Hxb12 and bsLY51Hxb12 were even lower, indicating there was hardly any lysosomal transport of the monovalent CD63 antibodies. Samples indicated with an asterisk (*) were not imaged. Data shown are mean±standard deviation of 3 images. FIGURE 6:
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To provide adequate written description and evidence of possession of the claimed second antigen-binding domain and multispecific antibody genus, the instant specification can structurally describe representative second antigen-binding domains that function in the multispecific antibodies as claimed, or describe structural features common to the members of the genus, which features constitute a substantial portion of the genus. Alternatively, the specification can show that the claimed invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics (see University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) and Enzo Biochem, Inc. V. Gen-Probe Inc.). A disclosure that does not adequately describe a product itself logically cannot adequately describe a method of using that product.
Although Applicants may argue that it is possible to screen for antibodies that bind CD63, including its extracellular domain, and function as claimed, the court found in Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004, that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention. “As we held in Lilly, “[a]n adequate written description of a DNA … ‘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.” 119 F.3d at 1566 (quoting Fiers, 984 F.2d at 1171). For reasons stated above, that requirement applies just as well to non-DNA (or RNA) chemical inventions.” Knowledge of screening methods provides no information about the structure of any future binding domains, antibodies, or mutations yet to be discovered that may function as claimed. The CD63 antigen and its extracellular epitopes provide no information about the structure of a binding domain or an antibody that binds to them and results in the claimed functions.
In this case, the only factor present in most of the claims is a recitation of the second binding domain or multispecific antibody functions as listed by the bullets above. Dependent claims 55-64 recite partial sequence structure of the second antigen binding domain comprising a substitution(s) at residue positions found in one or both of SEQ ID NO:1 and 5. The instant specification fails to describe structural features common to the members of the genus, which features constitute a substantial portion of the genus because the instant specification only discloses four exemplary highly homologous CD63 2192 monoclonal antibodies comprising a single defined histidine substitution at a specific residue (i.e., residue 54 of SEQ ID NO:5, and residue 71, 72, or 74 of SEQ ID NO:1). A definition by function does not suffice to define the genus because it is only an indication of what the binding domain and multispecific antibody do, rather than what they are. Other than for CD63 monoclonal antibody 2192 variants comprising the specifically defined CDR sequences recited in claim 32, the specification fails to provide the structural features coupled to the claimed functional characteristics. The instant specification fails to describe a representative number of second antigen-binding domain sequences for the genus of second antigen-binding domains that function as claimed. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus required to make the claimed multispecific antibody and to perform the claimed method.
Given the lack of representative examples to support the full scope of the claimed CD63 second antigen-binding domains used to make the multispecific antibody and used in the claimed methods, and lack of reasonable structure-function correlation with regards to the unknown sequences in the variable domains or CDRs of the CD63 binding domains or antibodies that provide the claimed functions listed by the bullets above, the present claims lack adequate written description. Thus, the specification does not provide an adequate written description of CD63 binding domains and mutated variants that is required to make the multispecific antibody and practice the claimed invention. Since the specification fails to adequately describe the product to which the claimed method uses, it also fails to adequately describe the method.
Examiner Suggestion: Bring the limitation of claim 32 into the independent claims, in order to specifically define the six CDR SEQ ID NOs critical to performing the claimed functions.
Response to Arguments
4. Applicants argue that the specification discloses a representative number of CD63 binding domains which bind within the claimed affinity range, as well as guidance for manipulating the amino acid sequences of CD63 antibodies to obtain the desired affinity. Applicants argue that Example 4 describes antigen binding domains that bind to CD63 at affinities between 2.0 x 10-9 and 7.3 x 10-9 M.
Applicants reiterate arguments made previously of record that the decisions relied upon by the Office, i.e., University of California v. Eli Lily and Co. and Rochester v. Searle do not apply to the instant claims for the reasons stated in the Remarks dated December 18, 2024. Applicants argue both decisions were based on the absence of the requisite knowledge and skill in the art at the time the invention was filed. Applicants argue that in contrast, in the instant case, in view of the knowledge and skill in the art at the maturity of the science at the relevant filing date and the teachings of the instant specification, the skilled artisan would have no reason to doubt that other CD63 binding domains which have or could be readily modified to have the claimed KD could be used in the claimed multispecific antibodies without undue experimentation.
In the Remarks dated December 18, 2024, Applicants argued that the decisions in Lily and Enzo that Examiner relied upon for the standards of written description were not applicable to the instant claims. Applicants argued that the claims in Lily were drawn to the nucleotide sequence of the rat insulin gene and a prophetic example in the specification for isolating the gene from other mammals including humans. Applicants argued that in Rochester, the claims were drawn to methods for selectively inhibiting PGHS-2 activity in a human host by administering a non-steroidal compound that selectively inhibits activity of the PGHS-2 gene product to a human host in need of such treatment. Applicants argued that the patent did not disclose any compounds or provide any suggestion as to how such a compound could be made. Applicants argued that assessing written description must take into account the nature and scope of the invention at issue and with the scientific and technologic knowledge already in existence.
Applicants argued that in both Lily and Rochester, it is clear that the courts’ decisions were based on the absence of the requisite knowledge and skill in the art at the time of filing. Applicants argue that in the instant case, there is knowledge in the art at the time of filing that CD63 binding domains were readily available and knowledge of modifying them to alter affinity (KD) without undue experimentation was known.
5. The arguments have been carefully considered but are not persuasive. Examiner relied upon the precedential decisions in University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) (“Lilly”) and Enzo Biochem, Inc. V. Gen-Probe Inc. (Fed. Cir. 2002) (“Enzo”) as the standards for determining adequate written description of the instant claims. Contrary to arguments, the precedential decisions in Lily and Enzo are relevant to assessing written description of the instant claims. Examiner established that:
the instant claims define the multispecific antibody first and second antigen-binding domains by function only without any antibody sequence structure recited or only partial sequence recited;
other than for the four histidine mutant 2192 monoclonal anti-CD63 antibodies binding to CD63 in the range of 2.0 x 10-9 and 7.3 x 10-9 M, the specification fails to provide the critical or shared core antibody sequence structure correlated to, and responsible for, the claimed functions (for example, the six complementarity determining region (CDR) sequences or variable light (VL) and heavy (VH) chain domain sequences critical to the antibody binding, internalizing, and treating functions) that is possessed by the broadly claimed genus of second antigen binding domains and multispecific antibodies; and
the specification fails to provide a representative number of species of antibodies for the broadly claimed genus of second antigen binding domains and resulting multispecific antibodies that function as claimed and listed in the bullet section of the rejection.
It is reiterated from the rejection that none of claims 55-64 require the VH and VL of the second antigen-binding domain to comprise any conserved regions of SEQ ID NOs: 1 and 5.
Contrary to arguments, the four single histidine substitution mutants of CD63 monoclonal antibody 2192 disclosed in the examples and Figure 2 (N54H, T71H, P72H, and N74H) are not sufficiently representative of the broad genus of second antigen-binding domains that bind to CD63 with a dissociation constant KD value of between 2.0 x 10-9 and 7.3 x 10-9 M. The claimed genus of second antigen-binding domains that bind to CD63 broadly encompasses any CD63 antibody comprising any heavy and light chain variable domain or CDR sequences. Examiner maintains that the disclosed four histidine substitution variants of monoclonal antibody 2192, that all comprise identical heavy and light chain variable domain sequences except for the single amino acid substitutions at N54H, T71H, P72H, or N74H, are not representative of the entire universe of, or broadly claimed genus of, anti-CD63 antibodies having any heavy and light chain variable domain sequences. The four histidine substitution variants of monoclonal antibody 2192 having a dissociation constant KD value of between 2.0 x 10-9 and 7.3 x 10-9 M all have a shared conservative heavy and light chain variable sequence of SEQ ID NOs:1 and 5, except for the single histidine substitutions, therefore only represent a very small portion of highly homologous antibodies having nearly identical CDR sequences listed in claim 32. It is well established in the art that the variability in CDR sequences for antibodies binding the same antigen is exponential, and knowledge of the antibody or epitope bound by an antibody provides no information on any identifying sequences and structures of the antibody binding to it.
Examiner maintains that the four disclosed histidine substitution variants of monoclonal antibody 2192, that all comprise identical heavy and light chain variable domain sequences except for the single specific amino acid substitutions at N54H, T71H, P72H, or N74H, are not representative of the broadly claimed genus of anti-CD63 antibodies having one or more substitutions anywhere in either the sequence of SEQ ID NO:1 or SEQ ID NO:5, or having any amino acid substitution found at any of positions 54, 71, 72, and 74 found in SEQ ID NO:1 or 5. The instant specification demonstrates the unpredictability of mutations in their 2192 parental CD63 monoclonal antibody on its affinity. Figure 2 and Table 2 demonstrate that various histidine mutations in the heavy or light chain CDRs resulted in a wide range of affinity variations, outside the range of 2.0 x 10-9 and 7.3 x 10-9 M. No information is provided on the effects of substituting any other amino acid positions with any other amino acid residues, outside of histidine. The only conserved, shared anti-CD63 antibody sequence structure demonstrated to function as claimed is the 2192 wild type monoclonal antibody comprising VH SEQ ID NO:1 and VL SEQ ID NO:5 and having any of four amino acid substitutions N54H, T71H, P72H, and N74H, or the anti-CD63 antibodies comprising the six defined CDR SEQ ID NOs recited in claim 32. These exemplary species provide the only disclosed, critical, and identifiable sequence structure for the claimed genus of CD63 antigen-binding domains to function as specifically claimed. Applicants have not persuasively argued that four highly homologous monoclonal antibodies, differing by only a single histidine substitution, are sufficiently representative of the vast genus of second antigen-binding domains required to immediately envision members of the broadly claimed genus. Applicants are not in possession of the broadly claimed second antigen-binding domains required to make the claimed multispecific antibody.
Contrary to arguments, the disclosure of known methods for mutating antibodies and screening for their affinities to CD63 does not provide any information on immediately identifying or recognizing the antibody sequences that are members of the broadly claimed genus and that function as claimed. As stated in the rejection, the court found in Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004, that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention. “As we held in Lilly, “[a]n adequate written description of a DNA … ‘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.” 119 F.3d at 1566 (quoting Fiers, 984 F.2d at 1171). For reasons stated above, that requirement applies just as well to non-DNA (or RNA) chemical inventions.” Knowledge of screening methods provides no information about the structure of any future binding domains, antibodies, or mutations yet to be discovered that may function as claimed. The target CD63 antigen or extracellular epitope provides no information about the structure of a binding domain or an antibody that binds to it and results in the claimed affinities and functions.
MPEP 2163 (II)(3)(a) states:
However, the claimed invention itself must be adequately described in the written disclosure and/or the drawings. For example, disclosure of an antigen fully characterized by its structure, formula, chemical name, physical properties, or deposit in a public depository does not, without more, provide an adequate written description of an antibody claimed by its binding affinity to that antigen, even when preparation of such an antibody is routine and conventional. See Amgen Inc. v. Sanofi, 872 F.3d 1367, 1378, 124 USPQ2d 1354, 1361 (Fed. Cir. 2017)("knowledge of the chemical structure of an antigen [does not give] the required kind of structure-identifying information about the corresponding antibodies"); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1351-52, 97 USPQ2d 1870, 1877 (Fed. Cir. 2011)(patent disclosed the antigen the claimed antibody was supposed to bind, but did not disclose any antibodies with the specific claimed properties).
In the instant case, the claimed multispecific antibody comprising a second antigen-binding domain specifically binding CD63 with a dissociation constant KD value with CD63 of between 2.0 x 10-9 and 7.3 x 10-9 M is claimed by its binding affinity to the CD63 antigen. Disclosure of the CD63 antigen, does not, without more, provide an adequate written description of the antibody claimed by its binding affinity to that antigen, even when preparation of such an antibody is routine and conventional. Therefore, although production of antibodies may be routine and conventional at the time of effective filing of the instant application, knowledge of routine methods for producing antibodies to a known antigen is not sufficient to satisfy written description requirement for resulting antibodies produced from such methods.
Applicants have not persuasively argued or demonstrated that anti-CD63 antibodies or antigen-binding domains having the specific dissociation constant KD value of between 2.0 x 10-9 and 7.3 x 10-9 M, and functioning in a multispecific antibody to internalize and treat cancer, were well established and readily recognizable in the state of the art at the time of filing. The fact that Applicants had to randomly mutate various amino acid positions of a monoclonal antibody, screen for their affinity to CD63, and test their internalization function as a multispecific antibody, suggests such antibodies and their sequence structures were not well known or readily identifiable at the time of filing.
Examiner Suggestion: Bring the limitation of claim 32 into the independent claims, in order to specifically define the six CDR SEQ ID NOs critical to performing the claimed functions.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
6. Claim(s) 1, 8, 20, 36-37, 44, 46-49, and 51 remain rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication 2013/0243775, Papadopoulos et al, published 2013.
Papadopoulos teaches a multispecific antigen-binding molecule comprising: (1) a first antigen-binding domain (D1) that binds a target molecule (T) that is a cell surface expressed tumor antigen, and (2) a second antigen-binding domain (D2) that binds an internalizing effector protein (E) (Figure 1; claims 1-33; [21-22]); wherein D1 or D2 bind the antigen with a KD of less than 500 µM ([24]).
Papadopoulos teaches ([64]): In the context of tumor killing applications, the D2 component may, in certain circumstances, bind with low affinity to the internalizing effector protein “E”. Thus, the multispecific antigen-binding molecule will preferentially target tumor cells that express the tumor-associated antigen. As used herein, “low affinity” binding means that the binding affinity of the D2 component for the internalizing effector protein (E) is at least 10% weaker (e.g., 15% weaker, 25% weaker, 50% weaker, 75% weaker, 90% weaker, etc.) than the binding affinity of the D1 component for the target molecule (T). In certain embodiments, “low affinity” binding means that the D2 component interacts with the internalizing effector protein (E) with a KD of greater than about 10 nM to about 1 μM (10 nM to about 1000 nM), as measured in a surface plasmon resonance assay at about 25° C.
Papadopoulos teaches known methods for assessing KD of antibodies, particularly by means of surface plasmon resonance assay at 25° C:
[28] Methods for determining whether two molecules specifically bind one another are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, and the like. For example, an antigen-binding domain, as used in the context of the present invention, includes polypeptides that bind a particular antigen (e.g., a target molecule [T] or an internalizing effector protein [E]) or a portion thereof with a KD of less than about 500 pM, less than about 400 pM, less than about 300 pM, less than about 200 pM, less than about 100 pM, less than about 90 pM, less than about 80 pM, less than about 70 pM, less than about 60 pM, less than about 50 pM, less than about 40 pM, less than about 30 pM, less than about 20 pM, less than about 10 pM, less than about 5 pM, less than about 4 pM, less than about 2 pM, less than about 1 pM, less than about 0.5 pM, less than about 0.2 pM, less than about 0.1 pM, or less than about 0.05 pM, as measured in a surface plasmon resonance assay.
[29] The term “surface plasmon resonance”, as used herein, refers to an optical phenomenon that allows for the analysis of real-time interactions by detection of alterations in protein concentrations within a biosensor matrix, for example using the BIAcore™ system (Biacore Life Sciences division of GE Healthcare, Piscataway, N.J.).
[30] The term “KD”, as used herein, means the equilibrium dissociation constant of a particular protein-protein interaction (e.g., antibody-antigen interaction). Unless indicated otherwise, the KD values disclosed herein refer to KD values determined by surface plasmon resonance assay at 25° C.
Papadopoulos teaches the D1 binds a tumor antigen or HER2 ([46-52]; [59-60]); the D2 binds CD63 and is IgG1 ([41-43]; [56]; Examples 2 and 3; claims 1-3, 26); wherein the multispecific antigen-binding molecule is a bispecific antibody that is a full length IgG1 antibody ([38-40]); wherein the multispecific antigen-binding molecule is recombinantly expressed by a nucleic acid in a vector and by a host cell ([23]; [37]); wherein the multispecific antigen-binding molecule is comprised in a pharmaceutical composition ([66-68]); wherein the multispecific antigen-binding molecule is administered to a subject to target a tumor and treat cancer such as breast, lung, ovarian, or prostate cancer ([59-60]; [65]; [67-68]; claim 32); wherein the binding of T and E induces internalization of the multispecific antigen-binding molecule to a greater extent than the binding of T alone (abstract; [5-6]; [22]; [55-58]).
Papadopoulos teaches making a CD63xHER2 bispecific antibody, as stated above, exemplifies making anti-CD63xtarget antigen bispecific antibody (Example 4), and exemplifies making a bispecific antigen-binding molecule targeting CD63 and a cell surface-expressed tumor antigen antibody with a commercially available anti-CD63 antibody (Examples 2 and 3). Papadopoulos demonstrates the bispecific antigen-binding molecule successfully internalized the effector protein CD63 to cause the internalization and degradative rerouting of the cell surface expressed tumor associated target molecule within a tumor cell. Papadopoulos demonstrates that simultaneous binding of the cell surface expressed tumor antigen and CD63 by the exemplary bispecific antigen-binding molecule successfully attenuated the activity of the cell surface expressed tumor antigen to a substantially greater extent (i.e., >10%) than the binding of the cell surface expressed tumor antigen by the control constructs alone (Example 2). Papadopoulos demonstrates that the bispecific antibody construct attenuated the cell surface expressed tumor antigen activity better than the parental antibody against the tumor antigen at concentrations out to 10-9 M and 10-8 M (Example 4, Figure 7).
Papadopoulos does not teach:
the CD63 antibody has a dissociation constant KD value with CD63 of between 2.0 x 10-9 and 7.3 x 10-9 M; and
the bispecific antibody has an EC50 value for binding cells expressing the cell surface-expressed tumor associated antigen of lower than 5.0 µg/ml as determined by flow cytometry assay.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed for Papadopoulos to produce a CD63 bispecific binding antibody that has a dissociation constant KD value with CD63 of between 2.0 x 10-9 and 7.3 x 10-9 M. One would have been motivated to and have a reasonable expectation of success to given: (1) Papadopoulos specifically suggests the binding affinity of the D2 component for the internalizing effector protein (E) is at least 10% weaker (e.g., 15% weaker, 25% weaker, 50% weaker, 75% weaker, 90% weaker, etc.) than the binding affinity of the D1 component for the target molecule (T); (2) Papadopoulos suggests “low affinity” binding means that the D2 component interacts with the internalizing effector protein (E) with a KD of greater than about 10 nM to about 1000 nM, as measured in a surface plasmon resonance assay at about 25° C which is close to the instantly claimed 7.3 nM value; and (3) Papadopoulos teaches a commercially available assay and known methods for determining the KD. Given Papadopoulos teaches: (1) the need to produce a multispecific antibody with a D2 binding domain having a lower affinity than the D1 and suggests exemplary low affinity dissociation constant values, (2) the known and commercially available methods or determining dissociation constant KD values, (3) the demonstrated success for making a bispecific antibody comprising anti- CD63 X tumor antigen; and (4) the demonstrated success for the anti- CD63 x tumor antigen bispecific antibody construct to attenuate the cell surface expressed tumor antigen activity better than the parental antibody against the tumor antigen, one of skill in the art could have pursued making and using an anti- CD63 x tumor antigen bispecific antibody comprising a CD63 binding domain with an affinity in the range of KD 2.0 x 10-9 and 7.3 x 10-9 M that is lower than any D1 antibody binding the tumor antigen, with a reasonable expectation of success.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed for Papadopoulos to produce a CD63 bispecific binding antibody that has a characteristic of an EC50 value for binding cells expressing the cell surface-expressed tumor associated antigen of lower than 5.0 µg/ml as determined by flow cytometry assay. One would have been motivated to and have a reasonable expectation of success to given Papadopoulos teaches motivation and demonstrates reasonable expectation of success to produce a CD63xtumor antigen bispecific antibody that has an increased efficiency in tumor cell activity inhibition over the parental single antibodies. Given methods of making the bispecific antibodies are demonstrated and methods to improve their anti-tumor activities are taught and demonstrated, it is well within the level of the ordinary skilled artisan to arrive at bispecific antibodies comprising a CD63 antibody as claimed and resulting in an improved anti-tumor cell activity encompassing EC50 values lower than 5.0 µg/ml for binding cells expressing the cell surface-expressed tumor associated antigen as determined by flow cytometry assay.
Response to Arguments
7. Applicants argue that Papadopoulos does not provide motivation to generate a multispecific antibody which binds to CD63 within the affinity range claimed and to a cell surface expressed tumor antigen. Applicants point to their arguments previously made in the Remarks dated December 18, 2024 and argue that the instantly claimed multispecific antibodies are efficiently internalized into cells when the second antigen-binding domain binds to CD63 with moderate affinity.
Applicants argue that the presently claimed invention is based on the discovery that multispecific antibodies which bind to a cell surface-expressed tumor antigen and CD63 are efficiently internalized into cells when the second antigen-binding domain binds to CD63 with moderate affinity. Applicants argue that the balance in cytotoxicity achieved with such CD63 binding domains, when combined with a binding domain for a cell surface expressed tumor antigen and used in ADC format, avoids undesired high toxicity to cells which do not express both the target tumor antigen and CD63. For instance, when using the multispecific antibody in ADC format with HER2 as the cell surface expressed tumor antigen, strong cytotoxic effects were observed with tumor cells expressing HER2, whereas a non-tumor targeting control ADC (e.g., a bispecific ADC binding to CD63 and HIV gp120-specific human antibody IgG1-b12) showed limitedcytotoxicity. This result was observed only for ADCs which bind to CD63 with
moderate affinity (i.e., KD value for CD63 between 2.0x10° and 7.3x10° M, as claimed). Indeed, ADCs with higher affinity for CD63 were not only highly cytotoxic, but the cytotoxicity was to some extent independent of binding to the tumor-associated antigen, an undesirable property when attempting to limit the cytotoxicity to cells expressing the tumor antigen of interest and CD63. Moreover, with ADCs having a lower affinity for CD63, only minor cytotoxicity was observed. These results suggest that multispecific antibodies having a CD63 binding domain with a moderate affinity for CD63 showed the most favorable characteristics, relative to CD63 binding domains having higher and lower affinities for CD63, for enhanced delivery of ADCs.
Applicants argue that Papadopoulos fails to recognize the benefits of the CD63 binding domain having a dissociation constant KD between 2.0 x 10-9 and 7.3 x 10-9 M in the multipecific antibody. Applicants argue that Papadopoulos suggests the CD63 binding domain have a lower affinity than the tumor targeting antibody in the multispecific antibody but does not teach or suggest utilizing a CD63 binding domain with “a moderate affinity for CD63”. Applicants argue that Papadopoulos fails to recognize the benefit of the claimed invention reducing undesirable effects on cells in the absence of the cell surface tumor associated antigen. Applicants argue the range of low binding affinity for the binding to the internalizing effector protein suggested by Papadopoulos (KD of greater than about 10 nM to about 1 μM = about 10 x 10-9 M to about 1000 x 10-9 M) is outside the claimed range of 2.0 x 10-9 and 7.3 x 10-9 M.
Applicants argue that one would not have been motivated to make a multispecific antibody having a CD63 binding domain which binds to CD63 within a moderate KD range between 2.0 x 10-9 and 7.3 x 10-9 M based on the teaching of Papadopoulos.
8. The arguments have been carefully considered but are not persuasive. Applicants are arguing limitations not recited in the rejected claims. Applicants are arguing that Papadopoulos fails to recognize the advantageous features for the specific anti-CD63 2192 monoclonal antibody binding domain demonstrated in the specification for in the multispecific antibody, however, this antibody is not recited in the rejected claims. Applicants are arguing that Papadopoulos fails to recognize the advantageous features of an ADC (antibody drug conjugate) comprising the anti-CD63 2192 monoclonal antibody having a KD between 2.0 x 10-9 and 7.3 x 10-9 M, however no ADC is claimed and no ADC comprising anti-CD63 2192 monoclonal antibody is recited in the rejected claims.
Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Although Applicants argue the claimed range of KD between 2.0 x 10-9 and 7.3 x 10-9 M is advantageous, Applicants have not demonstrated this advantage holds true or provides an unexpected beneficial result for any other CD63 antibody binding to any other epitope of CD63 with the same of KD between 2.0 x 10-9 and 7.3 x 10-9 M. The instant specification demonstrates this KD range is beneficial for anti-CD63 2192 monoclonal antibody comprising specific histidine mutations, all of which bind to the same epitope of CD63, and for anti-CD63 2192 in bispecific antibody format. The specification fails to demonstrate the advantage of this KD range is true for any other CD63 antibodies, binding to any other epitopes of CD63, and in any other multispecific antibody formats.
MPEP 716.02(d) states that to establish unexpected results over a claimed range, applicants should compare a sufficient number of tests both inside and outside the claimed range to show the criticality of the claimed range. In re Hill, 284 F.2d 955, 128 USPQ 197 (CCPA 1960). In the instant case, Applicants may argue that they demonstrated the criticality of the claimed range of KD between 2.0 x 10-9 and 7.3 x 10-9 M for the CD63 antigen-binding domain to optimize internalization and targeting of ADC activity, this claimed range was demonstrated for only anti-CD63 2192 monoclonal antibody, comprising a specific histidine substitution, and present in a bispecific antibody format. The specification fails to demonstrate the advantage of this KD range is true for any other CD63 antibodies, binding to any other epitopes of CD63, and in any other multispecific antibody formats.
MPEP 716.02(d) also states: Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980) (Claims were directed to a process for removing corrosion at "elevated temperatures" using a certain ion exchange resin (with the exception of claim 8 which recited a temperature in excess of 100C). Appellant demonstrated unexpected results via comparative tests with the prior art ion exchange resin at 110C and 130C. The court affirmed the rejection of claims 1-7 and 9-10 because the term "elevated temperatures" encompassed temperatures as low as 60C where the prior art ion exchange resin was known to perform well. The rejection of claim 8, directed to a temperature in excess of 100C, was reversed.). See also In re Peterson, 315 F.3d 1325, 1329-31, 65 USPQ2d 1379, 1382-85 (Fed. Cir. 2003) (data showing improved alloy strength with the addition of 2% rhenium did not evidence unexpected results for the entire claimed range of about 1-3% rhenium); In re Grasselli, 713 F.2d 731, 741, 218 USPQ 769, 777 (Fed. Cir. 1983) (Claims were directed to certain catalysts containing an alkali metal. Evidence presented to rebut an obviousness rejection compared catalysts containing sodium with the prior art. The court held this evidence insufficient to rebut the prima facie case because experiments limited to sodium were not commensurate in scope with the claims.).
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In the instant case, the claimed range of KD between 2.0 x 10-9 and 7.3 x 10-9 M for the CD63 monoclonal antibody 2192 histidine substitution mutants was demonstrated as beneficial in the specification over higher and lower affinities when present in a bispecific APC. The instant claims, however, are broadly drawn to any CD63 antigen-binding domain derived from any antibody, that can bind to any CD63 epitope, and is present in any multispecific antibody format and with any first antigen-binding domain.
Further, it is established in the art that dissociation constant values for an antibody with an antigen vary based on the assay and the assay conditions used to assess KD values. Temperature, pH, ionic strength, method of antigen mobilization, and substrates for assessing dissociation constant values are some variables that can result in different KD values for the same antibody and antigen. Papadopoulos recognizes this issue by disclosing:
[0030] The term “KD”, as used herein, means the equilibrium dissociation constant of a particular protein-protein interaction (e.g., antibody-antigen interaction). Unless indicated otherwise, the KD values disclosed herein refer to KD values determined by surface plasmon resonance assay at 25° C.
Given the unknown assay conditions for the instantly claimed KD range, one cannot definitively exclude the affinity values suggested by Papadopoulos from that claimed range.
Applicants argue the claims recite a second antigen binding domain having a beneficial “moderate affinity for CD63” that Papadopoulos fails to recognize, however, “moderate affinity” or middle range affinities can only be determined by a comparison or by relevance, and that range can change depending on what affinities of what antibodies are being compared, as well as what affinity assays are being used for measurement. A CD63 antibody binding to a different extracellular epitope or any epitope found in CD63, as broadly encompassed by the claims, is expected to result in a different range of affinities, and the range of “moderate affinity” is expected to be different for each antibody. There is no evidence presented of record that supports the claimed range of 2.0 x 10-9 and 7.3 x 10-9 M results in the benefits argued by Applicants for every CD63 antibody as broadly claimed.
Although Applicants argue that Papadopoulos fails to recognize the benefits of a mid-range affinity to CD63 for internalizing the bispecific antibody while minimizing cytotoxic effects on cells that express the internalizing effector protein (E) CD63 but do not express the tumor associated antigen (T), the motivation for Papadopoulos to arrive at the claimed KD in the rage of between 2.0 x 10-9 and 7.3 x 10-9 M for their CD63 binding domain does not have to be the same as Applicant’s motivation, in order to render the invention obvious. MPEP 2144 states: The reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006) (motivation question arises in the context of the general problem confronting the inventor rather than the specific problem solved by the invention); Cross Med. Prods., Inc. v. Medtronic Sofamor Danek, Inc., 424 F.3d 1293, 1323, 76 USPQ2d 1662, 1685 (Fed. Cir. 2005) ("One of ordinary skill in the art need not see the identical problem addressed in a prior art reference to be motivated to apply its teachings."); In re Lintner, 458 F.2d 1013, 173 USPQ 560 (CCPA 1972) (discussed below); In re Dillon,, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990), cert. denied, 500 U.S. 904 (1991).
In the instant case, Papadopoulos suggests the second binding domain (D2) to the internalizing effector protein (E) should have a lower affinity, KD, than the first binding domain (D1) to the cell surface-expressed tumor associated antigen (T) for reasons to allow the multispecific antibody D1 binding domain to target the tumor cells strongly, while still allowing the D2 binding domain to effectively internalize. Papadopoulos suggests the D2 affinity be at least 10%-90% weaker than the D1 binding affinity. This affinity can be in any range lower than any D1 binding domain, and Papadopoulos teaches known methods for assessing KD of antibodies, particularly by means of commercially available surface plasmon resonance assay at 25° C. Thus, Papadopoulos provides the motivation and means to successfully produce any D2 binding domain with an affinity in any range that is lower than any D1 binding arm affinity, including producing D2 binding domains with affinities in the KD range of 2.0 x 10-9 and 7.3 x 10-9 M for CD63, and that will predictably function to bind and internalize the multispecific antibody.
As stated in the rejection: It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed for Papadopoulos to produce a CD63 bispecific binding antibody that has a dissociation constant KD value with CD63 of between 2.0 x 10-9 and 7.3 x 10-9 M. One would have been motivated to and have a reasonable expectation of success to given: (1) Papadopoulos specifically suggests the binding affinity of the D2 component for the internalizing effector protein (E) is at least 10% weaker (e.g., 15% weaker, 25% weaker, 50% weaker, 75% weaker, 90% weaker, etc.) than the binding affinity of the D1 component for the target molecule (T); (2) Papadopoulos suggests “low affinity” binding means that the D2 component interacts with the internalizing effector protein (E) with a KD of greater than about 10 nM to about 1 μM, as measured in a surface plasmon resonance assay at about 25° C; and (3) Papadopoulos teaches a commercially available assay and known methods for determining the KD. Given Papadopoulos teaches: (1) the need to produce a multispecific antibody with a D2 binding domain having a lower affinity than the D1 and suggests exemplary low affinity dissociation constant values, (2) the known and commercially available methods or determining dissociation constant KD values, (3) the demonstrated success for making a multispecific antibody comprising anti- CD63 X tumor antigen; and (4) the demonstrated success for the anti- CD63 x tumor antigen bispecific antibody construct to attenuate the cell surface expressed tumor antigen activity better than the parental antibody against the tumor antigen, one of skill in the art could have pursued making and using an anti- CD63 X tumor antigen bispecific antibody comprising a CD63 binding domain with an affinity in the range of KD 2.0 x 10-9 and 7.3 x 10-9 M that is lower than a D1 antibody binding the tumor antigen, with a reasonable expectation of success.
9. Conclusion: Claim 32 is objected to. Claims 1, 8, 20, 36, 37, 44, 46-49, 51, 54-64 are rejected. All other objections and rejections under 35 U.S.C. 112(b)
recited in the Office Action mailed March 10, 2025 are hereby withdrawn in view of claim amendments.
10. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAURA B GODDARD whose telephone number is (571)272-8788. The examiner can normally be reached Mon-Fri, 7am-3:30pm.
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/Laura B Goddard/Primary Examiner, Art Unit 1642
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