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 .
DETAILED ACTION
1. Applicant’s amendment and response filed 7/8/2026 is acknowledged and has been entered. The Declaration of Inventor John C. Williams, Ph.D. under 37 C.F.R. 1.132 filed 7/8/2026 is acknowledged and has been entered.
2. Applicant is reminded of Applicant's election without traverse of Group I and species of first and second antibodies that both have a specific anti-cell surface antigen specificity, that of trastuzumab (anti-Her2/neu), first and second multivalent meditopes that are the sequence represented by SEQ ID NO: 1, a therapeutic agent that is a chemotherapeutic agent and a linker that is represented by SEQ ID NO: 200 in Applicant’s amendment and response filed 12/10/25.
Claims 4-6, 8-13, 15-20, 30 and 31 are being examined as they read upon the elected species, SEQ ID NO: 199-204 and SEQ ID NO: 1, 2, 15-55, 186-189 and 207.
Claims 4-6 are independent claims.
3. 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.
4. Claims 4-6, 8-13, 15-20, 30 and 31 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a new matter rejection.
This is a new ground of rejection necessitated by Applicant’s amendment filed 7/8/26.
The amendatory material not supported by the disclosure as originally filed is as follows:
“wherein said multivalent meditope comprises said first meditope bound to a second meditope” (as is recited in instant base claims 4-6).
Applicant states in the amendment and response filed 7/8/26 on page 10 at the top of the page that support for the amendments can be found in the claims and specification as originally filed.
However, the originally filed disclosure provides support for a meditope binding to an antibody, not to another meditope. The originally filed disclosure provides support for a first meditope attached to a second meditope via a linker (e.g., originally filed claim 7, [0039] of the instant specification). The specification does not disclose a limiting definition for “bind”, however, the said term is used exclusively throughout the originally filed disclosure to describe the specific binding interaction between a meditope and an antibody or between an antibody and its cognate antigen, which are specific non-covalent interactions. The meditopes do not have binding interaction with each other, non-covalent or otherwise.
5. Claims 4-6, 8-13, 15-20, 30 and 31 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
An applicant shows possession of the claimed invention by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention. Lockwood v. Amer. Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997). Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was "ready for patenting" such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaff v. Wells Elecs., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641, 1647 (1998); Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406; Amgen, Inc. v. Chugai Pharm., 927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991) (one must define a compound by "whatever characteristics sufficiently distinguish it"). "Compliance with the written description requirement is essentially a fact-based inquiry that will ‘necessarily vary depending on the nature of the invention claimed.' " Enzo Biochem, 323 F.3d at 963, 63 USPQ2d at 1612. An invention described solely in terms of a method of making and/or its function may lack written descriptive support where there is no described or art-recognized correlation between the disclosed function and the structure(s) responsible for the function. See MPEP 2163 I.A.
An applicant may also show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613 (quoting the Written Description Guidelines, 66 Fed. Reg. at 1106, n. 49, stating that "if the art has established a strong correlation between structure and function, one skilled in the art would be able to predict with a reasonable degree of confidence the structure of the claimed invention from a recitation of its function".). "Thus, the written description requirement may be satisfied through disclosure of function and minimal structure when there is a well-established correlation between structure and function." See MPEP 2163 II.3.
Applicant has broadly claimed:
a) a method for increasing cellular internalization of a first cell surface antigen and a second cell surface antigen (claims instant base claim 4 and its dependent claims 8-13, 15, 16, 18-20, 30 and 31) comprising
contacting the first cell surface antigen with a plurality of first meditope-enabled antibodies that bind to the first cell surface antigen;
contacting the second cell surface antigen with a plurality of second meditope-enabled antibodies that bind to the second cell surface antigen;
contacting a meditope-binding site of a first meditope-enabled antibody or antigen binding fragment thereof of the plurality of first meditope-enable antibodies with a first meditope from a multivalent meditope, wherein said multivalent meditope comprises said first meditope bound to a second meditope;
contacting a meditope-binding site of a second meditope-enabled antibody of the plurality of second meditope-enabled antibodies said second meditope from the multivalent meditope,
thereby crosslinking the first meditope-enabled antibody, and increasing cellular internalization of the first cell surface antigen and the second cell surface antigen; wherein
the meditope-binding site of the first meditope-enabled antibody and the meditope binding site of the second meditope-enabled antibody comprise a light chain variable (VL) region comprising a threonine at position 40, an asparagine at position 41, and an aspartate at position 85, according to Kabat numbering, and a heavy chain variable (VH) region comprising a serine or proline at position 40 and an isoleucine, tyrosine, methionine, phenylalanine, or a tryptophan at position 89, according to Kabat numbering (as is recited in instant base claim 4 and its dependent claims ), and
is a meditope-enabled antibody that specifically binds to an antigen selected from the recited Markush group in dependent claim 18, and including the other limitations of the dependent claims.
b) A method of decreasing a dosage of an antibody therapy needed to achieve a desired therapeutic effect in a subject, comprising:
(i) administering to a subject an effective amount of a plurality of first meditope-enabled antibodies capable of binding to a first cell surface antigen and an effective amount of a multivalent meditope, wherein said plurality of meditope-enabled antibodies comprises a first meditope-enabled antibody and a second meditope-enabled antibody , and wherein said multivalent meditope comprises a first meditope bound to a second meditope;
(ii) contacting a meditope-binding site of said first meditope-enabled antibody with said first meditope, thereby binding said first meditope-enabled antibody to said multivalent meditope; a first meditiope from the multivalent meditope;
(iii) contacting a meditope-binding site of a second meditope-enabled antibody with said second meditope, thereby binding said second meditope-enabled antibody to said multivalent meditope; and
crosslinking the first meditope-enabled antibody and the second meditope-enabled antibody, thereby decreasing the dosage of the antibody therapy needed to achieve the desired therapeutic effect in a subject; wherein
the meditope-binding site of the first meditope-enabled antibody and the meditope-binding site of the second meditope-enabled antibody comprise a light chain variable (VL) region comprising a threonine at position 40, an asparagine at position 41, and an aspartate at position 85, according to Kabat numbering, and a heavy chain variable (VH) region comprising a serine or proline at position 40 and an isoleucine, tyrosine, methionine, phenylalanine, or a tryptophan at position 89, according to Kabat numbering (as is recited in instant claim 6).
c) A method of increasing the efficacy of an antibody therapy needed to achieve a desired therapeutic effect in a subject, comprising
(i) administering to a subject an effective amount of a plurality of meditope-enabled antibodies capable of binding to a cell surface antigen and an effective amount of a multivalent meditope, wherein said plurality of meditope-enabled antibodies comprises a first meditope-enabled antibody and a second meditope-enabled antibody, and wherein said multivalent meditope comprises a first meditope bound to a second meditope;
(ii) contacting a meditope-binding site of said first meditope-enabled antibody with said first meditope of the multivalent meditope, thereby binding said first meditope-enabled antibody to said multivalent meditope;
(iii) contacting a meditope binding site of said second meditope-enabled antibody with said second meditope, thereby binding said second meditope-enabled antibody to said multivalent meditope; and
crosslinking the first and second meditope-enabled antibody to the second meditope-enabled antibody, thereby increasing the efficacy of the antibody therapy;
wherein the meditope-binding site of the first meditope-enabled antibody and the meditope-binding site of the second meditope-enabled antibody comprise a
light chain variable (VL) region comprising a threonine at position 40, an asparagine at position 41, and an aspartate at position 85, according to Kabat numbering, and a heavy chain variable (VH) region comprising a serine or proline at position 40 and an isoleucine, tyrosine, methionine, phenylalanine, or a tryptophan at position 89, according to Kabat numbering (as is recited in instant claim 5).
The specification does not disclose a representative number of species of such meditope-enabled antibody or antigen binding fragment thereof and/or cognate meditopes used in the in the claimed method, nor sufficient relevant identifying characteristics in the form of structure or functional characteristics coupled with a known or disclosed correlation between structure and function.
This is the case because:
The meditope-enabled antibodies that are used in the claimed methods are claimed by partial structure (i.e., the 40T/41N/D85 amino acid residues of an otherwise undefined variable light chain region “VL” of a generic or other antibody and the 40S/P/89IYMF or W amino acid residues of an otherwise undefined variable heavy chain “VH”) and function (i.e., the functional property of binding specifically to its cognate antigen and the functional property of binding to a meditope (peptide) (through the recited amino acid residues plus other non-recited amino acid residues), the meditope peptide being generic in all but dependent claims 19 and 20, and even so, the identity of the meditope peptide does not provide for the amino acid sequence of the VL/VH antibody that binds thereto), the specification and the art evidence that experimentation must be performed in order to determine the complete amino acid sequence of the VH/VL of the meditope-enabled antibodies, and the specification discloses one species of meditope-enabled antibody that is comparatively based upon one species of other antigen-binding meditope-enabled antibody. The presence of the recited residues of the VL and VH are not strictly correlated by themselves to the functional properties of binding to even the same (or different) meditopes or maintaining binding to the cognate antigen.
1) even though the claims recite some particular VL and VH substituents that are framework residues (i.e., 40T/N41/D85 for the VL according to Kabat numbering and 40S/P and 89 I/Y/M/F or W for the VH), these changes “comprise” (opening the claim to comprise other mutations in addition to those recited), the identity and position of changes in the framework amino acid residues can impact the functional property of being a meditope-enabled antibody or antigen binding fragment thereof (that is, the said limitation is functionally defined as is enunciated below, as is the definition of “meditope” as is also enunciated below), while the rest of the antibody sequence is generic since the antibody is generically recited (except for dependent claim 18 in part) and can also impact the functional property of antigen binding; and
2) the specification discloses that experimentation must be engaged to determine for each antibody, the differences relative to a template antibody, determination of which substituent amino acid residues in combination with others retains the functional property of antigen binding and binding to a generically and functionally recited meditope (the meditope being generic except for those recited instant dependent claims 19 and 20). In addition, instant dependent claim 18 recites generic antibodies that bind to an antigen selected from the laundry list of antigens recited in claim 18 (the latter category are not structurally defined except for the three defined residues in the VL framework region and the two defined residues in the VH region;
3) the specification discloses examples that are not universally applicable to possession of the functional properties of antigen binding and meditope binding for the generic (and the two Markush groups in claim 18) antibodies and generic (or defined in claim 19) meditopes even with the partial definition of variant residues on the VL and VH regions as recited in the instant claims for the reasons enunciated at “1)” and “2)” (lack of a representative number of species).
The specification discloses that the term “multivalent meditope” refers to a plurality of meditopes, and one or more linkers or linking means, and are not limited to those comprising the meditopes described in the instant specification ([0096]). The specification further discloses that the term “meditope” refers to a peptide or peptides that bind(s) to a central cavity such as a meditope-binding site of a meditope-enabled antibody or antigen binding fragment thereof, which antibody or antigen binding fragment thereof has a threonine at position 40, an asparagine at position 41, and an aspartate at position 85 of its light chain, according to Kabat numbering, or contains a meditope binding site containing residues that correspond to those within the meditope-binding site of cetuximab, meditiope-enabled trastuzumab, or meditope-enabled M5A, disclosed herein ([0097]).
The specification discloses that exemplary meditopes include but are not limited to the aQFD and CQYN peptide and variant s thereof ([0097]). The specification disclose that the term “linker” as used herein refers to the means by which the plurality of meditopes are linked or connected ([0098]).
The specification discloses that in some embodiments, the one or more residues that are replaced are selected from the light chain framework (FR) residues 10, 39-43, 45, 83, 85, 100 and/or 104 according to Kabat numbering, and/or heavy chain FR residue numbers 40, 89 and/or 105 according to Kabat numbering, while in some other embodiments those residues correspond to light chain residues 9, 10, 39, 40-43, 45, 83, 85, 100 and/or 104 and/or heavy chain residues 40, 89 and/or 105 according to Kabat numbering ([0217]), and in some instances the template antibody has one or more CDRs that are distinct from the CDRs of the meditope enabled antibody ([0227]). This disclosure is further indication that experimentation must be performed to determine the sequence of the antibody comprising a meditope binding site that has the functional properties of antigen binding and meditope binding.
The specification discloses that in some (non-limiting) examples, the meditope binding site is a structural feature of the mAb cetuximab and that the peptide consisting of the sequence of SEQ ID NO: 1 binds to a meditope binding site within the central cavity of the cetuximab Fab fragment, defined by various residues of the heavy and light chains ([0215]), but does not disclose what these residues are or the sequence of cetuximab ([0215]).
The specification further discloses that in some embodiments, the meditope enabled antibodies are generated by modifying an antibody other than cetuximab (the template antibody), such as an antibody having one or more CDRs distinct therefrom, to confer the ability to bind to one or more of the meditopes, wherein the template antibody can be human or humanized antibody or a mouse antibody. The specification discloses that in one aspect, the modifications include substituting residues within the central cavity of the Fab fragment, typically (but not exclusively) within the FRs of the heavy and light chain variable regions and/or the constant regions to render the template antibody meditope enabled, wherein in some embodiments residues are replaced with the corresponding residue present in cetuximab or a comparable amino acid residue ([0216]).
The specification discloses a laundry list of names of template antibodies 9[0233]-[0234]) and that meditope enabled antibodies may bind to one of a laundry list of antigens ([0235]).
The examples in the specification evidence that experimentation is required to determine the sequence of the VL and VH that retain the functional properties of binding to their cognate antigen and also possess the functional property of binding to a meditope peptide. The specification exemplifies making a meditope-enabled trastuzumab antibody by aligning and sequence identity mapping the sequence of cetuximab and trastuzumab onto the atomic model of trastuzumab bound to its cognate ligand, identifying residues that differ between the two antibodies and whose side chains either make direct contact with the meditope or potentially indirectly affect one species of meditope binding (i.e., the cQFD meditope), mutating equivalent positions in the trastuzumab sequence, and testing the antibody variant for binding to the cQFD meditope with sufficient affinity ([0424]-[0245]), followed by crystalization of the trastuzumab meditope enabled antibody with and without the cQFD meditope to ascertain whether or not the mutations significantly perturbed the overall structure of the Fab antibody variant ([0426]). (The cQFD meditope is cyclic CQFDLSTRRLKC (SEQ ID NO: 1) ([0057]). Note that the equivalent positions in the trastuzumab sequence that were mutated in the light chain comprise 13 changes, including the three recited in the instant claims.
Evidentiary reference Donaldson et al. (PNAS, 2013, 119(43): 17456-17461, of record) likewise underscores that experimentation must be engaged in to determine the structure of the particular antibodies (that are not cetuximab or trastuzumab) encompassed by the broad genus of antibodies that can bind to a cell surface antigen and that is engineered to comprise a meditope binding site for SEQ ID NO: 1 (or for any other meditope or in any other meditope). Donaldson et. al. teach that two peptides were identified by phage display (one of which is identical to instantly recited SEQ ID NO: 1 (“cQFD”) as thought to mimic the tumor epitope EGFR domain III. Donaldson et. al. teach that this said cQFD “meditope” binds to the Fab antigen-binding fragment of cetuximab, wherein the cocrystal structure revealed that the peptide docks in a cavity in the Fab framework. Donaldson et. al. examined the light and heavy chain sequences of cetuximab and compared them to that of a deco antibody (“CH 14.18”) as well as to that of non-binding antibodies trastuzumab, rituximab and M425, determined which sequence differences were likely to influence binding of the peptide, and mutated equivalent positions in trastuzumab. Donaldson et. al. produced the corresponding Fab fragment and cocrystalized it with the cQFD peptide and also determined that the changes did not significantly perturb the overall structure of this Fab or abrogate binding to the antigen (Her2/neu).
Thus, the specification discloses that each meditope-enabled antibody must be designed and subsequently tested for binding both to its antigen and with sufficient affinity to whichever meditope is under consideration (both functional properties).
In addition, the skilled artisan was aware that framework regions of both VH and VL domains can contribute to three-dimensional structure of the antibody as well as influence antigen binding, as is evidenced for example by:
Evidentiary reference MacCallum et al (J. Mol. Biol. 1996, 262, 732-74, of record), analyzed many different antibodies for interactions with antigen and state that although CDR3 of the heavy and light chain dominate, a number of residues outside the standard CDR definitions make antigen contacts (see page 733, right col) and non-contacting residues within the CDRs coincide with residues as important in defining canonical backbone conformations (see page 735, left col.).
Evidentiary reference Vajdos et. Al. (JMB, 2002, 320, 415-428, of record) additionally state that antigen binding is primarily mediated by the CDRs more highly conserved framework segments which connect the CDRs are mainly involved in supporting the CDR loop conformations and in some cases framework residues also contact antigen (page 416, left col.).
As is indicated above, the full sequence of the meditope-enabled antibodies and their corresponding meditopes which possess the functional property of binding to each other and with sufficient affinity and the functional property of the antibody binding specifically to its antigen cannot be envisioned a priori. One of skill in the art must employ methods of discovery to ascertain them.
Therefore, it appears that the instant specification does not adequately disclose the breadth of the meditope enabled antibody and the cognate meditopes used in the method recited in the instant claims. In light of this, a skilled artisan would reasonably conclude that Applicant was not in possession of the genus of all such meditope enabled antibodies and hence was not in possession of the method that uses them at the time the instant application was filed.
Applicant’s arguments have been fully considered but are not persuasive. Applicant’s said arguments are of record in the amendment and response filed 7/8/26 on pages 10-17 and reference the Declaration of Inventor John C. Williams, Ph.D. under 37 C.F.R. 1.132 filed 7/8/2026.
Applicant argues that meditopes were well known in the art at the time of filing the instant application as evidence by WO2013055404, with Tables 3 and 4 thereof describing the structural properties of more than 30 species of meditope peptides. Applicant further argues that corresponding binding assays using these meditopes are shown in Table 7 and described at [0423]-[0426]. Applicant argues that based on the specification as filed, a person having ordinary skill in the art would immediately recognize structural features required of a meditope for the recited function of binding a meditope-enabled antibody, with Tables 1 and 2 describing the structural properties of 40 meditope peptides contemplated for the invention claimed. Applicant concludes that for at least these reasons, a person having ordinary skill in the art would immediately recognize the structural features required of a meditope for the recited function of binding a meditope-enabled antibody at the time of filing the instant application. Applicant alleges that the specification and the said WI publication provide evidence that the meditope of Formula IV which falls under the meditope genus set forth in claims 4-6 effectively binds the meditope-binding site of a meditope-enabled antibody, and a person having ordinary skill in the art would easily recognize that Applicant was in possession of the meditopes set forth in the claims. Applicant references the Williams Declaration at section 6. The said section indicates that alignment of VL/VH FR region sequences of cetuximab with those of non-meditope-enabled antibodies illustrates the claimed residues of the meditope binding site as well as additional substitutions identified by sequence alignment necessary to design a meditope binding site.
However, Tables 3 and 4 describe exemplary peptides that are variants of two parent peptides aQFD and CQYN, whereas the instant specification discloses that meditopes are peptides that include but are not limited to these examples, wherein the limitation “meditopes” is functionally described. The claims except for claims 19 and 20 are functionally rather than structurally claimed. Table 7 and the said cited paragraphs pertain to affinities for some of these said meditope variants relative to binding a meditope-enabled cetuximab Fab, one antibody. Table 1 just describes the CDR positions of a two chain antibody with respect to three differing numbering systems, with further disclosure for identifying the positions of framework regions of the two chain antibody. Table 2 teaches the names of non-cetuximab antibodies that may be used as template antibodies to generate meditope-enabled antibodies [00195] using further experimentation to determine the full sequences thereof that can bind to the said variant meditopes. The instant claims are much broader than these said teachings.
Applicant argues that by aligning the sequences or superimposing the atomic structures of the VL and VH region of cetuximab with the VL and VH region of a template antibody, a person having ordinary skill in the art would immediately recognize that the VL framework residues Thre40, Asn41 and AP85 of cetuximab, which contains a natural meditope-binding site are necessary to meditope enable the template antibody (an pointing to section 5 of the Williams Declaration). As is stated above, section 6 of the Williams Declaration that alignment of VL/VH FR region sequences of cetuximab with those of non-meditope-enabled antibodies illustrates the claimed residues of the meditope binding site as well as additional substitutions identified by sequence alignment necessary to design a meditope binding site. Applicant argues that the Willaims Declaration states that at the time of filing the instant application, a person having ordinary skill in the art would immediately recognize if additional substitutions besides Thr40, Asn41 and Asp85 are necessary to design a meditope-enabled antibody using well known methods in the art such as sequence alignment and atomic structure superposition, and therefore would be able to generate a meditope-enabled antibody from any wild type antibody without undue experimentation (sections 7-10 of the said Declaration).
However, while the meditope-enabled antibody recited in the instantly claimed method must possess the amino acid residues at the three positions of the heavy chain and at the three positions of the light chain, the specification discloses that other framework modifications besides those recited in the instant claims must be assessed (i.e., the recited modifications are necessary but not sufficient for binding to a meditope peptide), the specification and the art disclose/teach that the residues are those in the framework regions of the antibody and often also in the constant region, while the art indicates that changes in the framework region can change the functional property of binding to a cognate antigen. The preponderance of the evidence indicates that based upon the amino acid sequences of the VL and VH of a non-meditope enabled antibody that further comprising the recited variant amino acid residues substituents at the recited position in each chain, one of skill in the art would not immediately recognize which of the substituted antibodies possess the functional properties of retaining binding to its cognate antigen and possess the functional property of binding to a generic or other meditope peptide, since other modifications are necessary and experimentation must be engaged in to determine if those combined changes in the context of each non-meditope enabled starting antibody possess the said requisite two functional properties. Experimentation is not a rationale for establishing adequate written description.
With regard to Applicant’s more detailed arguments regarding appendices submitted with the said Declaration in support of Applicant’s said arguments noted above (at sections 7-10 of the said Declaration), the following applies.
Applicant’s Appendix A is evidentiary reference Donaldson et al. (PNAS, 2013, 119(43): 17456-17461) that is cited in the instant rejection. Donaldson et al. teach that in grafting amino acid substituents into the light chain of anti-Her2/neu antibody trastuzumab more residues than those at positions 40, 41 and 85 of the light chain were substituted as well as multiple residues in the heavy chain (besides those recited in the instant claims, and accomplished by comparison of the amino acid sequence of non-modified trastuzumab with cetuximab cocrystalized with one of two meditope peptides cQFD or cQYN). Donaldson et al. teach that further studies were performed to determine that the modified trastuzumab bound the meditope peptides and bound to its cognate antigen. Different non-modified antibodies would be expected to have other amino acid residue differences with cetuximab besides those that are recited in the instant claims, indicating that the presence of 40T, 41N and 85D in the light chain of an antibody or substituted into the light chain of an antibody are necessary, but not sufficient to correlate with the required functional properties. See section 7 of the Williams Declaration.
Applicant’s Appendix B is Kuo et al. (J. Immunother. Cancer, 2022) who teach a meditope chimeric antigen receptor T cell and the same three antibodies taught by Donaldson et al. and the Examiner’s rebuttal of Donaldson et al. also applies hereto. In addition, Applicant argues that Supplementary Figure 2 of Kuo et al. illustrates an alignment of VL and VH framework regions sequence of cetuximab with corresponding sequences of template antibodies trastuzumab, anti-EGFR/HER3 antibody, anti-CD6 antibody, and lintuzumab, together with their respective meditope-enabled counter parts and that each are mutated to contain VL Thr40, ASn41 and Asp85. However, a color copy of Supplementary Figure 2 indicates that many more residues than the said three VL residues were substituted and including wherein the substitutions were not identical to those at corresponding positions of cetuximab, and in addition residue 40 in the one of the meditope enabled antibodies was changed to alanine rather than to serine or proline, while residue 89 was changed to isoleucine in all (note the other possible substituent amino acid residues at this position that are recited in the instant claims). See section 8 of the Williams Declaration. This once again illustrates that the VL Thr40, ASn41 and Asp85 are necessary but not sufficient for the structure (full amino acid sequence of the FR regions) of the VL with respect to the requisite functional properties.
Applicant’s Appendix C is Zer et al. (Prot. Eng. Des. Select., 2017, 30: 409-417) who teach that residues 40T, 41N, 83I, and 85D in the light chain are needed to convert a non-meditope enabled antibody M5A (anti-CEA) to an antibody that binds meditope peptide…, however residues 8, 9, 39, 42, 43, 45and 100 were also changed in the VL along with 40S and 89I of the VH being substituted in, thus demonstrating the residues recited in the instant claims are required but not sufficient for binding to a particular meditope peptide. As to Applicant’s argument that one having ordinary skill in the art would recognize how to make additional substitutions to further recreate the meditope-binding site of cetuximab by alignment of the VL and VH sequences of cetuximab with corresponding sequences of the template antibody, experimentation is not a rationale for establishing adequate written description. Also, many residues in the VL framework regions of unaltered M5A are very different from those found in the amino acid sequence of cetuximab that are apparent upon inspection of the linear sequence of both antibodies and these said different residues were not changed to those appearing in the sequence of cetuximab. See section 9 of the Williams Declaration.
Applicant has stated that based on the specification and the evidenced publications, a person having ordinary skill in the art would immediately recognize that a meditope-enabled antibody would have the functionality of meditope-binding while maintaining binding to its cognate antigen, pointing to [00125], [0480], [0515], and [00120] of the 404 publication (the WO document mentioned above), because the teachings therein specify that the FR regions of the antibody are non-CDR portions of the variable regions of the heavy and light chains, and since a person having ordinary skill would immediately recognize that the meditope-binding site is not part of the antigen-binding site of the antibody, and would therefore not interfere with antigen binding and testing of particular [limited] species in that document showed retention of antigen binding. Applicant argues that the specification as filed at paragraphs [0426] and [0427] show that point mutations made [in one antibody trastuzumab] do not cause alterations to the CDR loops of an antibody. However this argument is not persuasive, as the art cited in the instant rejection indicates that changes to the FR regions can also affect antigen binding, and this teaching is expected to be dependent upon the particular antibody. See paragraph spanning pages 15-16 of Applicant amendment and response filed 7/8/26 and section 12 of the Williams Declaration. The same rebuttal can be made to Applicant’s similar arguments regarding Appendix D which is King.
Applicant is also reminded that the written description requirement must be met as of the filing date of the claimed invention.
For these reasons and those enunciated in the instant rejection, a skilled artisan would reasonably conclude that Applicant was not in possession of the genus of all such meditope enabled antibodies and hence was not in possession of the method that uses them at the time the instant application was filed.
5. Upon further consideration, the prior rejection of record of claims 4-6, 8-13, 15-18, 30 and 31 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement is hereby withdrawn. Applicant’s arguments are persuasive.
6. The prior rejection of record of claim 18 on the basis that it contains an improper Markush grouping of alternatives is hereby withdrawn. Applicant has amended the claim to delete recitation of antibodies that compete for antigen binding or bind to the same epitope as the recited antibodies.
7. Applicant’s amendment filed 7/8/26 has overcome the prior rejection of record of claims 5, 6 and 17 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
8. No claim is allowed.
9. Applicant is reminded that SEQ ID NO: 199-204 are free of the prior art.
10. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
11. Any inquiry concerning this communication or earlier communications from the Examiner should be directed to MARIANNE DIBRINO whose telephone number is (571)272-0842. The examiner can normally be reached on M, T, Th, F.
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If attempts to reach the examiner by telephone are unsuccessful, the Examiner’s supervisor, MISOOK YU can be reached on 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Marianne DiBrino/
Marianne DiBrino, Ph.D.
Patent Examiner
Group 1640
Technology Center 1600
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
Prosecution Insights