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 amendments and responses filed 8/24/23 and 12/10/25 are acknowledged and have been entered.
2. 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 in Applicant’s amendment and response filed 12/10/25 is acknowledged.
Claims 4-6, 8-13, 15-20, 30 and 31 read on the elected species.
Accordingly, claim 14 (non-elected species of Group I) and claims 21-24 and 29 (non-elected Group II) are withdrawn from further consideration by the Examiner, 37 CFR 1.142(b), as being drawn to non-elected inventions.
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 lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which Applicant may become aware in the specification.
4. 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.
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 or antigen binding fragments thereof that bind to the first cell surface antigen;
contacting the second cell surface antigen with a plurality of second meditope-enabled antibodies or antigen binding fragments thereof 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 rist meditope-enable antibodies or antigen binding fragments thereof with a first meditope from a multivalent meditope;
contacting a meditope-binding site of a second meditope-enabled antibody or antigen-binding fragment thereof of the plurality of second meditope-enabled antibodies or antigen binding fragments thereof with a second meditope from the multivalent meditope,
thereby crosslinking the first meditope-enabled antibody or antigen binding fragment thereof, 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 or antigen binding fragment thereof comprise[s] 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
including wherein at least one of the meditope-enabled antibodies or antigen binding fragments thereof of the plurality of meditope-enable antibodies or antigen binding fragments thereof competes for antigen binding with, or binds to the same epitope as an antibody or antigen-binding fragment thereof selected from the recited Markush group in dependent claim 18 that specifically binds to one of the antigens selected from the recited Markush group alternatives, 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:
administering to a subject an effective amount of a plurality of first meditope-enabled antibodies or antigen binding fragments thereof that bind to the first cell surface antigen and an effective amount of a multivalent meditope;
contacting a meditope-binding site of a first meditope-enabled antibody or antigen binding fragment thereof of the plurality of meditope-enable antibodies or antigen binding fragments thereof with a first meditiope from the multivalent meditope;
contacting a meditope-binding site of a second meditope-enable antibody or antigen binding fragment thereof of the plurality of meditope-enabled antibodies or antigen binding fragments thereof with a second meditope from the multivalent meditope,
resulting in crosslinking of the first meditope-enabled antibody or antigen binding fragment thereof and the second meditope-enabled antibody or antigen binding fragment thereof, whereby crosslinking the first meditope-enabled antibody or antigen binding fragment thereof and the second meditope-enabled antibody or antigen binding fragment thereof increases the efficacy of the antibody therapy; wherein
the meditope-binding site of the first meditope-enabled antibody or antigen binding fragment thereof comprise[s] 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 5 and its dependent claim 17).
c) A method of decreasing a dosage of an antibody therapy needed to achieve a desired therapeutic effect in a subject, comprising
administering to a subject an effective amount of a plurality of meditope-enabled antibodies or antigen binding fragments thereof capable of binding to a cell surface antigen and an effective amount of a multivalent meditope;
contacting a meditope-binding site of a first meditope-enabled antibody or antigen binding fragment thereof of the plurality of meditope-enabled antibodies or antigen binding fragments thereof with a first meditope of the multivalent meditope,
contacting a meditope binding site of a second meditope-enabled antibody or antigen binding fragment thereof of the plurality of meditope-enabled antibodies or antigen binding fragments thereof with a second meditope of the multivalent meditope,
resulting in crosslinking of the first and second meditope-enabled antibodies or antigen binding fragments thereof, whereby crosslinking the first meditope-enabled antibody or antigen binding fragment thereof and the second meditope-enabled antibody or antigen binding fragment thereof and the second meditope-enabled antibody or antigen binding fragment thereof decreases 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 or antigen binding fragment thereof comprise[s] 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 6).
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 even the same (or different) meditopes or maintaining binding 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 claim18) 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 “wherein at least one of the meditope-enabled antibodies or antigen binding fragments thereof of the plurality of meditope-enabled antibodies or antigen binding fragments thereof competes for antigen binding with, or binds to the same epitope as an antibody or antigen-binding fragment thereof selected from the lengthy Markush list of antibodies that bind specifically bind to different antigens or 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. Except for antibodies that have exactly the same variant amino acid residues in the framework regions and are humanized (have the same CDRs), experimentation must be engaged in to determine which antibodies have the functional property of competing with or binding the same epitope of an antigen as another antibody (lack of a priori-envisioned structure/function relation correlation); and
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 cetuzimab 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 cetuzimab 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) 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 cetuzimab, 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 cetuzimab 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), 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) 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.).
Also, dependent claim 18 requires that at last one or both of the meditope-enabled antibodies or antigen binding fragment thereof competes for antigen binding with or binds to the same epitope as trastuzumab (or one of the other recited alternatives). As such, the structure of the template antibodies that compete for antigen binding with or binds to the same epitope as trastuzumab are not known until one of skill in the art employs a method to discover them.
In the instance in claim 18 that the meditope-enabled antibody or antigen binding fragment thereof that competes for antigen binding with or binds to the same epitope as an antibody or antigen binding fragment that binds to an antigen selected from the lengthy recited group of different antigens, there is no evidence of record of a representative number of species of such antibodies (either as template antibodies or having the three recited VL and the two recited VH amino acid residues), nor does the art provide a structure/function relationship for antibodies or their antigen binding fragments that bind to a particular antigen. The same is the case for an antibody or antigen binding fragment that competes for antigen binding with As pertains to structure/function, the following evidentiary references teach the large structural diversity inherent in different antibodies that bind to a same or overlapping epitopes of an antigen, let alone to different antigens.
Evidentiary reference Poosarla et. al. (Biotechn. Bioeng., 2017, 114(6): 1331-1342) teach substantial diversity in designed mAbs (sharing less than 75% sequence similarity to all existing natural antibody sequences) that bind to the same 12-mer peptide, binding to different epitopes on the same peptide. Said reference further teaches “most B-cell epitopes…in nature consist of residues from different regions of the sequence and are discontinuous...de novo antibody designs against discontinuous epitopes present additional challenges...". (See entire reference.)
Evidentiary reference Khan and Salunke (J. Immunol, 2014, 192: 6398-6405) teach that two structurally diverse germline mAbs recognizing overlapping epitopes of the same short peptide do so in different topologies, the said antibodies possessing entirely different CDR sequences. Said reference teaches that unrelated mAbs structurally adjust to recognize an antigen, indicating that the primary B cell response is composed of BCRs having a high degree of structural adaptability. Said reference also teaches that the common epitope(s) also adopt distinct conformations when bound to different mAbs, with the higher degree of structural plasticity inherent to the mAbs. Said reference further teaches “It has been shown that both the framework region and the CDRs have a considerable amount of inherent conformational plasticity…Therefore, it is not surprising that distinct germline Abs recognize the same epitope by rearranging the CDR conformations. This may well have implications of Ag specificity beyond the naïve BCR repertoire, because Kaji et al….have shown in a recent report that the B cell memory can contain both germline-encoded and somatically mutated BCRs.” (See entire reference).
Evidentiary reference Lloyd et. al. (Protein Engineering, Eng. Design & Selection, 2009, 22(3): 159-168) teach that a large majority of VH/VL germline gene segments are used in the antibody response to an antigen, even when the antibodies were selected by antigen binding. Said reference further teaches that in their studies, of the 841 unselected and 5,044 selected antibodies sequenced, all but one of the 49 functional VH gene segments was observed, and that there are on average about 120 different antibodies generated per antigen. Said reference also teaches that a wide variety of VH and VL pairings further increase diversity. (See entire reference.)
Evidentiary reference Edwards et. al. (JMB, 2008, 334: 103-118) teach that over 1,000 different antibodies to a single protein can be generated, all with different sequences, and representative of almost the entire extensive heavy and light chain germline repertoire (42/49 functional heavy chain germlines and 33 of 70 V-lamda and V-kappa light chain germlines, and with extensive diversity in the HCDR3 region sequences (that are generated by VDJ germline segment recombination) as well.
As is indicated above, the full sequence of the meditope-enabled antibodies and their corresponding meditopes that 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.
In addition, the specification does not disclose which variants of SEQ ID NO: 199-204 possess the functional property of linking a first or second meditope, nor a representative number of species therefore. (See instant dependent claim 11 for the recitation of “wherein the linker comprises a sequence of SEQ ID NO:” 199-204 or a variant thereof”). The specification discloses at [0074] that the geometry of the multivalent meditope can be controlled for receptor clustering, wherein in some instances it may be advantageous to brin two receptors in close proximity, whereas in others, it may be advantageous to keep receptors at a distance.
Therefore, it appears that the instant specification does not adequately disclose the breadth of the meditope enabled antibody or antigen binding fragment thereof 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 their antigen binding fragments thereof and hence was not in possession of the method that uses them at the time the instant application was filed.
6. Claims 4-6, 8-13, 15-19, 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The specification does not disclose how to use the instant invention:
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 or antigen binding fragments thereof that bind to the first cell surface antigen;
contacting the second cell surface antigen with a plurality of second meditope-enabled antibodies or antigen binding fragments thereof 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 rist meditope-enable antibodies or antigen binding fragments thereof with a first meditope from a multivalent meditope;
contacting a meditope-binding site of a second meditope-enabled antibody or antigen-binding fragment thereof of the plurality of second meditope-enabled antibodies or antigen binding fragments thereof with a second meditope from the multivalent meditope,
thereby crosslinking the first meditope-enabled antibody or antigen binding fragment thereof, 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 or antigen binding fragment thereof comprise[s] 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 (base claim 4), and
including wherein at least one of the meditope-enabled antibodies or antigen binding fragments thereof of the plurality of meditope-enable antibodies or antigen binding fragments thereof competes for antigen binding with, or binds to the same epitope as an antibody or antigen-binding fragment thereof selected from the recited Markush groups (that recite specific mAbs) or from the recited Markush group of antibodies or antigen binding fragments thereof in dependent claim 18 that specifically binds to one of the antigens selected from the recited Markush group alternatives, and including the other limitations of the dependent claims.
Instant independent claim 5 is drawn to a method of increasing efficacy of an antibody therapy, comprising administering to a subject an effective amount of a plurality of meditope-enabled antibodies or antigen binding fragments thereof capable of binding to a cell surface antigen and an effective amount of a multivalent meditope, contacting a meditope-binding site of a first meditope-enabled antibody or antigen binding fragment thereof of the plurality of meditope-enabled antibodies or antigen binding fragments thereof with a first meditiope from the multivalent meditope, contacting the meditope binding site of a second meditope-enabled antibody or antigen binding fragment thereof of the plurality of meditope-enabled antibodies or antigen binding fragments thereof with a second meditope from the multivalent meditope, resulting in crosslinking of the first meditope-enabled antibody or antigen binding fragment thereof and the second meditope-enabled antibody or antigen binding fragment thereof, and wherein the meditope-enabled antibody or antigen binding fragment thereof have the same said amino acid residues as those recited in claim 4.
Instant independent claim 6 (and its dependent claim 17) is drawn to a method of decreasing a dosage of an antibody therapy need to achieve a desired therapeutic effect in a subject comprising administering an effective amount of a plurality of meditope-enabled antibodies or antigen binding fragments thereof capable of binding to a cell surface antigen along with administering an effective amount of a generic multivalent meditope, wherein the meditope-enabled antibody or antigen binding fragment thereof have the same said amino acid residues as those recited in claim 4, followed by contacting a meditope binding site of a second meditope-enabled antibody or antigen binding fragment thereof of the said plurality with a second meditope of the multivalent meditope, resulting in crosslinking of the first and second meditope-enabled antibodies or antigen binding fragments thereof (claim 6).
The specification has not enabled the breadth of the claimed invention because the claims encompass determining for the method that uses them, the genus of a meditope-enabled antibody or antigen binding fragment thereof that binds to any in the genus of cell surface antigens (the generic claims 4-6, 8-13, 15-17, 19, 20, 30 and 31), or that competes for antigen binding with, or binds to the same epitope as an antibody or antigen-binding fragment thereof selected from the first recited group of specific mAbs, or from the second group of meditope-enabled antibodies that specifically bind to one of the recited antigens (dependent claim 18), wherein the invention cannot be practiced over its full scope without undue experimentation.
As stated above in this office action, experimentation must be engaged in to determine the identity of meditope-enabled antibodies or their antigen binding fragments thereof, even with the recitation of three fixed VL framework residues (i.e., 40T, N41 and D85 according to the Kabat numbering system) and two VH framework residues that must be present (the latter of which can potentially have one of two and one of five possible substituent amino acid residues, i.e., 40S/P and 89I/Y/M/F/W according to the Kabat numbering system), and relative to a particular meditope. The breadth of the claims is broad, encompassing a method that uses any meditope enabled antibody version of the antibody or antigen binding fragment thereof as well as any meditope (except for the ones recited in claims 19 and 20, the former of which encompasses a generic formula that has a minimum of 645,120 variant species considering the number of substituents that are recited). As stated above, the instant specification discloses that the candidate antibodies are compared to a template antibody, differences are noted in framework regions, a library or panel of framework variants are made and tested for antigen binding and for binding to a meditope, and crystal structures of the antigen with the meditope-enabled antibody are made (examples). It is unpredictable that the presence of the recited residues of the VL and VH will guarantee binding of the broad genus of meditope-enabled antibodies to the broad genus of meditopes, nor maintain binding to their cognate antigens (the latter because the changes to framework regions of the VH and the VL can influence the conformation of the CDRs that provide most of the binding interaction with the cognate antigens.
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 cetuzimab 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 specification exemplifies making a meditope-enabled trastuzumab antibody by aligning and sequence identity mapping the sequence of cetuzimab and trastuzumab onto the atomic model of trastuzumab, 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]).
Evidentiary reference Donaldson et. al. (PNAS, 2013, 119(43): 17456-17461) 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 cetuzimab, 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 cetuzimab 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).
Dependent claim 18 adds another level of experimentation to subsequently determine meditope-enabled antibodies and their antigen binding fragments thereof that compete for antigen binding with or bind to the same epitope as an antibody or antigen binding fragment thereof selected from the first recited Markush group of alternatives that are specific mAbs or as an antibody or antigen binding fragment thereof selected from the second recited Markush group of alternatives that bind to a specific antigen (and there is no structure except for the requirement of the five defined framework residues recited in instant base claim 4.
With regard to antibodies that react to a same epitope, evidentiary reference Anderson et. al. (1986, J. Clin. Microbiol. 23: 475-480) teaches identification of epitopes on RSV proteins by competitive binding immunoassay. However, Anderson et al teach “Although competitive binding can distinguish between competing and non-competing MAbs, it does not necessarily identify which MAbs react at which epitopes and antigenic sites…For example, two-way blocking between two MAbs suggests but does not prove that they react at the same or overlapping epitopes…Similarly, the lack of blocking between two MAbs suggests, but does not prove that they react at distinct epitopes or antigenic sites…” (paragraph spanning pages 478-479).
Similarly, the method of differential antigen disruption taught by evidentiary reference Shi et. al. (2006, J. Immunol. Meth. 314: 9-20) also suffers from the same deficiencies as the method taught by Anderson et. al., i.e., “if the...antibodies are found to share a binding profile with a ligand in the differential antigen disruption experiment, very likely, their epitopes overlap with the ligand-binding site, thereby infringing ligand-binding". That is, given this teaching and a general concordance with the competition assay method also taught by Anderson et al, the method suggests but does not prove that the antibodies react with the same epitope. Thus the evidentiary references underscore unpredictability in the art of identifying, and therefore making, antibodies that bind to the same epitope, even if they compete.
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. For example:
MacCallum et al (J. Mol. Biol. 1996, 262, 732-74), 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.).
Vajdos et al (JMB, 2002, 320, 415-428) 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.).
With regard to the second Markush group of binding specificities recited in claim 18, the skilled artisan was aware that the genus of antibodies that can bind to a same antigen, a same epitope of an antigen, or to overlapping epitopes of a same antigen is very broad and structurally diverse, as is evidenced below.
Evidentiary reference Poosarla et. al. (Biotechn. Bioeng., 2017, 114(6): 1331-1342) teach substantial diversity in designed mAbs (sharing less than 75% sequence similarity to all existing natural antibody sequences) that bind to the same 12-mer peptide, binding to different epitopes on the same peptide. Said reference further teaches “most B-cell epitopes…in nature consist of residues from different regions of the sequence and are discontinuous...de novo antibody designs against discontinuous epitopes present additional challenges...". (See entire reference.)
Evidentiary reference Khan and Salunke (J. Immunol, 2014, 192: 5398-5405) teach that two structurally diverse germline mAbs recognizing overlapping epitopes of the same short peptide do so in different topologies, the said antibodies possessing entirely different CDR sequences. Said reference teaches that unrelated mAbs structurally adjust to recognize an antigen, indicating that the primary B cell response is composed of BCRs having a high degree of structural adaptability. Said reference also teaches that the common epitope(s) also adopt distinct conformations when bound to different mAbs, with the higher degree of structural plasticity inherent to the mAbs. Said reference further teaches “It has been shown that both the framework region and the CDRs have a considerable amount of inherent conformational plasticity…Therefore, it is not surprising that distinct germline Abs recognize the same epitope by rearranging the CDR conformations. This may well have implications of Ag specificity beyond the naïve BCR repertoire, because Kaji et. al.….have shown in a recent report that the B cell memory can contain both germline-encoded and somatically mutated BCRs.” (See entire reference).
Evidentiary reference Lloyd et. al. (Protein Engineering, Eng. Design & Selection, 2009, 22(3): 159-168) teach that a large majority of VH/VL germline gene segments are used in the antibody response to an antigen, even when the antibodies were selected by antigen binding. Said reference further teaches that in their studies, of the 841 unselected and 5,044 selected antibodies sequenced, all but one of the 49 functional VH gene segments was observed, and that there are on average about 120 different antibodies generated per antigen. Said reference also teaches that a wide variety of VH and VL pairings further increase diversity. (See entire reference.)
Edwards et. al. (JMB, 2008, 334: 103-118) teach that over 1,000 different antibodies to a single protein can be generated, all with different sequences, and representative of almost the entire extensive heavy and light chain germline repertoire (42/49 functional heavy chain germlines and 33 of 70 V-lamda and V-kappa light chain germlines, and with extensive diversity in the HCDR3 region sequences (that are generated by VDJ germline segment recombination) as well.
There is insufficient guidance in the specification as to how to make and/or use the instant invention. Undue experimentation would be required of one skilled in the art to practice the instant invention. See In re Wands 8 USPQ2d 1400 (CAFC 1988).
7. Claim 18 is rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of: a) a meditope-enabled antibody or antigen binding fragment thereof that competes with or binds to the same epitope as antibody that is one of the recited specific mAbs (of which trastuzumab is one), and/or b) a meditope-enabled antibody or antigen binding fragment thereof that competes with or binds to the same epitope as antibody that specifically binds to one of the different antigens (of which Her2/neu is one) is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
the antibodies of “a)” bind to different antigens and/or have different sequences as do their meditope-enabled ‘competing’ or ‘same epitope binding’ antibodies, and the antibodies of “b)” bind to different antigens and will have different sequences. They do not share a single structural similarity for antigen binding.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
8. The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
9. Claims 5, 6 and 17 are rejected 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.
a) Claim 5 is indefinite in the recitation of the “contacting” steps because it is not clear what is meant, i.e., a plurality of meditope-enabled antibodies or antigen binding fragments thereof as well as an effective amount of a multivalent meditope are administered in the first step of the method, however it is not clear if the contacting steps are the same first administering step as well as an unrecited second administering step that describes the outcome of the administering, or are other active method steps.
b) Claim 6 is indefinite in the recitation of the “contacting steps” because it is not clear what is meant, i.e., a plurality of meditope-enabled antibodies or antigen binding fragments thereof as well as an effective amount of a multivalent meditope are administered in the first step of the method, however it is not clear if the contacting steps are the same first administering step as well as an unrecited second administering step that describes the outcome of the administering, or are other active method steps.
With regard to both claims 5 and 6, at a minimum, Applicant should recite in the administering step that an effective amount of a plurality of meditope-enabled antibodies or antigen binding fragments thereof comprises both a first and second meditope-enabled antibody, if that is what is meant, as a second meditope-enabled antibody lacks antecedent basis in the administering step.
10. Claim 18 is objected to because of the following informalities:
Claim 18 recites “antigen-binding” as well as “antigen binding” (the remaining claims recited “antigen binding”). Claim 18 also recites “HER2, neu” which should be HER2/neu.
Appropriate correction is required.
11. No claim is allowed.
12. SEQ ID NO: 199-204 are free of the prior art.
13. 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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/Marianne DiBrino/
Marianne DiBrino, Ph.D.
Patent Examiner
Group 1640
Technology Center 1600
/MICHAEL SZPERKA/Primary Examiner, Art Unit 1641