DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The claim listing filed on August 22, 2025 is pending.
Claims 3-6, 8, 9, 11, 14, 15, 17, 18, 21, 23, 25, 32-36, 38-43, 45, 47-49 are canceled.
Claims 1, 2, 7, 10, 12, 13, 16, 19, 20, 22, 24, 26-31, 37, 44, and 46 are pending.
Election/Restriction
Applicant’s election without traverse to the species of SEQ ID NO: 66 as the specific scFv amino acid sequence; SEQ ID NO: 19 as the specific P1 amino acid sequence; SEQ ID NO: 36 as the specific L1 amino acid sequence; SEQ ID NO: 46 as the specific L2 amino acid sequence; and SEQ ID NO: 1 as the specific P2 amino acid sequence in the reply filed on August 22, 2025 is acknowledged.
Claims 1, 2, 7, 10, 12, 13, 16, 19, 20, 22, 24, 26-31, 37, 44, and 46 are currently under consideration.
Claim Interpretation
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The claims are drawn to a polypeptide complex comprising (1) a single chain variable fragment (scFv) that binds to an effector cell antigen cell antigen (green in figure below) and (2) an antigen recognizing molecule that binds to a tumor cell antigen (red in the molecule below).
Annotated snapshot of instant Figure 11.
The scFv is linked, by a linking moiety (L1) that is a substrate for a tumor specific protease, to a peptide (P1) at the N terminus of the scFv, wherein P1 impairs binding of the scFv to the effector cell antigen, and wherein P1 is further linked to a half- life extending molecule.
The antigen recognizing molecule comprises a Fab which is linked, by a linking moiety (L2) that is a substrate for a tumor specific protease, to a peptide (P2), wherein P2 comprises a peptide that impairs binding of the antigen recognizing molecule to the tumor cell antigen.
Claim Rejections - 35 USC § 112
Indefinite Language
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.
Claims 1, 2, 7, 10, 12, 13, 16, 19, 20, 22, 24, 26-31, 44, and 46 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) Claims 1, 2, 7, 10, 12, 13, 16, 19, 20, 22, 24, 26-31, 44, and 46 are indefinite for following reasons:
The phrase “binding of the scFv to an effector cell antigen” in lines 4 and 5 of claim 1 lacks antecedent basis in the claim because the scFv recited in line 2 of claim 1 does not recite the binding of scFv.
Additionally, line 8 of independent claim 1 recites “wherein the antigen recognizing molecule is linked to the scFv”. However, it is not clear how the antigen recognizing molecule is linked to scFv since the N-terminus of the scFv is already linked to P1 via L1.
Furthermore, the clause following semicolon in line 5 of claim is indefinite because it is currently written it in unclear in the antigen recognizing molecule is an additional domain of the polypeptide complex or if the antigen recognizing molecule is linked to P1. The Examiner recommends amending claim 1, to recite the phrase “wherein the polypeptide complex further comprises” in place of the word “and” after the semicolon in line 5.
B) Claim 12 recites the limitation “wherein the scFv comprises complementary determining regions (CDR)s of SP34” in lines1 and 2; claim 30 recites the limitation “wherein the single domain antibody comprises 10G or 10GE” in lines 1 and 2; and claim 31 recites the limitation “wherein the single domain antibody comprises 10G” in lines 1 and 2.
The claims are indefinite in the recitation of “SP34,” “10G,” and “10GE” because their characteristics are not known. The use of “SP34,” “10G,” and “10GE” as the sole means of identifying the claimed antibodies renders the claim indefinite because “SP34,” “10G,” and “10GE” are merely laboratory designations which do not clearly define the claimed product, since different laboratories may use the same designations to define completely distinct biological materials.
Amending claims 12, 30, and 31 to recite the appropriate Deposit Accession Number or SEQ ID NOs would obviate this rejection. See the rejection under the first paragraph of 35 U.S.C. 112 for the deposit of biological materials below.
For the purposes of applying prior art, the terms “SP34,” “10G,” and “10GE” are being used as the names of the claimed antibodies.
Enablement
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.
Claims 12, 30, and 31 are rejected under 35 U.S.C. 112, first paragraph, as containing 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.
Claim 12 recites the limitation “wherein the scFv comprises complementary determining regions (CDR)s of SP34” in lines1 and 2; claim 30 recites the limitation “wherein the single domain antibody comprises 10G or 10GE” in lines 1 and 2; and claim 31 recites the limitation “wherein the single domain antibody comprises 10G” in lines 1 and 2.
It is apparent that the hybridomas that produce the SP34, 10G, and 10GE are required to practice the claimed invention. As a required element, the SP34, 10G, and 10GE hybridomas must be known and readily available to the public or obtainable by a repeatable method set forth in the specification. If it is not so obtainable or available, the enablement requirements of 35 USC 112, first paragraph, may be satisfied by a deposit of the cell lines/hybridomas which produce the SP34, 10G, and 10GE. See 37 CFR 1.1801-1.1809.
If the deposit has been made under the terms of the Budapest Treaty, an affidavit or declaration by applicants or someone associated with the patent owner who is in a position to make such assurances, or a statement by an attorney of record over his or her signature, stating that the SP34, 10G, and 10GE hybridomas have been deposited under the Budapest Treaty and that the SP34, 10G, and 10GE hybridomas will be irrevocably and without restriction or condition released to the public upon the issuance of a patent, would satisfy the deposit requirement made herein. See 37 CFR 1.808.
Further, the record must be clear that the deposit will be maintained in a public depository for a period of 30 years after the date of deposit or 5 years after the last request for a sample or for the enforceable life of the patent whichever is longer. See 37 CFR 1.806.
If the deposit has not been made under the Budapest treaty, then an affidavit or declaration by applicants or someone associated with the patent owner who is in a position to make such assurances, or a statement by an attorney of record over his or her signature must be made, stating that the deposit has been made at an acceptable depository and that the criteria set forth in 37 CFR 1.801-1.809, have been met.
If the deposit was made after the effective filing date of the application for a patent in the United States, a verified statement is required from a person in a position to corroborate the fact, and should state, that the SP34, 10G, and 10GE hybridomas, which are deposited, are biological material specifically identified in the application as filed, except if the person is an attorney or agent registered to practice before the Office, in which case the statement need not be verified. See MPEP 1.804(b). Corroboration may take the form of a showing of a chain of custody from applicant to the depository coupled with corroboration that the deposit is identical to the biological material described in the specification and in the applicant’s possession at the time the application was filed.
Further, amendment of the specification to disclose the date of deposit and the complete name and address of the depository (ATCC.10801 University Boulevard, Manassas, VA 20110-2209) is required as set forth in 37 C.F.R. 1.809(d). As an additional means for completing the record, applicant may submit a copy of the contract with the depository for deposit and maintenance of each deposit.
It is apparent that the SP34, 10G, and 10GE are required to practice the claimed invention. It is noted that the Applicant has provided the heavy and light chain amino acid sequences of SP34 which are denoted at Ab-9 (SEQ ID NO: 64) and Ab-10 (SEQ ID NO: 65), respectively (e.g. see pages 71 and 72 of table 1). The Applicant has also provided the amino acid sequence of the single domain antibody 10G, denoted HE-1, (SEQ ID NO: 52) (e.g. see page 72 of table 1). The Applicant has not disclosed any structure for 10GE.
It is noted that the sequence of an entire immunoglobulin satisfies the enablement requirements under 35 USC 112, first paragraph as well. Note that satisfaction for the enablement of biological deposit of the specific SP34, 10G, and 10GE requires the disclosure and recitation of their entire amino acid sequence and not based upon partial sequences.
Applicant is invited to make the record clear whether satisfaction of the requirements under 35 USC 112, first paragraph, enablement for biological materials has been satisfied in a current U.S. Patent for “SP34”, “10G”, and “10GE” in order to make the record of the instant application complete.
Written Description
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.
Claims 1, 2, 7, 10, 12, 13, 16, 19, 20, 22, 24, 26-31, 37, 44, and 46 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 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.
The instant claims are drawn to a genus of polypeptide complexes comprising: (1) a single chain variable fragment (scFv) that binds to an effector cell antigen and (2) an antigen recognizing molecule that binds to a tumor cell antigen, wherein the scFv is linked, by a linking moiety (L1) that is a substrate for a tumor specific protease, to a peptide (P1) at the N terminus of the scFv, wherein P1 impairs binding of the scFv to an effector cell antigen, and wherein P1 is further linked to a half- life extending molecule; and wherein the antigen recognizing molecule comprises a Fab which is linked, by a linking moiety (L2) that is a substrate for a tumor specific protease, to a peptide (P2), wherein P2 comprises a peptide that impairs binding of the antigen recognizing molecule to the tumor cell antigen.
Dependent claim 7 recites “wherein the polypeptide complex has a molecular weight of less than about 110KDa”.
Dependent claim 12 encompasses scFv comprises CDRs of SP34 without reciting the antigen specificity.
Dependent claim 13 recites “wherein the scFv comprises an amino acid sequence that has at least 85% sequence identity to SEQ ID NOs: 66 …” without reciting the antigen specificity of the scFv.
Dependent claim 16 recites “wherein P1 comprises an amino acid sequence of at least 10 amino acids in length and no more than 20 amino acids in length”.
Dependent claims 20 and 44 recite wherein the linker “comprises a urokinase cleavable amino acid sequence, a matriptase cleavable amino acid sequence, matrix metalloprotease cleavable amino acid sequence, or a legumain cleavable amino acid sequence.”
Dependent claim 27 recites “wherein the half-life extending molecule comprises an antibody,” dependent claim 28 recites “wherein the antibody comprises a single domain antibody, a single chain variable fragment, or a Fab,” and dependent claim 29 recites “wherein the single domain antibody binds to albumin.”
To support such polypeptide complexes (PCs), the instant specification discloses two examples: PC-4 (e.g. see pages 74 and 75 of table 1) and PC-12 (e.g. see pages 78 and 79 of table 1). The Applicant discloses the full length light and heavy chain amino acid sequences of PC-4 (SEQ ID NOs: 70 and 73, respectively) and PC-12 (SEQ ID NOs: 80 and 81, respectively). Only PC-4 and PC-12 comprise all of the elements recited in claim 1. The scFvs of PC-4 and PC-12 specifically bind CD3 and their antigen recognizing molecules specifically bind EGFR and HER2, respectively. The specification further discloses L1 linker has a formular comprising GS (e.g. see page 3).
When given the broadest reasonable interpretation in light of specification, the polypeptide complexes of the instant invention are defined broadly to be any molecule comprising: two different protease-activatable masked functional binding domains, in which the first functional binding domain is any scFv that binds to any effector cell antigen and the second binding domain is any Fab-derived antigen recognizing molecule that binds any tumor cell antigen, wherein the functional binding domains are linked, by any protease cleavable linker, to any peptide (mask) that blocks interaction of their respective functional binding domains with their targets, and wherein the scFv masking peptide is further linked to any half-life extending molecule. (e.g. see [0004]).
It is noted that the scFv, the Fab-derived antigen recognizing molecule, the protease cleavable linkers, and the peptide masks include genera of polypeptide structures that have the desired respective functions. It is further noted that the half-life extending molecule includes a genus of structures comprising any ligand, small molecule, or peptide that is capable of extending the half-life of the polypeptide complex.
The broadest claim (claim 1) does not indicate any specific structure for the genus of polypeptide complexes claimed. Indeed, dependent claims 13, 19, 22, 26, 31, 37, and 46, do recite the amino acid sequences of the individual elements of the polypeptide complexes (the scFv (claim 13), the protease cleavable linkers (claims 22, 26, and 46), the peptide masks (claims 19 and 37), and the half-life extending molecules (claim 31)). Yet, no claim recites the entire structure of the polypeptide complex as is required for sufficient written description.
Moreover, independent claim 1 does not indicate any specific species of effector cell antigen or tumor cell antigen that the polypeptide complexes would bind nor where upon them it would bind. It is noted that dependent claim 10 does recite that the effector cell antigen is CD3 but still fails to recite the required structure.
The guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, § 1 "Written Description" Requirement make clear that if a claimed genus does not show actual reduction to practice for a representative number of species, then the Requirement may be alternatively met by reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the genus (Federal Register, Vol. 66, No. 4, pages 1099-1111, January 5, 2001, see especially page 1106 column 3). In The Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412) 19 F. 3d 1559, the court held that disclosure of a single member of a genus (rat insulin) did not provide adequate written support for the claimed genus (all mammalian insulins). In this same case, the court also noted:
“A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is. See Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen). It is only a definition of a useful result rather than a definition of what achieves that result. Many such genes may achieve that result. The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate.”). Accordingly, naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.”
Artisans are well aware that knowledge of a given antigen (for instance an effector cell antigen, such as CD3; a tumor cell antigen) provides no information concerning the sequence/structure of antibodies that bind the given antigen. For example, Edwards et al. (J. Mol. Biol., 2003, 334:103-118) teach that over 1,000 different antibodies to a single protein can be generated, all with different sequences spanning almost the entire heavy and light chain germline repertoire (42/49 functional heavy chain germlines and 33 of 70 V-lambda 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, see entire document).
As such, it does not seem possible to predict the sequence/structure of an antibody that binds a given antigen, as there does not appear to be any common or core structure present within all antibodies that gives rise to the function of antigen binding. Further, given data, such as that of Edwards et al., indicating the diversity of sequences in a population of antibodies that bind to a given antigen, no number of species appears to reasonably representative of the breadth of the genus of antibodies that bind the given antigen.
It should be pointed out that it is well established in the art that the formation of an intact antigen-binding site requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three different complementarity determining regions, CDR1, 2 and 3, which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin (Janeway Jr et al., Immunology, 3rd Edition, 1997 Garland Publishing Inc., pages 3:1-3:11.see entire selection). Thus, based upon the prior art, skilled artisans would reasonably understand that it is the structure of the CDRs within an antibody which gives rise to the functional property of antigen binding, the epitope to which said CDRs bind is an inherent property which appears to necessarily be present due to conservation of critical structural elements, namely the CDR sequences themselves.
As noted above, the specification only discusses two examples of the instantly claimed polypeptide complexes, PC-4 and PC-12, such a disclosure does not serve to provide sufficient written description of the claimed genus of polypeptide complexes. Further, the disclosure does not identify any specific structural features or combination of features which give rise to the function of binding to an effector cell antigen, such as CD3, or a tumor cell antigen. Additionally, there does not appear to be any reasonable shared structure present in the genus of recited “polypeptide complexes” which gives rise to their functional activity. As such, the instant specification appears to disclose applicant’s wish for polypeptide complexes that bind to an effector cell antigen and a tumor cell antigen without informing artisans what such polypeptide complexes actually are.
Ultimately, identifying an antibody simply on the basis of what it binds rather than by identifying the sequence/structure of the antibody in question is generally insufficient to provide written description of the antibody in question.
This reasoning further applies to claim 13 which recites the limitation “wherein the scFv comprises an amino acid sequence that has at least 85% sequence identity to SEQ ID NO: 66” in lines 1 and 2. Claim 13, does not satisfy the written description requirement because the claim language allows for up to 15% variability in the amino acid sequence structure of the scFv, inclusive of the antigen-binding sites (complementarity determining regions or CDRs), which would be expected to impact the functional binding activity of the scFv based on the state of the prior art. Claim 13 is drawn to a broad subgenus of scFv structures which are functionally defined by their ability to bind to an effector cell antigen without reciting a corresponding structure expected to correlate with this ability as supported by Applicant’s disclosure.
Regarding claims 12 and 13, which recite the structure of scFv without reciting its specific effector cell antigen specificity, these claims do not satisfy the written description requirement because an scFv comprising the claimed structure in the absence of an antigen specificity for CD3 would retain substantially the same binding specificity of the anti-CD3 scFvs of the instant disclosure (see Detailed Description, etc.)
Antibodies (or immunoglobulins) are glycoproteins that possess the ability to react in vitro and in vivo specifically and selectively with antigenic determinants or epitopes (or those that are closely related) to elicit their production. It has been well established in the art that knowledge of antigen binding specificity is critical for the skilled artisan to employ antibodies in various modalities (e.g., affinity purification, detection or diagnostic assays, bioassays, treatment), including those consistent with the instant disclosure (see specification, including the Detailed Description).
Nakakido et al. (Scientific Report 2023, 14:19533:1-13) teach that an antibody recognizes a unique target antigen and antibody applications are based on the high affinity and specificity of antibodies for their cognate antigen (e.g. see 1st paragraph under Abstract in page 1).
Given the well-known complexity and unpredictability of using antibodies with no particular antigen specificity, one of ordinary skill in the art cannot envision from the disclosed species the breadth of polypeptide complexes comprising the claimed scFv in scope with the claimed invention without the recitation of the binding specificity for CD3 in claims 12 and 13.
Regarding the lack of written description for the masking peptides and tumor specific protease cleavable linkers, the same logic above applies: structure does not necessarily correlate with function. Lui and Chen teach, “The efficacy of peptide masking and protease digestion need to be investigated in the future for broader application. The immunogenicity of the peptide mask also needs to be identified for the safety” (e.g. see Liu and Chen, Med. Rev. 2022, 2(6): pgs. 555-569, pg. 562, 2nd col. end of 1st para).
Regarding the masking peptides specifically, Chen teaches, “because of their low molecular weight and proximity to the binding site, these peptides must be carefully selected for their ability to fully inhibit target binding while attached to the antibody, yet readily permit cognate antigen-associated functions after tumor-residing enzymes hydrolyze the tethering cleavage site” (see Chen, T. 2022. Expert Opinion on Biological Therapy, 22:8, 955-963, pg. 958, 2nd col. 1st para).
Regarding the tumor specific protease cleavable linkers, Chen also teaches, “selecting the appropriate protease cleavage sequence is probably one, if not the most critical, aspect for creating this class of conditionally active T cell engagers” (see Chen pg. 959, 2nd col. last para), “peptide linkers that are too sensitive to this steady-state activity could result in nonspecific activation of the drug, causing on-target/off target damage and/or CRS” (see Chen pg. 960, 1st col. 1st para), and “beyond the relative sensitivity, little is known about precisely which proteases are active in the TME, presuming that these are similar between different tumor types. Matching the proper proteolytic linker sequence with a suitable tumor antigen targeting domain for appropriate clinical indication remains one of the biggest challenges for this class of drugs” (see Chen pg. 960, 1st col. 1st para).
Together, the art suggests that identifying masking peptides and tumor specific protease cleavable linkers is highly unpredictable.
Thus, one of ordinary skill in the art cannot envision from the disclosed species provided (i.e., PC-4 and PC-12), the breadth of polypeptide complexes of the instant invention comprising: two different protease-activatable masked functional binding domains, in which the first functional binding domain is any scFv that binds to any effector cell antigen and the second binding domain is any Fab-derived antigen recognizing molecule that binds any tumor cell antigen, wherein the functional binding domains are linked, by any protease cleavable linker, to any peptide (mask) that blocks interaction of their respective functional binding domains with their targets, and wherein the scFv masking peptide is further linked to any half-life extending molecule.
Therefore, in view of the breadth of the claims and the limited disclosure, artisans would reasonably conclude that applicant was not in possession of the full breadth of polypeptide complexes encompassed by the claims at the time the instant application was filed.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 2, 7, 10, 12, 16, 20, 22, 37, and 44 are rejected under 35 U.S.C. 103 as being unpatentable over Irving et al. 2016 (US20160194399A1, an IDS reference filed 12/15/2021) in view of Lowman et al. 2017 (US20170196996A1, an IDS reference filed 12/15/2021).
Irving et al. teach antibodies, activatable antibodies, multispecific antibodies, and multispecific activatable antibodies that specifically bind to at least CD3, an effector cell antigen (e.g. see Abstract). Irving et al. specifically teach an activatable antibody that comprises an antibody or an antigen binding fragment thereof (AB) that specifically binds to CD3ε; a masking moiety (MM) that inhibits the binding of the AB to CD3ε when the activatable antibody is in an uncleaved state; and a cleavable moiety (CM) coupled to the AB, wherein the CM is a polypeptide that functions as a substrate for a protease (e.g. see claim 11). The antigen binding fragment thereof may be a scFv (e.g. see claim 38) and the protease is produced by a tumor (e.g. see claim 17).
Irving et al.’s activatable antibodies and/or a multispecific activatable antibodies comprise one of the following formulae (where the formula below represent an amino acid sequence in either N- to C-terminal direction or C- to N-terminal direction): (MM)-L1-(CM)-(AB); (MM)-(CM)-L2-(AB); or (MM)-L1-(CM)-L2-(AB), wherein L1 and L2 are the same or different flexible linkers (e.g. see [0442] – [0445]). In addition, the formulae above provide for additional amino acid sequences that may be positioned N-terminal or C-terminal to the activatable antibody and/or the multispecific activatable antibodies elements (e.g. [0445]). Additional amino acid sequences include targeting moieties (e.g., a ligand for a receptor of a cell present in a target tissue) and serum half-life extending moieties (e.g., polypeptides that bind serum proteins, such as immunoglobulin (e.g., IgG) or serum albumin (e.g., human serum albumin (HSA)) (e.g. [0445]).
Irving et al. also teach that their activatable anti-CD3ε antibody may be formulated as part of a pro-Bispecific T Cell Engager (BITE) molecule (e.g. see [0126]). The T-cell engaging multispecific antibody includes an anti-CD3 epsilon (CD3ε) scFv that is derived from SP34 (e.g. see [0149]). The MM is a polypeptide of no more than 40 amino acids in length (e.g. see [0051]). The CM is a substrate for uPA, legumain, matriptase (also referred to herein as MT-SP1 or MTSP1), MMP-9, MMP-12, MMP-13, or MMP-14 (e.g. see [0054]).
It is noted that Figure 6D, copied below, depicts a multispecific activatable antibody that comprises an Ig antibody and a scFv in which the with primary antibody and secondary scFv sites are masked. The scFv (red) of this multispecific activatable antibody is attached to the Fc domain (green) of the Ig antibody. It is well known that the Fc domain is a species of half-life extending moiety. Giving instant claim 1 the broadest reasonable interpretation, the half-life extending moiety of the instant invention may be linked to P1(yellow) directly or indirectly. As such, Figure 6D of Irving et al. depicts a half-life extending moiety, in the form of an Fc domain, indirectly linked to P1 of the scFv through the Fc itself. Furthermore, the antigen recognizing molecule (blue) is linked to the scFv through the Fc.
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Figure 6D of Irving et al.
Irving et al. fail to teach their pro-BiTE comprising the activatable anti-CD3ε antibody further comprises an antigen recognizing molecule that binds to a tumor cell antigen, wherein the antigen recognizing molecule comprises a Fab light chain polypeptide and a Fab heavy chain polypeptide, wherein the antigen recognizing molecule is linked to the scFv, and the antigen recognizing molecule is further linked to P2 and L2, wherein P2 comprises a peptide that impairs binding of the antigen recognizing molecule to the tumor cell antigen; and L2 comprises a linking moiety that connects the antigen recognizing molecule to P2 and is a substrate for a tumor specific protease.
Lowman et al. teach activatable antibodies that include a masking moiety (MM), a cleavable moiety (CM), and an antibody (AB) that specifically bind to epidermal growth factor receptor (EGFR), a tumor cell antigen (e.g. see Abstract). Target-mediated toxicity constitutes a major limitation for the development of therapeutic antibodies (e.g. see [0366]). This is best exemplified by the skin rash that afflicts 88% of patients treated with cetuximab, an antibody that specifically binds EGFR and that has been approved for the treatment of colorectal and head and neck cancer. Lowman et al.’s activatable anti-EGFR antibodies were designed to address the toxicity associated with the inhibition of the target in normal tissues by traditional therapeutic antibodies. These activatable anti-EGFR antibodies remain masked until proteolytically activated at the site of disease (e.g. see [0366]). Lowman et al. also teach scFv (e.g. see [0081]).
Starting with cetuximab as a parental therapeutic antibody, Lowman et al. engineered the activatable anti-EGFR antibodies by coupling the antibody to an inhibitory mask through a linker that incorporates a protease substrate (e.g. see [0366]). In vitro, the binding to EGFR and the cell-based activity of the activatable anti-EGFR antibody was diminished compared to cetuximab. In vivo studies demonstrated that the activatable anti-EGFR antibody remained masked in normal tissues, but was activated and accumulated in the tumor environment. The tumor activation of the activatable anti-EGFR antibody translated into an in vivo efficacy that was equivalent to the efficacy of cetuximab (e.g. see [0366]).
Lowman et al. further teach that the activatable anti-EGFR antibody can be formulated as part of a pro-BITE molecule ([0327]). Lowman et al. also teach that CM is a substrate for uPA, legumain, MT-SP1, MMP-9, MMP-12, MMP-13, or MMP-14 (e.g. see [0282]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Irving et al. to incorporate the teachings of Lowman et al. to include that pro-BiTE comprising the activatable anti-CD3ε antibody further comprises an antigen recognizing molecule that binds to a tumor cell antigen, wherein the antigen recognizing molecule comprises a Fab light chain polypeptide and a Fab heavy chain polypeptide, wherein the antigen recognizing molecule is linked to the scFv, and the antigen recognizing molecule is further linked to P2 and L2, wherein P2 comprises a peptide that impairs binding of the antigen recognizing molecule to the tumor cell antigen; and L2 comprises a linking moiety that connects the antigen recognizing molecule to P2 and is a substrate for a tumor specific protease.
Given that both Irving et al. and Lowman et al. teach that their activatable antibodies can be formulated as part of a pro-BiTE molecule; it would have been obvious to a skilled artisan that by combining the activatable anti-CD3ε antibody of Irving et al., which comprises a half-life extending moiety, and the activatable anti-EGFR antibody of Lowman et al., a bispecific polypeptide complex could be produced that includes a first activatable binding moiety against CD3, an effector cell antigen, and a second activatable binding moiety against EGFR, a tumor antigen, and that specifically targets a cytotoxic T cell to a tumor. This platform would restrict target binding to within the tumor microenvironment given that the expression of tumor-specific proteases are restricted to these sites, thereby avoiding unwanted toxicities associated with binding to normal cells. Regarding the limitation in claim 7 which recites that “the polypeptide complex has a molecular weight of less than about 110 kDa” in lines 1 and 2, Irving et al. and Lowman et al. are silent on this property. However, silence about a particular property does not necessarily constitute its absence. The office does not have the facilities and resources to provide the factual evidence needed in order to establish that there is a difference between the materials, i.e., that the claims are directed to new materials and that such a difference would have been considered unexpected by one of ordinary skill in the art, that is, the claimed subject matter, if new, is unobvious. In the absence of evidence to the contrary, the burden is on the Applicant to prove that the claimed materials are different from those taught by the prior art and to establish patentable differences. See In re Best 562F.2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2d 1922 (PTO Bd. Pat. App. & Int. 1989).
It is noted that an average Fab domain has a molecular weight of approximately 50 kDa and an average scFv has a molecular weight of approximately 25-30 kDa. Thus, given that the two peptides and two linkers would only contribute marginally to the overall molecular weight of the claimed polypeptide complex, a skilled artisan would assume that a molecule made up of a Fab and an scFv would generally have a molecular weight of less than about 110 kDa.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Irving et al. 2016 (US20160194399A1, an IDS reference filed 12/15/2021) in view of Lowman et al. 2017 (US20170196996A1, an IDS reference filed 12/15/2021), as applied to claim 1, and further in view of Olbrich et al. (US 20150335706 A1).
The combined teachings of Irving et al. in view of Lowman et al. pertaining to claim 1 and the rationale for combining them is outlined in the 103 rejection above.
The combined reference teachings differ from the instant invention by not teaching that the scFv comprises an amino acid sequence that has at least 85% sequence identity to SEQ ID NO: 66.
Olbrich et al. disclose pharmaceutical compositions which contain polypeptides having at least two antigen-binding domains (e.g. see Abstract). Specifically, Olbrich et al. teach that the composition may comprise BiTE molecules, the first binding domain of which can bind to an epitope of the human and Callithrix jacchus, Saguinus oedipus or Saimiri sciureus CD3 epsilon chain (e.g. see [0044]). BiTE molecules are designed to transiently enlist cytotoxic T cells for the lysis of particular target cells and are especially suitable for cancer therapy (e.g. see [0041]).
A BiTE molecule is a polypeptide which comprises two scFv antibody binding domains, with the first scFv binding domain being able to bind to human CD3 epsilon and the second scFv binding domain binding a second, further surface antigen (e.g. see [0042]). Preference is given to human surface antigens of cancer cells (e.g. see [0042). Olbrich et al. specifically teach that SEQ ID NO: 5 displays the amino acid sequence of an anti-CD3 scFv binding domain which meets the above criteria (e.g. see [0045]). In particular, the first binding domain of Olbrich et al.’s polypeptide comprises the amino acid sequence reproduced in SEQ ID NO: 5 (e.g. see [0046]). Olbrich et al. also explicitly teach a bispecific T-cell engager comprising the amino acid sequence of SEQ ID NO: 8, which includes the anti-CD3 scFv of SEQ ID NO: 5 (see sequence alignment below) (e.g. see claim 1).
It its noted that Olbrich et al.’s SEQ ID NO: 5 is identical to instant SEQ ID NO: 66 (see sequence alignment below).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the combined teachings of Irving et al. in view of Lowman et al., as applied to claim 1, and to incorporate the teachings of Olbrich et al. to include that the scFv comprises an amino acid sequence that has at least 85% sequence identity to SEQ ID NO: 66. Given that Olbrich et al. has already successfully incorporated the anti-CD3 scFv amino acid sequence of instant SEQ ID NO:66 into a BiTE molecule; it would have been obvious to a skilled artisan to apply Olbrich et al.’s SEQ ID NO: 5 in the pro-BiTE taught by Irving et al. in view of Lowman et al., which comprises an anti-CD3 scFv, with a reasonable expectation of success.
Combining prior art elements according to known methods to yield predictable results is obvious to one of ordinary skill in the art (see MPEP § 2143(A)). From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Alignment of instant SEQ ID NO: 66 and Olbrich et al.’s SEQ ID NO: 5:
Query Match 100.0%; Score 1338; DB 1; Length 249;
Best Local Similarity 100.0%;
Matches 249; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAMNWVRQAPGKGLEWVARIRSKYNNYAT 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAMNWVRQAPGKGLEWVARIRSKYNNYAT 60
Qy 61 YYADSVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYISYWAYWGQGTL 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 YYADSVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYISYWAYWGQGTL 120
Qy 121 VTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCGSSTGAVTSGNYPNWVQQ 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 VTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCGSSTGAVTSGNYPNWVQQ 180
Qy 181 KPGQAPRGLIGGTKFLAPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCVLWYSNRWVF 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 KPGQAPRGLIGGTKFLAPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCVLWYSNRWVF 240
Qy 241 GGGTKLTVL 249
|||||||||
Db 241 GGGTKLTVL 249
Alignment of Olbrich et al.’s SEQ ID NOs: 5 and 8:
Query Match 100.0%; Score 1338; DB 1; Length 504;
Best Local Similarity 100.0%;
Matches 249; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAMNWVRQAPGKGLEWVARIRSKYNNYAT 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 250 EVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAMNWVRQAPGKGLEWVARIRSKYNNYAT 309
Qy 61 YYADSVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYISYWAYWGQGTL 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 310 YYADSVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYISYWAYWGQGTL 369
Qy 121 VTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCGSSTGAVTSGNYPNWVQQ 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 370 VTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCGSSTGAVTSGNYPNWVQQ 429
Qy 181 KPGQAPRGLIGGTKFLAPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCVLWYSNRWVF 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 430 KPGQAPRGLIGGTKFLAPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCVLWYSNRWVF 489
Qy 241 GGGTKLTVL 249
|||||||||
Db 490 GGGTKLTVL 498
Claim 24 and 26 is rejected under 35 U.S.C. 103 as being unpatentable over Irving et al. 2016 (US20160194399A1, an IDS reference filed 12/15/2021) in view of Lowman et al. 2017 (US20170196996A1, an IDS reference filed 12/15/2021), as applied to claim 1, and further in view of Beirnaert et al. 2017 (Front. Immunol. 8:867, 1-13).
The combined teachings of Irving et al. in view of Lowman et al. pertaining to claim 1 and the rationale for combining them is outlined in the 103 rejection above.
The combined reference teachings differ from the instant invention by not teaching that the half-life extending molecule comprises a linking moiety (L3) that connects the half-life extending molecule to P1; or L3 comprises an amino acid sequence according to SEQ ID NO: 51.
Beirnaert et al. teach the engineering of bivalent and bispecific VHH formats by using linkers of variable length to fuse the VHHs (e.g. see page 5, left column, third paragraph). As a linker between the two VHHs, either a stretch of 9GS, 12GS, and 30GS sequence was used. Depending on the VHH and the length of the linker, a dramatic increase in potency was observed (e.g. see page 5, left column, third paragraph).
It is noted that the 9GS linker is identical to instant SEQ ID NO: 51 (GGGGSGGGS).
Beirnaert et al. specifically teach engineering of TNF Nanobodies™ in combination with an anti-HSA Nanobody™ (which cross-reacts with mouse serum albumin) to achieve appropriate serum half-lives (e.g. see page 11, right column, first paragraph). The TNF Nanobodies™ and the anti-HSA Nanobody™ are separated by an appropriately long linker.
The VHH#3-based bivalent construct which consists, in sequence, of the following: a VHH#3 molecule, a 9GS linker, a VHH#3 molecule, a 9GS linker, and finally, an antihuman serum albumin VHH (anti-HSA VHH) at the carboxy-terminus to avoid rapid clearance of the compound from circulation (i.e., a construct of: VHH#3-9GS-VHH#3-9GS-HSA VHH) (e.g. see page 4, paragraph spanning left and right columns).
The VHH#1-based bivalent construct consisted of the following, in sequence: VHH#1, a 9GS linker, the anti-HSA VHH, another 9GS linker, and a VHH#1 molecule (i.e., a construct of: VHH#1-9GS-HSA VHH- 9GS-VHH#1) (e.g. see page 4, paragraph spanning left and right columns).
Beirnaert et al. indicate that that both the 9 amino acid linker of VHH#3-9GS-VHH#3-9GS-HSA and the ~30 amino acid (9GS-HSA-9GS) linker of VHH#1-9GS-HSA-9GS-VHH#1 (taking into account that the albumin-specific Nanobody™ spans a length of approximately 12 amino acids) provide distances compatible with the binding of both VHH#3 and VHH#1 modules to the same TNF molecule (e.g. see page 11, right column, first paragraph).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the combined teachings of Irving et al. in view of Lowman et al. as applied to claim 1, and to incorporate the teachings of Beirnaert et al. to include that the half-life extending molecule comprises a linking moiety (L3) that connects the half-life extending molecule to P1; and that L3 comprises an amino acid sequence according to SEQ ID NO: 51.
Given that Beirnaert et al. has already successfully incorporated SEQ ID NO: 51, also known as 9GS, as a linker to separate an anti-albumin VHH (a half-life extending molecule) from a target binding domain; it would have been obvious to a skilled artisan to use Beirnaert et al.’s 9GS linker to tether Beirnaert et al.’s anti-albumin VHH to Irving et al.’s anti-CD3 scFv portion of the pro-BiTE taught by Irving et al. in view of Lowman et al. with a reasonable expectation of success.
Combining prior art elements according to known methods to yield predictable results is obvious to one of ordinary skill in the art (see MPEP § 2143(A)). From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 27-31 are rejected under 35 U.S.C. 103 as being unpatentable over Irving et al. 2016 (US20160194399A1, an IDS reference filed 12/15/2021) in view of Lowman et al. 2017 (US20170196996A1, an IDS refer