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
Status of the Claims
1. Claims 1-20 are the original claims filed 5/19/2023. In the Preliminary Amendment of 10/30/2023, claims 1-20 are canceled and new claims 21-37 are added. Claims 21-37 are pending.
Priority
2. USAN 18/320,599, filed 05/19/2023, is a Continuation of 16/805,105, filed 02/28/2020, now U.S. Patent # 11697684, 16/805,105 is a Divisional of 15/313,765, filed 11/23/2016, now U.S. Patent # 10633440, 15/313,765 is a National Stage entry of PCT/US2015/033081, International Filing Date: 05/29/2015,
PCT/US2015/033081 Claims Priority from Provisional Application 62/107,824, filed 01/26/2015, PCT/US2015/033081 Claims Priority from Provisional Application 62/008,229, filed 06/05/2014, PCT/US2015/033081 Claims Priority from Provisional Application 62/004,571, filed 05/29/2014.
Information Disclosure Statement
3. As of 1/20/2026, a total of one (1) IDS is filed: 10/30/2023. The corresponding initialed and dated 1449 form is considered and of record.
Objections
Specification
4. The disclosure is objected to because of the following informalities:
The use of the term, e.g., NCBI, BiaCore, BiTE, DART [0035], and which is a trade name or a mark used in commerce, has been noted in this application. It should be capitalized wherever it appears and be accompanied by the generic terminology. Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
5. Claims 26-27 are objected to because of the following informalities:
a) Claims 26-27 are unclear in reciting “chosen from” in Claim 26, which does not distinguish the language being closed or open.
b) Claim 26 is replete with grammatical and idiomatic errors.
For example, “Interleukin-13; Receptor a2 (IL13Ra2)”.
For example, some species are presented by both full and abbreviated name (EGFR (Epidermal Growth Factor Receptor); Ephrin receptor A2 (EphA2)” whilst other are presented by only an abbreviated name (ErbBl; ErbB3; ErbB4; GAGE-1; GAGE-2).
For example, some species are presented by only full name (lung adenocarcinoma antigen F3 or prostatic acid phosphate).
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Written Description
6. Claims 21-37 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim interpretation
Claim 21: a method for treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a Tri-Specific Binding Molecule that immunospecifically binds to three different epitopes…
“therapeutically effective amount”: a therapeutic amount is prophylactic or therapeutic effective amount, accordingly, the method of treatment claims are construed as therapeutic.
[0667] In another embodiment, the patient is administered a treatment regimen comprising one or more doses of such prophylactically or therapeutically effective amount of a Tri-Specific Binding Molecule of the present invention, wherein the treatment regimen is administered over 2 days, 3 days, 4 days, 5 days, 6 days or 7 days. In certain embodiments, the treatment regimen comprises intermittently administering doses of the prophylactically or therapeutically effective amount of the Tri-Specific Binding Molecules of the present invention (for example, administering a dose on day 1, day 2, day 3 and day 4 of a given week and not administering doses of the prophylactically or therapeutically effective amount of the Tri-Specific Binding Molecule
(A) The claims are drawn to numerous combinations of the total of four polypeptide chains recited in generic Claim 21 so long as VL1/VH1, VLII/VHII, VLIII/VHIII and CH2-CH3/CH2-CH-CH3 form an “association” to create the resultant structures having three separate and functional (immunospecific) antigen binding domains. The pairwise association between the four polypeptide chains even to where the minimum “associative” pairing occurs would result in species of molecules having overlapping domains that could interfere with, produce steric hindrance or loss of function for the overall configuration of the molecule and its three separate binding domains or particular binding domains. Thus, the possible number of trispecific binding molecule species comprising different order and orientation for the combination of recited domains exceeds what Applicants are in possession of at the time of filing.
i) Actual reduction to practice in the Specification:
[0135] FIGS. 4A-4G provide a diagrammatic representation of the Domains of preferred Tri-Specific Binding Molecules of the present invention. The figures illustrate schematically the order and orientation of the Domains of embodiments of the preferred Tri-Specific Binding Molecules of the present invention. FIGS. 4A, 4B and 4G illustrate embodiments in which the Tri-Specific Binding Molecule is composed of four polypeptide chains. FIGS. 4C, 4D, 4E and 4F illustrate embodiments in which the binding molecule is composed of three polypeptide chains. The molecule may possess Hinge and/or CL domains (FIGS. 4A, 4B, 4C, 4E) or may contain an alternative linker peptide (FIG. 4D, 4F, 4G).
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Table 2 indicates that preferred cancer antigen-binding domains having a broad applicability to treatment of any types of cancers would include Eph2A and CEACAM5 antigens [00469]. Otherwise, there is no suggestion what the structure for any one of the domains would be much less the order and/or orientation for the cancer antigen-binding domains vis-a-vis the CD3 domain in a construct comprising the four polypeptide chains.
Thus, the construct formats are not shown to have just any orientation of the four polypeptide chains much less a positional variation for the three separate binding domains as evidenced from the working examples.
The specification teaches the importance of the linker length for the first and second polypeptide chains at [0441, 0442, 0456] to “prevent the association of these Domains.”
ii) Predictability in the Art:
MPEP 2144.08 states in part:
The claims encompass re-organized, rearranged antibody domains into non-conventional multichain, multispecific “molecules” further comprising non-conventional heterodimerization domains and cysteine-containing domains, which lend further complexity to the conformation and configuration of the molecule as a whole.
In the area of biotechnology, an exemplified species may differ from a claimed species by a conservative substitution (“the replacement in a protein of one amino acid by another, chemically similar, amino acid... [which] is generally expected to lead to either no change or only a small change in the properties of the protein.” Dictionary of Biochemistry and Molecular Biology 97 (John Wiley & Sons, 2d ed. 1989)). The effect of a conservative substitution on protein function depends on the nature of the substitution and its location in the chain. Although at some locations a conservative substitution may be benign, in some proteins only one amino acid is allowed at a given position. For example, the gain or loss of even one methyl group can destabilize the structure if close packing is required in the interior of domains. James Darnell et al., Molecular Cell Biology 51 (2d ed. 1990).”
Beyond these structurally similar antibodies the specification does not disclose what antibody structure(s) are sufficient to make a tri-specific binding molecule having retained antigen binding specificity. Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function … does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is”).
Applicant has not described the claimed invention sufficiently to show they had possession of the claimed genus of tetra-specific antibody monomers having binding specificity for the four separate and distinct binding domains much less being cancer therapeutic.
B) The claims are drawn to numerous combinations of antigen binding domains having specific binding for a genus of epitope I, epitope II or epitope III on a genus of effector cell antigens (Claims 25 and 30), and 1st cancer antigens or 2nd cancer antigens (Claim 26-27) and specifically colon cancer antigen 19.9; a gastric cancer mucin; antigen 4.2; glycoprotein A33 (gpA33); ADAM-9; gastric cancer antigen AH6; ALCAM; malignant human lymphocyte antigen APO-1; cancer antigen B1; B7-H3; beta-catenin; blood group ALeb/Ley; Burkitt's lymphoma antigen-38.13, colonic adenocarcinoma antigen C14: ovarian carcinoma antigen CA125; Carboxypeptidase M; CD5; CD19; CD20; CD22; CD23; CD25; CD27; CD28; CD30; CD33; CD36; CD45; CD46; CD52; CD79a/CD79b; CD103; CD317; CDK4; carcinoembryonic antigen (CEA); CEACAM5; CEACAME6; CO17-1A; CO-43 (blood group Leb): CO-514 (blood group Lea), CTA-1; CTLA4; Cytokeratin 8; antigen D1.1; antigen D156-22; DR5; E1 series (blood group B); EGFR (Epidermal Growth Factor Receptor); Ephrin receptor A2 (EphA2); ErbB1: ErbB3; ErbB4; GAGE-1; GAGE-2: GD2/GD3/GM2; lung adenocarcinoma antigen F3; antigen FC10.2; G49, ganglioside GD2; ganglioside GD3; ganglioside GM2; ganglioside GM3; GD2; GD3; GICA 19-9; GM2; gp100; human leukemia T cell antigen Gp37; melanoma antigen gp75; gopA33; HER2 antigen (p185HER2): human milk fat globule antigen (HMFG); human papillomavirus-E6/human papillomavirus-E7; high molecular weight melanoma antigen (HMW-MAA); | antigen (differentiation antigen) I(Ma); Integrin Alpha-V-Beta-6 Integrinβ6 (ITGB6); Interleukin-13; Receptor α2 (IL13Rα2); JAM-3; KID3; KID31; KS 1/4 pan-carcinoma antigen; human lung carcinoma antigens L6 and L20; LEA; LUCA-2; M1:22:25:8; M18; M39: MAGE-1; MAGE-3; MART; MUC-1; MUM-1; Myl; N- acetylglucosaminyltransferase; neoglycoprotein; NS-10; OFA-1; OFA-2; Oncostatin M; p15; melanoma-associated antigen p97; polymorphic epithelial mucin (PEM); polymorphic epithelial mucin antigen (PEMA); PIPA: prostate-specific antigen (PSA); prostate-specific membrane antigen (PSMA); prostatic acid phosphate; R24; ROR1; sphingolipids; SSEA-1; SSEA-3; SSEA-4; sTn; T cell receptor derived peptide; T5A7; TAG-72; TL5 (blood group A); TNF-α receptor; TNF-β receptor; TNF-γ receptor; TRA-1-85 (blood group H); Transferrin Receptor; tumor-specific transplantation antigen (TSTA), oncofetal antigen-alpha- fetoprotein (AFP); VEGF, VEGFR; VEP8; VEP9; VIM-D5; and Y hapten, Ley (Claim 2).
A priori, the number of multi-chain polypeptide containing tri-specific binding molecules encompassed by the claims is very large and unpredictable. It is possible a large number of antigen binding domains in the context of the claimed tri-specific molecules will maintain binding specificity, or, conversely, few antigen binding domains of the claimed tri-specific molecules will maintain binding specificity. The specification does not provide sufficient direction or guidance as to the particular structural elements necessary to put the skilled artisan in possession of the claimed genus of recombinant structures much less the combination of all possible antigen binding domains that are not defined by a structure much less a sequence combination. In the present case, the genus of antigen binding domains may encompass anything less than a full complement of VH and VL CDRs or single VH and VL domains which are recognized in the art as being unpredictable in binding specificity and affinity.
One reason the instant specification does not put the skilled artisan in possession of the claimed genus of antigen binding domains is because the skilled artisan knows the immune response to any given immunogen, and, in turn, the structure of an antibody produced during the immune response is a function of a number of unpredictable factors including, e.g., the precise structure of the immunizing antigen, the method of immunization, and the process of antibody variation, i.e., the immune response is very sensitive.
Again, as described above the number of antigen binding domains having the functional feature of the instant claims may be vast or they may be small; regardless what is certain is that the number of antibodies that would need to be screened to determine if one has obtained members of the claimed genera representative of their potential diversity is vast.
Moreover, the teachings of the instant specification fail to put the skilled artisan in possession of the breadth of tri-specific binding molecules having binding specificity for just any effector cell antigen, just any cancer antigen and just any combination thereof, much less that the combination of elements are therapeutically effective because specific CDR combinations are expected, a priori, to contribute to antigen binding. However, neither the instant specification nor the knowledge in the art establish which CDR or which VH and VL are structurally essential to antigen binding versus those that are tolerant to change, and to what degree, i.e., conservative or radical for the full breadth and scope of the antigen binding domains for the instant claims.
A description adequate to satisfy 35 U.S.C. § 112(a) must clearly allow persons of ordinary skill in the art to recognize that the inventor invented what is claimed (Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en banc) (citation omitted, alteration in original). The purpose of the written description requirement is to “ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent’s specification” (In re Katz Interactive Call Processing Patent Litig. 639 F.3d 1303, 1319 (Fed. Cir 2011).
C) Scope of the claimed genus of antigen binding domains
By the time the invention was made, it was also well-established in the art that the formation of an intact antigen-binding surface on an antibody required the association of the complete heavy and light chain variable regions, each of which consists of three CDRs which provide the majority of the contact residues for the binding of the antibody to its target epitope (Almagro & Franssen, Frontiers in Bioscience, 13:1619-33 (2008) (PTO-892) (see Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1). While this overall architecture is shared among antibodies from a wide variety of sources (human, rat, mouse, rabbit), the structure each antibody uses to bind its particular epitope on an antigen is structurally distinct and is formed by a recombination event that results in high variability at the amino acid sequence level, even when the same antigen is bound (Edwards et al., J Mol Biol 334:103-118 (2003) (PTO-892); see also Marchalonis et al., Dev & Comp Immunol. 30:223-247 (2006) (PTO-892), summarized in Abstract and Conclusion.
Methods of preparing antibodies from a variety of species to a protein or peptide of interest were well-established in the art at the time the invention was made. But application of those methods to any given antibody was still a matter of trial-and-error testing, and the skilled person could not automatically predict which residues in the CDRs would be tolerant of mutations, or which amino acid substitutions would maintain antigen binding. Overall, at the time the invention was made, the level of skill for preparing antibodies and then selecting those antibodies with desired functional properties was high. For example, it is generally the case that absent the fundamental structure provided for by all six CDRs of a parental antibody in the context of appropriate VH and VL framework sequences, a person of ordinary skill cannot visualize or otherwise predict, what an antibody with a particular set of functional properties would look like structurally.
Moreover, persons of ordinary skill in the art have long since acknowledged that even minor changes in the amino acid sequences of the VH and VL, particularly in the CDRs, may dramatically affect antigen-binding function. Moreover, persons of ordinary skill in the art have long since acknowledged that even minor changes in the amino acid sequences of the VH and VL, particularly in the CDRs, may dramatically affect antigen-binding function. Lippow, for example, teaches that a single point mutation in the CDR of a parent antibody led to as much as an eightfold improvement in binding affinity in the resulting mutant (p. 1172, left col., lines 7-8 from end of first full paragraph and Table 1a) (Lippow et al., “Computational design of antibody-affinity improvement beyond in vivo maturation,” Nature Biotechnology, 25(10):1171-1176 (2007) (PTO-892).
Sulea teaches that individual point mutations gave an improvement of one order of magnitude in binding affinity, which in turn, generated a 6-fold enhancement of efficacy at the cellular level (Abstract) (Sulea et al., “Application of Assisted Design of Antibody and Protein Therapeutics (ADAPT) improves efficacy of a Clostridium difficile toxin A single-domain antibody," Scientific Reports, 8(260):1-11 (2018) (PTO-892). Hasegawa et al. reports that a single amino acid substitution in the variable region was sufficient to alter the efficiency of biosynthesis and the variant antibody acquired stronger binding affinity to its antigen than the parent (Hasegawa et al., “Single amino acid substitution in LC-CDR1 induces Russell body phenotype that attenuates cellular protein synthesis through elF2a phosphorylation and thereby downregulates IgG secretion despite operational secretory pathway traffic,” MABS, VOL. 9, NO. 5, pp. 854-873 (2017) (PTO-892)). Altshuler teaches that generally, “CDR mutations should not involve residues that can play structural functions (form parts of the domain ‘internal core’, internal salt bridges, hydrogen bonds, etc.).” “Usually these are conservative residues, and any substitution of these residues causes decrease[s] in affinity” (Altshuler et al., “Generation of Recombinant Antibodies and Means for Increasing Their Affinity,” Biochemistry (Moscow), 75(13):1584-1605 (2010) at p. 1600, col. 1, para. 2, lines 1-5 (PTO-892). Accordingly, a person of ordinary skill in the art would have recognized that it was highly unpredictable that any of the CDRs or FRs could be modified to create an unlimited change in amino acids for both the CDRs and FRs of the claimed antibodies, without increasing, eliminating, or in some way altering antigen binding.
Are the disclosed species representative of the claimed genus?
It is asserted that the disclosed species of antigen binding domains are not representative of the claimed genus because the claims encompass any and all kinds of antigen binding domains for the combination of the tri-specific construct. The genus of all possible antigen binding domains is unpredictable whether the structure/function correlation is for binding to the genus of claimed antigens.
Has Applicant provided a common structure sufficient to visualize the genus?
It is unclear what structural features these antigen binding domains within the format of the tri-specific molecule need to share in order to maintain binding affinity and therapeutic effects on the genus of cancers encompassed by the method claims. Therapeutic antibodies are still not understood well enough to allow researchers to predict with certainty what modifications can be made to a primary antibody sequence such that binding is maintained. “[T]he major test of understanding is whether the changes associated with antibody maturation can be predicted with any reasonable accuracy, and whether there is sufficient information for developing therapeutic antibodies,” Vajda et al., “Progress toward improved understanding of antibody maturation,” Current Opinion in Structural Biology, 67 pp. 226-231 (2021 (PTO 892)) at p. 226, col. 2, lines 20-24.
As recently as 2020, researches were still speculating as to how to reliably identify further putative binders from antibody sequence data, see, e.g., Marks et al., “How repertoire data are changing antibody science,” J. Biol. Chem. 295(29) 9823-9837 (2020 (PTO 892)), acknowledging that “there is a vast amount of the antibody sequence space that remains unknown,” p. 9831, col. 2, para. 2.
Even though the protein sequence of many of the claimed antigens (see Claims 25-26) was known in the art, this would not have translated into knowledge of the genus of antibodies that could possibly engage it. Computational and machine learning approaches for sequence-based prediction of paratope-epitope interactions are accumulating, but “it remains unclear whether antibody-antigen binding is predictable” (Akbar et al., Cell Reports 34, 108856, Mar. 16, 2021 at p. 2, col. 2, para. 2 (PTO 892)). The current state of the art continues to work toward finding an effective and efficient prediction tool for reliably assigning antibody structure based on known target epitopes. See e.g., Lo et al., “Conformational epitope matching and prediction based on protein surface spiral features,” BMC Genomics volume 22, Article number: 116 (2021 (PTO 892)) (disclosing new algorithms that calculate physicochemical properties, such as polarity, charge or the secondary structure of residues within the targeted protein sequences, and then applying quantitative matrix analyses or machine-learning algorithms to predict linear and conformational epitopes).
It is asserted that neither the specification nor the state of art at the time of filing disclosed structural features common to the members of the genus of antigen binding domains much less within the context of the tri-specific format for reliably assigning different antibody structures based on sequence data for two antibody clones, which would support the premise that the inventors possessed the full scope of the claimed invention.
Conclusion
Given the above the skilled artisan cannot extrapolate from the disclosure of the instant specification to establish possession of the breadth of tetra-specific antibody monomers having four separate and distinct binding domains with a binding specificity for different antigens encompassed by the instant method claims. Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function … does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is”).
Applicant has not described the claimed method invention sufficiently to show they had possession of the claimed genus of tetra-specific antibody monomer/ tetra-specific antibodies having four separate and distinct binding domains for infinite genus of tumor antigens or infinite genus of immune signaling antigens or combinations thereof presented from N- to C-terminal as domains 1-4 for the general use in the treatment of just any cancer.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969). A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP §§ 706.02(l)(1) - 706.02(l)(3) for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
7. Claims 21-37 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 10647768 in view of claims 1-13 of U.S. Patent 11697684.
The reference patent ‘768 is not afforded safe harbor protection under 35 USC 121 because it does not share restriction/speciation status to the instant application.
The reference patent ‘684 is not afforded safe harbor protection under 35 USC 121 because the instant application is a bona fide continuation of the ‘684 patent.
The claim sets relate to Tri-Specific Binding Molecules, which are 4 chain polypeptide molecules that possess three Binding Domains and are thus capable of mediating coordinated binding to three epitopes. The Binding Domains may be selected such that the Tri-Specific Binding Molecules are capable of binding to any three different epitopes. Such epitopes may be epitopes of the same antigen or epitopes of two or three different antigens. The Tri-Specific Binding Molecules possess an E-coil and a K-coil, respectively, on a 1st and 2nd polypeptide, and a cysteine-containing domain.
As regards Claim 21, Generic Claim 1 of ‘768 anticipates and renders obvious the claimed subject matter:
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Ref linker 1 (SEQ ID NO: 1) vs linker 1 (SEQ ID NO:33) is identical.
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Ref linker 2 (SEQ ID NO:2) vs linker 2 (SEQ ID NO:34) is identical.
GGCGGG
Ref linker 2 (SEQ ID NO:131) vs linker 2 (SEQ ID NO:47) is identical.
ASTKG
Ref linker 3 (GGG) vs linker 3 (GGG) is identical. Ref linker 3 (SEQ ID NO. 5) vs linker 3 (48) is identical= DKTHTCPPCP.
Ref E-coil (SEQ ID NO: 3 or 115) vs E-coil (SEQ ID NO: 39 or 41):
EVAALEKEVA ALEKEVAALE KEVAALEK (3/39) and EVAACEKEVA ALEKEVAALE KEVAALEK (15/41), respectively, are identical.
Ref K-coil (SEQ ID NO: 4 or 116) vs K-coil (SEQ ID NO: 40 or 42): KVAALKEKVA ALKEKVAALKEKVAALKE (4/40) and KVAACKEKVAALKEKVAALKEKVAALKE (116/42), respectively, are identical.
Ref cysteine-containing domain (SEQ ID NO: 2, 5, 10-14, 127-130 and 133) vs cysteine-containing domain (SEQ ID NO: 34, 36, 38, 48, 210 and 211): GGCGGG (2/34), DKTHTCPPCP (5/48), RTVAAPSVFI FPPSDEQLKS GTASVVCLLN NFYPREAKVQ WKVDNALQSG NSQESVTEQDSKDSTYSLSS TLTLSKADYE KHKVYACEVT HQGLSSPVTK SFNRGEC (13/210), QPKAAPSVTL FPPSSEELQA NKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTPSKQSNNKYAASSYL SLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (14 /211). respectively, are identical.
As regards claim 22, Claim 2 of ‘768 anticipates and renders obvious the subject matter:
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AS regards claim 25, Claim 3 of ‘768 anticipates and renders obvious the claimed subject matter. AS regards Claim 24, Claim 4 of ‘768 anticipates and renders obvious the claimed subject matter.
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AS regards Claim 26, Claim 6 of ‘768 anticipates and renders obvious the claimed subject matter:
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AS regards claims 28-29, Claims 12-13 of ‘768 anticipate and render obvious the claimed subject matter:
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AS regards claim 30, claims 8-10 of ‘768 anticipate and renders obvious the subject matter:
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AS regards claim 31-32, Claims 14-15 of ‘768 anticipate and renders obvious the subject matter:
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AS regards claim 33, Claim 16 of ‘768 anticipates and renders obvious the subject matter:
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As regards claims 34-35, Claims 17-18 of ‘768 anticipate and render obvious the claimed subject matter:
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As regards claims 36-37, Claims 19-20 of ‘768 anticipate and render obvious the claimed subject matter:
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AS regards claim 23, claim 4 of ‘684 anticipates and renders obvious the claimed subject matter:
4. The Tri-Specific Binding Molecule of claim 1, wherein the CH2-CH3 Domain of the first polypeptide chain and the third polypeptide chain comprise at least one amino acid substitution, relative to the sequence of SEQ ID NO:1, and the Fc Domain formed from their association exhibits altered FcγR-mediated effector function.
As regards claim 27, claim 12 of ‘684 anticipates and renders obvious the claimed subject matter:
12. The Tri-Specific Binding Molecule of claim 11, wherein one of Epitope I, Epitope II or Epitope III is an epitope of a Cancer Antigen and the Antigen-Binding Domain that immunospecifically binds to the epitope comprises: the six CDRs of SEQ ID NO: 3 and 8; 13 and 18; 23 and 31; 25 and 31; 27 and 31; 29 and 31; 54 and 58; 62 and 66; 70 and 74; 78 and 82; 86 and 90; 94 and 98; 153 and 158; 163 and 167; 172 and 177; 181 and 186; 191 and 192; 193 and 194; 195 and 196; 197 and 198; 199 and 200; 201 and 202; 203 and 204; 205 and 206; 302 and 303; 304 and 305; 306 and 307; 308 and 309; 310 and 311; 312 and 313; 314 and 315; or 321 and 322; or the Light Chain Variable Domain of SEQ ID NO:3 and the Heavy Chain Variable Domain of SEQ ID NO:8; the Light Chain Variable Domain of SEQ ID NO:13 and the Heavy Chain Variable Domain of SEQ ID NO:18; the Light Chain Variable Domain of SEQ ID NO:23 and the Heavy Chain Variable Domain of SEQ ID NO:31; the Light Chain Variable Domain of SEQ ID NO:25 and the Heavy Chain Variable Domain of SEQ ID NO:31; the Light Chain Variable Domain of SEQ ID NO:27 and the Heavy Chain Variable Domain of SEQ ID NO:31; the Light Chain Variable Domain of SEQ ID NO:29 and the Heavy Chain Variable Domain of SEQ ID NO:31; the Light Chain Variable Domain of SEQ ID NO:54 and the Heavy Chain Variable Domain of SEQ ID NO:58; the Light Chain Variable Domain of SEQ ID NO:62 and the Heavy Chain Variable Domain of SEQ ID NO:66; the Light Chain Variable Domain of SEQ ID NO:70 and the Heavy Chain Variable Domain of SEQ ID NO:74; the Light Chain Variable Domain of SEQ ID NO:78 and the Heavy Chain Variable Domain of SEQ ID NO:82; the Light Chain Variable Domain of SEQ ID NO:86 and the Heavy Chain Variable Domain of SEQ ID NO:90; the Light Chain Variable Domain of SEQ ID NO:94 and the Heavy Chain Variable Domain of SEQ ID NO:98; the Light Chain Variable Domain of SEQ ID NO:153 and the Heavy Chain Variable Domain of SEQ ID NO:158; the Light Chain Variable Domain of SEQ ID NO:163 and the Heavy Chain Variable Domain of SEQ ID NO:167; the Light Chain Variable Domain of SEQ ID NO:172 and the Heavy Chain Variable Domain of SEQ ID NO:177; the Light Chain Variable Domain of SEQ ID NO:181 and the Heavy Chain Variable Domain of SEQ ID NO:186; the Light Chain Variable Domain of SEQ ID NO:191 and the Heavy Chain Variable Domain of SEQ ID NO:192; the Light Chain Variable Domain of SEQ ID NO:193 and the Heavy Chain Variable Domain of SEQ ID NO:194; the Light Chain Variable Domain of SEQ ID NO:195 and the Heavy Chain Variable Domain of SEQ ID NO:196; the Light Chain Variable Domain of SEQ ID NO:197 and the Heavy Chain Variable Domain of SEQ ID NO:198; the Light Chain Variable Domain of SEQ ID NO:199 and the Heavy Chain Variable Domain of SEQ ID NO:200; the Light Chain Variable Domain of SEQ ID NO:201 and the Heavy Chain Variable Domain of SEQ ID NO:202; the Light Chain Variable Domain of SEQ ID NO:203 and the Heavy Chain Variable Domain of SEQ ID NO:204; the Light Chain Variable Domain of SEQ ID NO:205 and the Heavy Chain Variable Domain of SEQ ID NO:206; the Light Chain Variable Domain of SEQ ID NO:302 and the Heavy Chain Variable Domain of SEQ ID NO:303; the Light Chain Variable Domain of SEQ ID NO:304 and the Heavy Chain Variable Domain of SEQ ID NO:305; the Light Chain Variable Domain of SEQ ID NO:306 and the Heavy Chain Variable Domain of SEQ ID NO:307; the Light Chain Variable Domain of SEQ ID NO:308 and the Heavy Chain Variable Domain of SEQ ID NO:309; the Light Chain Variable Domain of SEQ ID NO:310 and the Heavy Chain Variable Domain of SEQ ID NO:311; the Light Chain Variable Domain of SEQ ID NO:312 and the Heavy Chain Variable Domain of SEQ ID NO:313; the Light Chain Variable Domain of SEQ ID NO:314 and the Heavy Chain Variable Domain of SEQ ID NO:315; or the Light Chain Variable Domain of SEQ ID NO:321 and the Heavy Chain Variable Domain of SEQ ID NO:322.
AS regards claim 30, claim 10 of ‘684 anticipates and renders obvious the claimed subject matter:
10. The Tri-Specific Binding Molecule of any of claim 9, wherein: (A) the epitope of an Effector Cell Antigen is a CD2 epitope recognized by antibody Lo-CD2a; (B) the epitope of an Effector Cell Antigen is a CD3 epitope recognized by antibody OKT3, M291, YTH12.5, Anti-CD3 mAb 1 or Anti-CD3 mAb 2; (C) the epitope of an Effector Cell Antigen is a CD16 epitope recognized by antibody 3G8 or A9; (D) the epitope of an Effector Cell Antigen is a CD19 epitope recognized by antibody MD1342, MEDI-551, blinatumomab or HD37; (E) the epitope of an Effector Cell Antigen is a CD20 epitope recognized by antibody rituximab, ibritumomab, ofatumumab, and tositumomab; (F) the epitope of an Effector Cell Antigen is a CD22 epitope recognized by antibody epratuzumab; (G) the epitope of an Effector Cell Antigen is a CD32B epitope recognized by antibody CD32B mAb 1; (H) the epitope of an Effector Cell Antigen is a CD64 epitope recognized by antibody CD64 mAb 1; (I) the epitope of an Effector Cell Antigen is a BCR/CD79 epitope recognized by antibody CD79 mAb 1; (J) the epitope of an Effector Cell Antigen is a TCR epitope recognized by antibody BMA 031; (K) the epitope of an Effector Cell Antigen is a NKG2D Receptor epitope recognized by antibody KYK-2.0; or (L) one of Epitope I, Epitope II or Epitope III is an epitope of an Effector Cell Antigen and the Antigen-Binding Domain that immunospecifically binds to the epitope comprises: the six CDRs of SEQ ID NO:102 and 103; 104 and 108; 104 and 112; 114 and 115; 116 and 117; 118 and 119; 120 and 121; 122 and 123; 124 and 125; 126 and 127; 128 and 129; 130 and 131; 132 and 133; 134 and 135; or 136 and 137; or the Light Chain Variable Domain of SEQ ID NO:102 and the Heavy Chain Variable Domain of SEQ ID NO:103; the Light Chain Variable Domain of SEQ ID NO:104 and the Heavy Chain Variable Domain of SEQ ID NO:108; the Light Chain Variable Domain of SEQ ID NO:104 and the Heavy Chain Variable Domain of SEQ ID NO:112; the Light Chain Variable Domain of SEQ ID NO:114 and the Heavy Chain Variable Domain of SEQ ID NO:115; the Light Chain Variable Domain of SEQ ID NO:116 and the Heavy Chain Variable Domain of SEQ ID NO:117; the Light Chain Variable Domain of SEQ ID NO:118 and the Heavy Chain Variable Domain of SEQ ID NO:119; the Light Chain Variable Domain of SEQ ID NO:120 and the Heavy Chain Variable Domain of SEQ ID NO:121; the Light Chain Variable Domain of SEQ ID NO:122 and the Heavy Chain Variable Domain of SEQ ID NO:123; the Light Chain Variable Domain of SEQ ID NO:124 and the Heavy Chain Variable Domain of SEQ ID NO:125; the Light Chain Variable Domain of SEQ ID NO:126 and the Heavy Chain Variable Domain of SEQ ID NO:127; the Light Chain Variable Domain of SEQ ID NO:128 and the Heavy Chain Variable Domain of SEQ ID NO:129; the Light Chain Variable Domain of SEQ ID NO:130 and the Heavy Chain Variable Domain of SEQ ID NO:131; the Light Chain Variable Domain of SEQ ID NO:132 and the Heavy Chain Variable Domain of SEQ ID NO:133; the Light Chain Variable Domain of SEQ ID NO:134 and the Heavy Chain Variable Domain of SEQ ID NO:135; or the Light Chain Variable Domain of SEQ ID NO:136 and the Heavy Chain Variable Domain of SEQ ID NO:137.
The combination of three polypeptide trispecific binding molecule taught by both references to include a fourth polypeptide comprising (creating a four-chain, 3-antigen binding structure in ‘768) makes a difference primarily by enabling the creation of a stable, IgG-like structure that allows for more complex engineering, such as incorporating a third target specificity (e.g., CD28, CD38, or a checkpoint inhibitor) while improving stability and pharmacological properties compared to simpler, fragmented, or 3-chain formats. Accordingly, where the structure is identified in both references for optimized use of the polypeptides in multispecific targeting of different antigens, the POSA is not only motivated but assured of predictable and reasonable success.
11. Claims 21-37 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 10633440. The reference patent is not afforded safe harbor protection under 35 USC 121 because Applicants have not established on the record that the instant application is a de facto DIV of the parent much less does the patent prosecution history in the claims for the allowed parent case read away from the instant claims.
Claim 1 of ‘440 anticipates and renders obvious instant Claim 21
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Claim 2 of ‘440 anticipates and renders obvious instant Claim 22:
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Claim 3 of ‘440 anticipates and renders obvious instant Claim 23:
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Claim 4 of ‘440 anticipates and renders obvious instant Claim 24:
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Claim 5 of ‘440 anticipates and renders obvious instant Claim 25:
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Claim 6 of ‘440 anticipates and renders obvious instant Claim 26:
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Claim 7 of ‘440 anticipates and renders obvious instant Claim 27:
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Claims 8-9 of ‘440 anticipate and render obvious instant Claims 28-29:
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Claim 10 of ‘440 anticipates and renders obvious instant Claim 30:
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Claims 11-12 of ‘440 anticipate and render obvious instant Claims 31-32:
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Claim 13 of ‘440 anticipates and renders obvious instant Claim 33:
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Claims 14-15 of ‘440 anticipates and renders obvious instant Claims 34-35:
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Claims 16-17 of ‘440 anticipate and render obvious instant Claims 36-37:
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The combination of a four- polypeptide trispecific binding molecule (creating a four-chain, 3-antigen binding structure) makes a difference primarily by enabling the creation of a stable, IgG-like structure that allows for more complex engineering, such as incorporating a third target specificity (e.g., CD28, CD38, or a checkpoint inhibitor) while improving stability and pharmacological properties compared to simpler, fragmented, or 3-chain formats. The POSA is motivated and assured of predictable and reasonable success.
12. Claims 21-37 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of U.S. Patent No. 11820818 in view of claims 1-13 of U.S. Patent 11697684 and 1-21 of U.S. Patent No. 10633440.
The reference patent ‘818 is not afforded safe harbor protection under 35 USC 121 because it does not share restriction/speciation status to the instant application.
The reference patent ‘684 is not afforded safe harbor protection under 35 USC 121 because the instant application is a bona fide continuation of the ‘684 patent.
The reference patent ‘440 is not afforded safe harbor protection under 35 USC 121 because Applicants have not established on the record that the instant application is a de facto DIV of the parent much less does the patent prosecution history in the claims for the allowed parent case read away from the instant claims.
The claim sets relate to Tri-Specific Binding Molecules, which are 4 chain polypeptide molecules that possess three Binding Domains and are thus capable of mediating coordinated binding to three epitopes. The Binding Domains may be selected such that the Tri-Specific Binding Molecules are capable of binding to any three different epitopes. Such epitopes may be epitopes of the same antigen or epitopes of two or three different antigens. The Tri-Specific Binding Molecules possess an E-coil and a K-coil, respectively, on a 1st and 2nd polypeptide, and a cysteine-containing domain.
Claim 1 of ‘818 anticipates or renders obvious instant Claim 21:
1. A multi-chain polypeptide-containing Tri-Specific Binding Molecule that immunospecifically binds to three different epitopes, comprising: (I) three different polypeptide chains covalently complexed together; (II) an Antigen-Binding Domain I that immunospecifically binds to an Epitope I present on a first antigen, an Antigen-Binding Domain II that immunospecifically binds to an Epitope II present on a second antigen, and an Antigen-Binding Domain III that immunospecifically binds to an Epitope III present on a third antigen; and (III) a Fc Domain; wherein: (A) a first polypeptide chain comprises, in the N-terminus to C-terminus direction: (VL1 Domain)-(Linker 1)-(VH.sub.II Domain)-(Linker 2)-(Heterodimer-Promoting Domain)-(Linker 3)-(CH2-CH3 Domain); or (Cysteine-Containing Domain)-(CH2-CH3 Domain)-(Linker 4)-(V.sub.L1 Domain)-(Linker 1)-(VH.sub.II Domain)-(Linker 2)-(Heterodimer-Promoting Domain); (B) a second polypeptide chain comprises, in the N-terminus to C-terminus direction: (VL.sub.II Domain)-(Linker 1)-(VH.sub.I Domain)-(Linker 2)-(Heterodimer-Promoting Domain); (C) a third polypeptide chain comprises, in the N-terminus to C-terminus direction: Domain)-(Flexible Linker)-(VH.sub.III Domain)-(Cysteine-Containing Domain2)-(CH2-CH3 Domain); or (CL Domain)-(VL.sub.III Domain)-(Flexible Linker)-(VH.sub.III Domain)-(CH1 Domain)-(Cysteine-Containing Domain)-(CH2-CH3 Domain); (D) the VL.sub.I Domain is a Light Chain Variable Domain of an immunoglobulin that binds to Epitope I, the VH.sub.I Domain is a Heavy Chain Variable Domain of an immunoglobulin that binds to Epitope I, the VL.sub.II Domain is a Light Chain Variable Domain of an immunoglobulin that binds to Epitope II, the VH.sub.II Domain is a Heavy Chain Variable Domain of an immunoglobulin that binds to Epitope II, the V.sub.III Domain is a Light Chain Variable Domain of an immunoglobulin that binds to Epitope III, and the VH.sub.III Domain is a Heavy Chain Variable Domain of an immunoglobulin that binds to Epitope III; (E) the VL.sub.I Domain and the VH.sub.I Domain associate to form the Antigen-Binding Domain I, the VL.sub.II Domain and the VH.sub.II Domain associate to form the Antigen-Binding Domain II, the VL.sub.III Domain and the VH.sub.III Domain associate to form the Antigen-Binding Domain III, and the CH2-CH3 Domain of the first polypeptide chain and the CH2-CH3 Domain of the third polypeptide chain associate to form the Fc Domain, the Antigen-Binding Domain I and the Antigen-Binding Domain II are Diabody-Type Binding Domains, and the Antigen-Binding Domain Ill is a Non-Diabody-Type Binding Domain; (F) the first, second and third antigens are the same antigen, or are independently the same or different from another of the antigens; and (G) the Linker 1 comprises the sequence of SEQ ID NO: 1; the Linker 2 comprises the sequence of SEQ ID NO: 2 or 131; the Linker 3 comprises the sequence of SEQ ID NO: 5 or GGG; the Linker 4 comprises the sequence of SEQ ID NO: 15, 16, 131 or 132, or GGC or GGG; the CH2-CH3 Domain comprises the sequence of SEQ ID NO: 7 or 8; the Cysteine-Containing Domain independently comprises the sequence of SEQ ID NO: 2, 5, 10, 11, 12, 13, 14, 127, 128, 129, 130 or 133; the Heterodimer-Promoting Domain on the first polypeptide chain is an E-coil Domain and the Heterodimer-Promoting Domain on the second polypeptide chain is a K-coil Domain, or the Heterodimer-Promoting Domain on the first polypeptide chain is a K-coil Domain and the Heterodimer-Promoting Domain on the second polypeptide chain is an E-coil Domain, the E-coil Domain independently comprises the sequence of SEQ ID NO: 3 or 115, and the K-coil Domain independently comprises the sequence of SEQ ID NO: 4 or 116; the CH1 Domain comprises the sequence of SEQ ID NO: 9; and the CL Domain comprises the sequence of SEQ ID NO: 13 or 14.
Claim 2 of ‘818 anticipates or renders obvious instant Claim 31:
2. The Tri-Specific Binding Molecule of claim 1, wherein: the Linker 2 comprises a cysteine residue, the E-coil Domain and the K-coil Domain adjacent to the Linker 2 each comprises a cysteine residue, or the Linker 2 comprises a cysteine residue and the E-coil Domain or the K-coil Domain adjacent to the Linker 2 comprises a cysteine residue.
Claim 3 of ‘818 anticipates or renders obvious instant Claim 32:
3. The Tri-Specific Binding Molecule of claim 2, wherein: the E-coil Domain of SEQ ID NO:115 or the K-coil Domain of SEQ ID NO:116 is adjacent to the Linker 2 when the Linker 2 comprises the sequence of SEQ ID NO: 131; the E-coil Domain of SEQ ID NO: 3 or the K-coil Domain of SEQ ID NO: 4 is adjacent to the Linker 2 when the Linker 2 comprises the sequence of SEQ ID NO: 2; or the E-coil Domain of SEQ ID NO: 115 or the K-coil Domain of SEQ ID NO: 116 is adjacent to the Linker 2 when the Linker 2 comprises the sequence of SEQ ID NO: 2.
Claim 4 of ‘818 anticipates or renders obvious instant Claim 28:
4. The Tri-Specific Binding Molecule of claim 1, wherein: the CH2-CH3 Domain of the first polypeptide chain is a knob-bearing CH2-CH3 Domain and the CH2-CH3 Domain of the third polypeptide chain is a hole-bearing CH2-CH3 Domain; or the CH2-CH3 Domain of the third polypeptide chain is a knob-bearing CH2-CH3 Domain and the CH2-CH3 Domain of the first polypeptide chain is a hole-bearing CH2-CH3 Domain.
Claim 5 of ‘818 anticipates or renders obvious instant Claim 29:
5. The Tri-Specific Binding Molecule of claim 4, wherein: the knob-bearing CH2-CH3 Domain comprises the sequence of SEQ ID NO: 7, and the hole-bearing CH2-CH3 Domain comprises the sequence of SEQ ID NO: 8.
Claim 6 of ‘818 anticipates or renders obvious instant Claim 30:
6. The Tri-Specific Binding Molecule of claim 1, wherein the CH2-CH3 Domain of the first polypeptide chain and the third polypeptide chain comprise: (A) one substitution selected from the group consisting of: F243L, R292P, Y300L, V305I, and P396L; (B) two substitutions selected from the group consisting of: (1) F243L and P396L; (2) F243L and R292P; and (3) R292P and V305I; (C) three substitutions selected from the group consisting of: (1) F243L, R292P and Y300L; (2) F243L, R292P and V305I; (3) F243L, R292P and P396L; and (4) R292P, V305I and P396L; (D) four substitutions selected from the group consisting of: (1) F243L, R292P, Y300L and P396L; and (2) F243L, R292P, V305I and P396L; or (E) five substitutions selected from the group consisting of: (1) F243L, R292P, Y300L, V305I and P396L; and (2) L235V, F243L, R292P, Y300L and P396L.
Claim 7 of ‘818 anticipates or renders obvious instant Claim 25:
7. The Tri-Specific Binding Molecule of claim 1, wherein one of Epitope I, Epitope II or Epitope III is an epitope of: an effector cell selected from CD2, CD3, CD16, CD19, CD20, CD22, CD32B, CD64, B cell Receptor (BCR), T cell Receptor (TCR), or NKG2D Receptor; or CD8; or a Disease-Associated Antigen.
Claim 8 of ‘818 anticipates or renders obvious instant Claim 24:
8. The Tri-Specific Binding Molecule of claim 7, wherein: (A) the Epitope I, Epitope II and Epitope III are, respectively, an epitope of CD3, an epitope of CD8 and an epitope of the Disease-Associated Antigen; (B) the Epitope I, Epitope II and Epitope III are, respectively, an epitope of CD3, an epitope of the Disease-Associated Antigen and an epitope of CD8; (C) the Epitope I, Epitope II and Epitope III are, respectively, an epitope of CD8, an epitope of CD3, and an epitope of the Disease-Associated Antigen; (D) the Epitope I, Epitope II and Epitope III are, respectively, an epitope of CD8, an epitope of the Disease-Associated Antigen and an epitope of CD3; (E) the Epitope I, Epitope II and Epitope III are, respectively, an epitope of the Disease-Associated Antigen, an epitope of CD3, and an epitope of CD8; or (F) the Epitope I, Epitope II and Epitope III are, respectively, an epitope of the Disease-Associated Antigen, an epitope of CD8, and an epitope of CD3.
Claim 9 of ‘818 anticipates or renders obvious instant Claims 24 and 30:
9. The Tri-Specific Binding Molecule of claim 8, wherein one of Epitope I, Epitope II or Epitope III is an epitope of CD3 and the Antigen-Binding Domain that immunospecifically binds to the epitope of CD3 comprises the six CDRs of SEQ ID NO: 17 and 18; 19 and 20; 21 and 22; 23 and 25; 24 and 25; 26 and 27; 26 and 28; or 101 and 102; or comprises: the light chain variable domain of SEQ ID NO: 17 and the heavy chain variable domain of SEQ ID NO: 18, the light chain variable domain of SEQ ID NO: 19 and the heavy chain variable domain of SEQ ID NO: 20, the light chain variable domain of SEQ ID NO: 21 and the heavy chain variable domain of SEQ ID NO: 22, the light chain variable domain of SEQ ID NO: 23 and the heavy chain variable domain of SEQ ID NO: 25, the light chain variable domain of SEQ ID NO: 24 and the heavy chain variable domain of SEQ ID NO: 25, the light chain variable domain of SEQ ID NO: 26 and the heavy chain variable domain of SEQ ID NO: 27, the light chain variable domain of SEQ ID NO: 26 and the heavy chain variable domain of SEQ ID NO: 28, or the light chain variable domain of SEQ ID NO: 101 and the heavy chain variable domain of SEQ ID NO: 102.
Claim 10 of ‘818 anticipates or renders obvious instant Claim 24:
10. The Tri-Specific Binding Molecule of claim 8, wherein one of Epitope I, Epitope II or Epitope III is an epitope of CD8 and the Antigen-Binding Domain that immunospecifically binds to the epitope of CD8 comprises the six CDRs of SEQ ID NO: 29 and 30; or 31 and 32; or comprises: the light chain variable domain of SEQ ID NO: 29 and the heavy chain variable domain of SEQ ID NO: 30, or the light chain variable domain of SEQ ID NO: 31 and the heavy chain variable domain of SEQ ID NO: 32.
Claim 11 of ‘818 anticipates or renders obvious instant Claim 24:
11. The Tri-Specific Binding Molecule of claim 8, wherein the Disease-Associated Antigen is: a cancer antigen on the surface of a cancer cell; or a pathogen antigen on the surface of a pathogen or pathogen-infected cell.
Claim 12 of ‘818 anticipates or renders obvious instant Claim 26:
12. The Tri-Specific Binding Molecule of claim 11, wherein the cancer antigen is colon cancer antigen 19.9; gastric cancer mucin antigen 4.2; colorectal carcinoma antigen A33; ADAM-9; AFP oncofetal antigen-alpha-fetoprotein; ALCAM; B7-H3; BAGE; beta-catenin; CA125; Carboxypeptidase M; B1; CD5; CD19; CD20; CD22; CD23; CD25; CD27; CD28; CD30; CD33; CD36; CD40/CD154; CD45; CD56; CD46; CD52; CD79a/CD79b; CD103; CD317; CDK4; CEA carcinoembryonic antigen; CEACAM5 and CEACAM6; CO-43 (blood group Leb) and CO-514 (blood group Lea); CTLA-1 and CTLA-4; Cytokeratin 8; DRS; E1 series (blood group B); EGF-R epidermal growth factor receptor; Ephrin receptors (EphA2); Erb (ErbB1; ErbB3; ErbB4); lung adenocarcinoma antigen F3; antigen FC10.2; GAGE-1; GAGE-2; GD2/GD3/GD49/GM2/GM3; GICA 19-9; gp37 (human leukemia T cell antigen); gp75 (melanoma antigen); gp100; HER-2/neu; human B-lymphoma antigen-CD20; human milk fat globule antigen; human papillomavirus-E6/human papillomavirus-E7; HMW-MAA (high molecular weight melanoma antigen); I antigen (differentiation antigen); I(Ma) as found in gastric adenocarcinomas; Integrin Alpha-V-Beta-6 Integrinβ6 (ITGB6); Interleukin-13 Receptor α2 (IL13Rα2); JAM-3; KID3; KID31; KS 1/4 pan-carcinoma antigen; KSA (17-1A); human lung carcinoma antigens L6 and L20; LEA; LUCA-2; M1:22:25:8, M18, M39; MAGE MAGE-1; MAGE-3; MART; My1, MUC-1; MUM-1; N-acetylglucosaminyltransferase; neoglycoprotein; NS-10; OFA-1 and OFA-2; Oncostatin M (Oncostatin Receptor Beta); ρ15; PSA (prostate specific antigen); PSMA; PEMA (polymorphic epithelial mucin antigen); PIPA; prostatic acid phosphate; R24; ROR1; SSEA-1, SSEA-3 and SSEA-4; sTn; T cell receptor derived peptide; T.sub.5A.sub.7; Tissue Antigens 37; TAG-72; TL5 (blood group A); TNF-α receptor; TNF-β receptor; TNF-γ receptor; TRA-1-85 (blood group H); Transferrin Receptor; TSTA tumor-specific transplantation antigen; VEGF-R; Y hapten, Le.sup.y; or 5T4.
Claim 13 of ‘818 anticipates or renders obvious instant Claim 27:
13. The Tri-Specific Binding Molecule of claim 12, wherein one of Epitope I, Epitope II or Epitope III is an epitope of B7-H3, A33, 5T4 or ROR1 and the Antigen-Binding Domain that immunospecifically binds to the epitope of B7-H3, A33, 5T4 or ROR1 comprises: the six CDRs of SEQ ID NO: 39 and 40; 41 and 42; 43 and 44; 45 and 46; 47 and 48; 49 and 50; 51 and 52; 53 and 54; 55 and 56; or 57 and 58; or the light chain variable domain of SEQ ID NO: 39 and the heavy chain variable domain of SEQ ID NO: 40, the light chain variable domain of SEQ ID NO: 41 and the heavy chain variable domain of SEQ ID NO: 42, the light chain variable domain of SEQ ID NO: 43 and the heavy chain variable domain of SEQ ID NO: 44, the light chain variable domain of SEQ ID NO: 45 and the heavy chain variable domain of SEQ ID NO: 46, the light chain variable domain of SEQ ID NO: 47 and the heavy chain variable domain of SEQ ID NO: 48, the light chain variable domain of SEQ ID NO: 49 and the heavy chain variable domain of SEQ ID NO: 50, the light chain variable domain of SEQ ID NO: 51 and the heavy chain variable domain of SEQ ID NO: 52, the light chain variable domain of SEQ ID NO: 53 and the heavy chain variable domain of SEQ ID NO: 54, the light chain variable domain of SEQ ID NO: 55 and the heavy chain variable domain of SEQ ID NO: 56, or the light chain variable domain of SEQ ID NO: 57 and the heavy chain variable domain of SEQ ID NO: 58.
Claims 1, 4-7 of ‘684 anticipate or render obvious instant claims 21, 23, 31-33:
1. A multi-chain polypeptide-containing Tri-Specific Binding Molecule that immunospecifically binds to three different epitopes, comprising: (I) three different polypeptide chains covalently complexed together;… the Cysteine-Containing Domain independently comprises the sequence of SEQ ID NO: 34, 36, 38, 48, 210 or 211; the CH1 Domain comprises the sequence of SEQ ID NO: 207 or 208; and the CL Domain comprises the sequence of SEQ ID NO: 210 or 211.
4. The Tri-Specific Binding Molecule of claim 1, wherein the CH2-CH3 Domain of the first polypeptide chain and the third polypeptide chain comprise at least one amino acid substitution, relative to the sequence of SEQ ID NO:1, and the Fc Domain formed from their association exhibits altered FcγR-mediated effector function.
5. The Tri-Specific Binding Molecule of claim 4, wherein the CH2-CH3 Domain of the first polypeptide chain and the third polypeptide chain comprise: (A) one substitution selected from the group consisting of: F243L, R292P, Y300L, V305I, and P396L; (B) two substitutions selected from the group consisting of: (1) F243L and P396L; (2) F243L and R292P; and (3) R292P and V305I; (C) three substitutions selected from the group consisting of: (1) F243L, R292P and Y300L; (2) F243L, R292P and V305I; (3) F243L, R292P and P396L; and (4) R292P, V305I and P396L; (D) four substitutions selected from the group consisting of: (1) F243L, R292P, Y300L and P396L; and (2) F243L, R292P, V305I and P396L; or (E) five substitutions selected from the group consisting of: (1) F243L, R292P, Y300L, V305I and P396L; and (2) L235V, F243L, R292P, Y300L and P396L.
6. The Tri-Specific Binding Molecule of claim 1, wherein: the Linker 2 comprises a cysteine residue, the E-coil Domain and the K-coil Domain adjacent to the Linker 2 each comprises a cysteine residue, or the Linker 2 comprises a cysteine residue and the E-coil Domain or the K-coil Domain adjacent to the Linker 2 comprises a cysteine residue.
7. The Tri-Specific Binding Molecule of claim 6, wherein: the E-coil Domain of SEQ ID NO: 41 or the K-coil Domain of SEQ ID NO: 42 is adjacent to the Linker 2 when the Linker 2 comprises the sequence of SEQ ID NO: 47; the E-coil Domain of SEQ ID NO: 39 or the K-coil Domain of SEQ ID NO: 40 is adjacent to the Linker 2 when the Linker 2 comprises the sequence of SEQ ID NO: 34; or the E-coil Domain of SEQ ID NO: 41 or the K-coil Domain of SEQ ID NO: 42 is adjacent to the Linker 2 when the Linker 2 comprises the sequence of SEQ ID NO: 34.
Claim 2 of ‘440 anticipates and renders obvious instant Claim 22:
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Claim 10 of ‘440 anticipates and renders obvious instant Claim 30:
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Claims 14-15 of ‘440 anticipates and renders obvious instant Claims 34-35:
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Claims 16-17 of ‘440 anticipate and render obvious instant Claims 36-37:
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The combination of a four- polypeptide trispecific binding molecule (creating a four-chain, 3-antigen binding structure) makes a difference primarily by enabling the creation of a stable, IgG-like structure that allows for more complex engineering, such as incorporating a third target specificity (e.g., CD28, CD38, or a checkpoint inhibitor) while improving stability and pharmacological properties compared to simpler, fragmented, or 3-chain formats. The POSA is motivated and assured of predictable and reasonable success.
Conclusion
13. No claims are allowed.
14. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LYNN A. BRISTOL whose telephone number is (571)272-6883. The examiner can normally be reached Mon-Fri 9 AM-5 PM.
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LYNN ANNE BRISTOL
Primary Examiner
Art Unit 1643
/LYNN A BRISTOL/Primary Examiner, Art Unit 1643