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 1-23 are the original claims filed 10/11/2023. In the preliminary amendment of 2/21/2024, claims 1-23 are canceled and new claims 24-43 are added.
Claims 24-43 are the pending claims.
Priority
2. USAN 18/484,921, filed 10/11/2023, is a Continuation of 16/818,893, filed 03/13/2020, now U.S. Patent # 11820818, 16/818,893 is a Divisional of 15/313,741, filed 11/23/2016, now U.S. Patent # 10647768, 15/313,741 is a National Stage entry of PCT/US15/33076, International Filing Date: 05/29/2015,
PCT/US15/33076 Claims Priority from Provisional Application 62/107,824, filed 01/26/2015, PCT/US15/33076 Claims Priority from Provisional Application 62/008,229, filed 06/05/2014, PCT/US15/33076 Claims Priority from Provisional Application 62/004,571, filed 05/29/2014.
Information Disclosure Statement
3. As of 6/25/2026, a total of one (1) IDS is filed: 9/13/2024. 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:
a) The use of the term BiTE, Tris, DART (e.g., see Table 26), 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 24-43 are objected to because of the following informalities:
a) Claims 24-43 recite for the phrase “heterodimer-promoting domain” where no structure is suggested in the most generic claims to confer how heterodimerization is to occur and to what elements within the structure of the tri-specific binding molecule the heterodimer structures interact. It is also not clear how the first and second polypeptides comprising the “heterodimer-promoting domain” relate to each other much less the third and fourth polypeptide chains.
See [0444] The Heterodimer-Promoting Domain of the first polypeptide and the Heterodimer-Promoting Domain of the second polypeptide are coordinately selected. The Domains differ from one another and are designed to associate with one another so as to promote the association of the first and second polypeptide chains. For example, one of the Heterodimer-Promoting Domains will be engineered to have a negative charge at pH 7, while the other of the two polypeptide chains will be engineered to have a positive charge at pH 7. The presence of such charged Domains promotes association between the first and second polypeptides, and thus fosters heterodimerization. It is immaterial which Heterodimer-Promoting Domains is provided to which chain, as long as the Domains employed on the first and second polypeptide chains differ so as to foster heterodimerization between such chains.
b) Claims 24-43 recite the phrase “Cysteine-Containing Domain” where no structure is suggested for any such domain, the number of cysteine residues present nor is it apparent why the domain is present in the third and fourth polypeptide chains.
c) Claims 24-43 recite the phrase “A tri-specific binding molecule” because the term “molecule” is not defined in the specification for a generic meaning. It is not clear whether other elements are inclusive nor what they represent, e.g., proteins, sugars, lipids, phospholipids, or combinations thereof.
d) Claim 31 is unclear in reciting “chosen from” which does not distinguish the language being closed or open.
e) Claim 33 recites the phrase “capable of physiospecific binding” and it is inherently incongruous for the domain to be capable of a binding property and specific in its binding property for the same antigen. The recitation “capable of physiospecific binding” implies that some undefined structure or condition is what predicates whether binding does or does not occur. Capacity and capability suggest that the binding may sometimes occur but not always, and what determines the degree or amount of binding is not definite by the use of those terms.
f) Amend claim 34 to recite “(EGF-R).”
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
6. Claim 34 is 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 broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c).
In the present instance, claim 34 recites the broad recitation Erb, and the claim also recites ErbB1, ErbB2, ErbB3, ErbB4, which is the narrower statement of the range/limitation.
In the present instance, claim 34 recites the broad recitation GAGE, and the claim also recites GAGE-1, GAGE-2, which is the narrower statement of the range/limitation.
In the present instance, claim 34 recites the broad recitation MAGE, and the claim also recites MAGE-1, MAGE-2, which is the narrower statement of the range/limitation.
In the present instance, claim 34 recites the broad recitationTNF-receptor, and the claim also recites TNF-α receptor, TNF-β receptor; or TNF-γ receptor, which is the narrower statement of the range/limitation.
The claim(s) is considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
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
7. Claims 24-43 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.
(A)(i) Claim construction/interpretation
The claims are drawn to numerous combinations of the total of three polypeptide chains recited in generic Claim 2 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.
(A)(ii) Disclosure 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 amny types of cancers would include Eph2A and CEACAM5 antigens [00469]. Otherwise, there is no suggesiton 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-avis the CD3 domain in a construct comprising the four polypeptide chains.
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.”
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.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Vas-Cath, Inc., v. Mahurkar, 935 F.2d at 1563, 19 U.S.P.Q.2d at 1116.
In particular MPEP § 2163 instructs that the “written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice…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 claimed genus…See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
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A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus.").”
(A)(iii) Predictability in the Art: MPEP 2144.08 states in part: The claims encompass re-organized, rearranged antibody domains into non-conventional multichain, trispecific “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 tri-specific antibody monomers having binding specificity for the three separate and distinct binding domains.
B)(i) 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 1st, 2nd and 3rd, respectively (Claim 24).
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, 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).
(B)(ii) 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) (IDS) (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) (IDS); see also Marchalonis et al., Dev & Comp Immunol. 30:223-247 (2006) (IDS), 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) (IDS).
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) (IDS). 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) (IDS)). 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 (IDS). 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?
Applicant has not provided a common structure much less any specific structure sufficient to visualize the genus of all possible antigen binding domains.
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 stability. 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) (IDS) 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 (IDS)), 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 17-18) 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 (IDS)). 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 (IDS)) (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 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 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. Furthermore, where the presentation of the data is not clear based on the labeling of monomers shown to possess a four-way antigen binding specificity, Applicants are not in possession of the claimed invention as a whole nor in part at the time of filing.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
7. Claims 24-25, 31-34, is/are rejected under 35 U.S.C. 103 as being obvious over Kellner et al (20100291112; IDS) in view of Macrogenics (WO 2012018687; IDS).
Because of the ambiguity of the meaning for “heterodimer-promoting-domain” as discussed under the objections to the claims, this aspect of the claimed molecule is excluded from the analysis.
Because of the ambiguity for the structural embodiments falling within the broadly claimed four polypeptide chains with respect to the order and orientation for the combination of recited domains, the claims are analyzed for a structure that falls within the instant claim scope.
Kellner discloses a Tri-Specific Binding Molecule capable of immunospecifically binding to three different epitopes (Tri-Specific Binding Molecule capable of immunospecifically binding to three different epitopes; abstract; figure 1; paragraph [0120]), said Epitopes being Epitope I (first immunoglobulin domain capable of binding to an antigen expressed on tumor cells (Epitope I); abstract; paragraphs [0037], [0038], [0120]), Epitope II (second immunoglobulin domain capable of binding to an antigen expressed on tumor cells (Epitope II); abstract; paragraphs [0037], [0038], [0120]), and Epitope III (third immunoglobulin domain capable of binding to an effector cell antigen (Epitope III); abstract; paragraph [0039], [0120]), wherein two of said three epitopes are epitopes of Cancer Antigen(s) (first and second immunoglobulin domains bind to antigens expressed on tumor cells (two of said three epitopes are epitopes of Cancer Antigen(s)); abstract; paragraph [0120]), and the third of said three epitopes is an epitope of an Effector Cell Antigen (third of said three epitopes is an epitope of an Effector Cell Antigen; abstract; paragraph [0120]). (See Claim 24)
Kellner further discloses wherein said Effector Cell Antigen is arrayed on the surface of an effector cell (said Effector Cell Antigen is arrayed on the surface of an effector cell; paragraph [0030]) and wherein said Cancer Antigens are arrayed on the surface of a cancer cell (tumor (Cancer) Antigens are expressed on tumor cells (arrayed on the surface of a cancer cell); paragraphs [0037]-[0039]), and wherein said immunospecific binding is sufficient to co-localize said Effector Cell Antigen (wherein said immunospecific binding is sufficient to co-localize said Effector Cell expressing CD16 (said Effector Cell Antigen); figure 3A: paragraph [0150]), and said Cancer Antigens (and a cancer cell expressing CD19 said Cancer Antigens); figure 3A: paragraph [0150]), thereby facilitating the activation of said effector cell against said cancer cell (increased ADCC (thereby facilitating the activation of said effector cell against said cancer cell); figure 5; paragraphs [0057], [0107]). (See Claims 24, 31-34)
Kellner further discloses a capability of immunospecifically binding to three different epitopes (abstract), and comprises: (I) an Antigen-Binding Domain I that is capable of immunospecifically binding to an Epitope I present on a first antigen (first immunoglobulin domain capable of binding to an antigen expressed on tumor cells (an Antigen-Binding Domain I that is capable of immunospecifically binding to an Epitope I present on a first antigen); abstract; paragraphs [0037], [0038]), and an Antigen-Binding Domain II that is capable of immunospecifically binding to an Epitope II present on a second antigen (second immunoglobulin domain capable of binding to an antigen expressed on tumor cells (Antigen-Binding Domain II that is capable of immunospecifically binding to an Epitope II present on a second antigen); abstract; paragraphs [0037], [0038]), (II) an Antigen-Binding Domain III that is capable of immunospecifically binding to an Epitope III present on a third antigen (third immunoglobulin domain capable of binding to an effector cell antigen (Antigen-Binding Domain III that is capable of immunospecifically binding to an Epitope III present on a third antigen); abstract; paragraph [0039]); and wherein one of Epitope I, Epitope II or Epitope III is an epitope of an Effector Cell Antigen (third immunoglobulin domain capable of binding to an effector cell antigen (Epitope III); abstract; paragraph [0039], [0120]), a second of Epitope I, Epitope II or Epitope III is an epitope of a first Cancer Antigen (first immunoglobulin domain capable of binding to an antigen expressed on tumor cells (Epitope I); abstract; paragraphs [0037], [0038], [0120]) and the third of Epitope I, Epitope II or Epitope III is an epitope of a second Cancer Antigen (second immunoglobulin domain capable of binding to an antigen expressed on tumor cells (Epitope II); abstract; paragraphs [0037], [0038], [0120]), and wherein the Antigen-Binding Domains I, II and III of the Binding Molecules (sctb ds [19 x 16 x 19] (Antigen-Binding Domains I, II and III of the Binding Molecules); figure 3A; paragraph [0150]) mediate coordinated binding of an immune system effector cell expressing said Effector Cell Antigen and a cancer cell expressing said first and second Cancer Antigens (mediated coordinated binding of an immune system effector cell expressing CD16 (said Effector Cell Antigen) and a cancer cell expressing CD19 (said first and second Cancer Antigens); figure 3A: paragraph [0150]) and a Fc Domain (capable of binding CD16 or CD64 of an effector cell (Fc Domain); paragraph [0041]). Kellner does riot disclose wherein said binding molecule comprises four different polypeptide chains covalently complexed together, wherein said Antigen-Binding Domain I and said Antigen-Binding Domain II are both Diabody-Type Binding Domains or an Fc Domain that is formed by the complexing of two CH2-CH3 Domains to one another.
Macrogenics discloses a binding molecule comprising four different polypeptide chains covalently complexed together (DART species (a binding molecule) comprising four different polypeptide chains covalently complexed together; abstract; figure 32; paragraph [0099]), an Antigen-Binding Domain I Antigen-Binding Domain II are both Diabody-Type Binding Domains (an Antigen-Binding Domain I Antigen-Binding Domain II are both Diabody-Type Binding Domains; figure 32; paragraph [0099]) and an Fc Domain that is formed by the complexing of two CH2-CH3 Domains to one another (Fc Domain that is formed by the complexing of two CH2-CH3 Domains to one another; figure 32; paragraph [00125]). It would have been obvious to a person of ordinary skill in the art, at the time of the invention, to have modified the previous disclosure of Kellner, for integrating a binding molecule comprising four different polypeptide chains covalently complexed together, wherein said Antigen-Binding Domain I and said Antigen-Binding Domain II are both Diabody-Type Binding Domains and an Fc Domain that is formed by the complexing of two CH2-CH3 Domains to one another, as previously disclosed by Macrogenics, for developing a trispecific binding molecule having the ability to bind to three different epitopes, as previously disclosed by Kellner, and comprises four polypeptide chains which include the formation of a diabody binding domain, as previously disclosed by Macrogenics, for achieving simultaneous binding to a cancer cell and an effector cell for efficiently activating the immune system to kill the cancer cell. (See Claims 24-25 and 31-34)
Kellner and Macrogenics, in combination, discloses the Tri-Specific Binding Molecule of claims 24-25, and Kellner further discloses wherein said Effector Cell Antigen is arrayed on the surface of an effector cell (paragraph [0030]) and wherein said Cancer Antigens are arrayed on the surface of a cancer cell (tumor (Cancer) Antigens are expressed on tumor cells (arrayed on the surface of a cancer cell); paragraphs [0037]-[0039]), and wherein said immunospecific binding is sufficient to co-localize said Effector Cell Antigen (wherein said immunospecific binding is sufficient to co-localize said Effector Cell expressing CD16 (said Effector Cell Antigen); figure 3A; paragraph [0150]), and said Cancer Antigens ((and a cancer cell expressing CD19 said Cancer Antigens); figure 3A; paragraph [0150]), thereby facilitating the activation of said effector cell against said cancer cell (increased ADCC (thereby facilitating the activation of said effector cell against said cancer cell); figure 5; paragraphs [0057, [0107]).
Accordingly, the reference structures encompassed by the disclosures of Kellner and MacroGenics would have provided more than sufficient motivation and a reasonable measure of success in making and using tri-specific structures comprising three polypeptide chains including an Fc domain based on the need to generate antibody formats that could be used for diagnostic and therapeutic applications.
The applied reference has a common inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
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.
9. Claims 24-32 and 34-43 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 8-10, 16-21 of U.S. Patent No. 10647768 (IDS). The reference patent is not afforded safe harbor protection under 35 USC 121 because it does not share restriction status to the instant application.
Although the claims at issue are not identical, they are not patentably distinct from each other because of the claim sets relate to Tri-Specific Binding Molecules, which are multi-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.
Generic Claim 1 of ‘768 anticipates and renders obvious instant Claims 24, 26-30:
1. A multi-chain polypeptide-containing Tri-Specific Binding Molecule that immunospecifically binds to three different epitopes, comprising: (I) four 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 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, from the N-terminus to the C-terminus: (VL.sub.I Domain)-(Linker 1)-(VH.sub.II Domain)-(Linker 2)-(Heterodimer-Promoting Domain)-(Linker 3)-(CH2-CH3 Domain); (B) a second polypeptide chain comprises, from the N-terminus to the C-terminus: (VL.sub.II Domain)-(Linker 1)-(VH.sub.I Domain)-(Linker 2)-(Heterodimer-Promoting Domain); (C) a third polypeptide chain comprises, from the N-terminus to the C-terminus: (VH.sub.III Domain)-(Cysteine-Containing Domain)-(CH2-CH3 Domain); (D) a fourth polypeptide chain comprises, from the N-terminus to the C-terminus: (VL.sub.III Domain)-(Cysteine-Containing Domain); (E) the VL.sub.I Domain is a Light Chain Variable Domain of an immunoglobulin 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 VL.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; (F) the VL.sub.I Domain and the VH1 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, 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 III is a Non-Diabody-Type Binding Domain; (G) the first, second and third antigens are the same antigen, or are independently the same or different from another of the antigens; and (H) 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 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; and 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.
Claim 2 of ‘768 anticipates and renders obvious instant Claim 25:
2. The Tri-Specific Binding Molecule of claim 1, wherein (i) the first polypeptide chain and the second polypeptide chain are covalently bonded to one another; (ii) the first polypeptide chain and the third polypeptide chain are covalently bonded to one another; and (iii) the third polypeptide chain and the fourth polypeptide chain are covalently bonded to one another.
Claims 3-4 of ‘768 anticipates and renders obvious instant Claims 31-32:
3. 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 chosen 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.
4. The Tri-Specific Binding Molecule of claim 3, 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.
Claims 5-6 of ‘768 anticipates and renders obvious instant Claim 34:
5. The Tri-Specific Binding Molecule of claim 4, 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.
6. The Tri-Specific Binding Molecule of claim 5, 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 Le.sup.b) and CO-514 (blood group Lea); CTLA-1 and CTLA-4; Cytokeratin 8; DR5; 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 (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; Myl, 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; T5A7; Tissue Antigens 37; TAG-72; TL5 (blood group A); TNF-receptor (TNF-α receptor, TNF-β receptor; or 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.
Claims 8-10 of ‘768 anticipates and renders obvious instant Claim 35-37:
8. The Tri-Specific Binding Molecule of claim 4, 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.
9. The Tri-Specific Binding Molecule of claim 4, 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.
10. The Tri-Specific Binding Molecule of claim 6, 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.
Claim 16 of ‘768 anticipates and renders obvious instant Claim 38:
16. 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.
Claims 17-21 of ‘768 anticipates and renders obvious instant Claims 39-43:
17. The Tri-Specific Binding Molecule of claim 1, wherein the third polypeptide chain comprises a CH1 Domain.
18. The Tri-Specific Binding Molecule of claim 17, wherein the CH1 Domain comprises the sequence of SEQ ID NO: 9.
19. The Tri-Specific Binding Molecule of claim 17, wherein the fourth polypeptide chain comprises a CL Domain.
20. The Tri-Specific Binding Molecule of claim 19, wherein the CL Domain comprises the sequence of SEQ ID NO: 13 or 14.
21. A pharmaceutical composition comprising the Tri-Specific Binding Molecule of claim 1 and a pharmaceutically acceptable carrier, excipient or diluent.
10. Claims 24-32, 34 38-43 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 5-6 and 13-18 of U.S. Patent No. 10633440 (IDS). 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 Claims 24, 26-30 where the fourth polypeptide of Claim 1 is the same as the cysteine-containing domain of instant Claim 24:
1. A multi-chain polypeptide-containing Tri-Specific Binding Molecule that immunospecifically binds to three different epitopes, comprising: (I) four 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) one of Epitope I, Epitope II or Epitope III is an epitope of an Effector Cell Antigen, a second of Epitope I, Epitope II or Epitope III is an epitope of a first Cancer Antigen, and a third of Epitope I, Epitope II or Epitope III is an epitope of a second Cancer Antigen; (B) a first polypeptide chain comprises, from the N-terminus to the C-terminus: (VL.sub.I Domain)-(Linker 1)-(VH.sub.II Domain)-(Linker 2)-(Heterodimer-Promoting Domain)-(Linker 3)-(CH2-CH3 Domain); (C) a second polypeptide chain comprises, from the N-terminus to the C-terminus: (VL.sub.II Domain)-(Linker 1)-(VH.sub.I Domain)-(Linker 2)-(Heterodimer-Promoting Domain); (D) a third polypeptide chain comprises, from the N-terminus to the C-terminus: (VH.sub.III Domain)-(Cysteine-Containing Domain)-(CH2-CH3 Domain); (E) a fourth polypeptide chain comprises, from the N-terminus to the C-terminus: (VL.sub.III Domain)-(Cysteine-Containing Domain); (F) 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 VL.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; (G) the VL.sub.I Domain and the VH1 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, 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 III is a Non-Diabody-Type Binding Domain; and (H) the Linker 1 comprises the sequence of SEQ ID NO: 33; the Linker 2 comprises the sequence of SEQ ID NO: 34 or 47; 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: 39 or 41, and the K-coil Domain independently comprises the sequence of SEQ ID NO: 40 or 42; the Linker 3 comprises the sequence of SEQ ID NO: 46, 47, 48, 49, 50, 51, 152, or GCG or GGG; and the Cysteine-Containing Domain independently comprises the sequence of SEQ ID NO: 34, 36, 38, 48, 210 or 211.
Claim 2 of ‘440 anticipates and renders obvious instant Claim 25:
2. The Tri-Specific Binding Molecule of claim 1, wherein (i) the first polypeptide chain and the second polypeptide chain are covalently bonded to one another; (ii) the first polypeptide chain and the third polypeptide chain are covalently bonded to one another; and (iii) the third polypeptide chain and the fourth polypeptide chain are covalently bonded to one another.
Claim 5 of ‘440 anticipates and renders obvious instant Claims 31-32
5. The Tri-Specific Binding Molecule of claim 1, wherein the Effector Cell Antigen is CD2, CD3, CD16, CD19, CD20, CD22, CD32B, CD64, B cell Receptor (BCR), T cell Receptor (TCR), or NKG2D Receptor.
Claim 6 of ‘440 anticipates and renders obvious instant Claim 34
6. The Tri-Specific Binding Molecule of claim 1, wherein the first Cancer Antigen and the second Cancer Antigen are independently chosen from: 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 ALe.sup.b/Le.sup.y; 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; CEACAM6; CO17-1A; CO-43 (blood group Le.sup.b); CO-514 (blood group Le.sup.a); CTA-1; CTLA4; Cytokeratin 8; antigen D1.1; antigen D.sub.156-22; DR5; E.sub.1 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; G.sub.D2; G.sub.D3; GICA 19-9; G.sub.M2; gp100; human leukemia T cell antigen Gp37; melanoma antigen gp75; gpA33; HER2 antigen (p185.sup.HER2); human milk fat globule antigen (HMFG); human papillomavirus-E6/human papillomavirus-E7; high molecular weight melanoma antigen (HMW-MAA); I 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; R.sub.24, ROR1; sphingolipids; SSEA-1; SSEA-3; SSEA-4; sTn; T cell receptor derived peptide; T.sub.5A.sub.7; TAG-72; TL5 (blood group A); TNF-α receptor; TNF-ß 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; Y hapten, Le.sup.y and 5T4.
Claims 13-18 of ‘440 anticipates and renders obvious instant Claims 38-43
13. 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.
14. The Tri-Specific Binding Molecule of claim 1, wherein the third polypeptide chain comprises a CH1 Domain.
15. The Tri-Specific Binding Molecule of claim 14, wherein the CH1 Domain comprises the sequence of SEQ ID NO: 207 or 208.
16. The Tri-Specific Binding Molecule of claim 14, wherein the fourth polypeptide chain comprises a CL Domain.
17. The Tri-Specific Binding Molecule of claim 16, wherein the CL Domain comprises the sequence of SEQ ID NO: 210 or 211.
18. A pharmaceutical composition comprising the Tri-Specific Binding Molecule of claim 1 and a pharmaceutically acceptable carrier, excipient or diluent.
11. Claims 24, 26-31, 34, 38, 43 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5, 9, 11, 13 of U.S. Patent No. 11697684 B2. The reference patent is not afforded safe harbor protection under 35 USC 121 because it does not share relation by continuity or restriction status to the instant application. Although the claims at issue are not identical, they are not patentably distinct from each other because the claim sets relate to Tri-Specific Binding Molecules, which are multi-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.
Claim 1 of the ‘684 anticipates or renders obvious instant Claims 24 and 26-30
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) one of Epitope I, Epitope II or Epitope III is an epitope of an Effector Cell Antigen, a second of Epitope I, Epitope II or Epitope III is an epitope of a first Cancer Antigen, and a third of Epitope I, Epitope II or Epitope III is an epitope of a second Cancer Antigen; (B) a first polypeptide chain comprises, in the N-terminus to C-terminus direction: (VL.sub.I 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)-(VL.sub.I Domain)-(Linker 1)-(VH.sub.II Domain)-(Linker 2)-(Heterodimer-Promoting Domain); (C) 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); (D) a third polypeptide chain comprises, in the N-terminus to C-terminus direction: (VL.sub.III Domain)-(Flexible Linker)-(VH.sub.III Domain)-(Cysteine-Containing Domain)-(CH2-CH3 Domain); or (CL Domain)-(VL.sub.III Domain)-(Flexible Linker)-(VH.sub.III Domain)-(CH1 Domain)-(Cysteine-Containing Domain)-(CH2-CH3 Domain); I 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 VL.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; (F) 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; and (G) the Linker 1 comprises the sequence of SEQ ID NO: 33; the Linker 2 comprises the sequence of SEQ ID NO: 34 or 47; the Linker 3 comprises the sequence of SEQ ID NO: 46, 47, 48, 49, 50, 51, 152, or GCG or GGG; the Linker 4 comprises the sequence of SEQ ID NO: 50 or 152; 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: 39 or 41, and the K-coil Domain independently comprises the sequence of SEQ ID NO: 40 or 42; 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.
Claim 5 of the ‘684 anticipates or renders obvious instant Claim 38
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 I five substitutions selected from the group consisting of: (1) F243L, R292P, Y300L, V305I and P396L; and (2) L235V, F243L, R292P, Y300L and P396L.
Claim 9 of the ‘684 anticipates or renders obvious instant Claim 31
9. The Tri-Specific Binding Molecule of claim 1, wherein the Effector Cell Antigen is CD2, CD3, CD16, CD19, CD20, CD22, CD32B, CD64, B cell Receptor (BCR), T cell Receptor (TCR), or NKG2D Receptor.
Claim 11 of the ‘684 anticipates or renders obvious instant Claim 34
11. The Tri-Specific Binding Molecule of claim 8, wherein the first Cancer Antigen and the second Cancer Antigen are independently selected from: 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 Ale.sup.b/Le.sup.y; 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; CEACAM6; C017-1A; CO-43 (blood group Le.sup.b); CO-514 (blood group Le.sup.a); CTA-1; CTLA4; Cytokeratin 8; antigen D1.1; antigen D.sub.156-22; DR5; E.sub.1 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; G.sub.D2; G.sub.D3; GICA 19-9; GM2; gp100; human leukemia T cell antigen Gp37; melanoma antigen gp75; gpA33; HER2 antigen (p185.sup.HER2); human milk fat globule antigen (HMFG); human papillomavirus-E6/human papillomavirus-E7; high molecular weight melanoma antigen (HMW-MAA); I antigen (differentiation antigen) I(Ma); Integrin Alpha-V-Beta-6 Integrinβ6 (ITGB6); Interleukin-13; Receptor α2 (IL13Rα2); JAM-3; KID3; KID31; KS ¼ 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-acetylglucosam inyltransferase; 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; R.sub.24, ROR1; sphingolipids; SSEA-1; SSEA-3; SSEA-4; sTn; T cell receptor derived peptide; T.sub.5A.sub.7; 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, Le.sup.y.
Claim 13 of the ‘684 anticipates or renders obvious instant Claim 43
13. A pharmaceutical composition comprising the Tri-Specific Binding Molecule of claim 1, and a pharmaceutically acceptable carrier, excipient or diluent.
12. Claims 24-31, 34, 3842 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 21-22, 25-26, 33-37 of copending Application No. 18/320,599 (reference application US 20240117036). The reference 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 case to “599 much less does the patent prosecution history in the claims for the allowed parent case read away from the instant claims.
Although the claims at issue are not identical, they are not patentably distinct from each other because of the claim sets relate to Tri-Specific Binding Molecules, which are multi-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.
Claim 21 of ‘559 anticipates and renders obvious instant Claims 24, 26-30
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Claim 22 of ‘559 anticipates and renders obvious instant Claim 25
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Claim 25 of ‘559 anticipates and renders obvious instant Claim 31
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Claim 26 of ‘559 anticipates and renders obvious instant Claim 34
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Claim 33-37 of ‘559 anticipates and renders obvious instant Claim 38-42
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This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
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
Prosecution Insights