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. In the Response of 4/29/2026, claims 21 and 26 are amended and new claims 38-39 are added. Claims 21-39 are pending.
The Office Action is final.
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 6/22/2026, a total of one (1) IDS is filed: 10/30/2023. The corresponding initialed and dated 1449 form is considered and of record.
Withdrawal of Objections
Specification
4. The objection to the disclosure because of informalities is withdrawn.
The specification is amended to rectify the improper use of the term, e.g., NCBI, BiaCore, BiTE, DART [0035], and which is a trade name or a mark used in commerce.
Claim Objections
5. The objection to Claims 26-27 because of informalities is withdrawn.
a) Claims 26-27 are amended to replace “chosen from” with “selected from the group consisting of” in Claim 26.
b) Claim 26 is amended to rectify the grammatical and idiomatic errors.
Rejections Maintained
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. The rejection of Claims 21-37 and 38-39 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 is maintained. New claims 38-39 are joined under the rejection and that limit the species otherwise shown in previously rejected claim 26.
A. Applicants restate the amendments to the claims as "administering to a subject in need thereof a Tri-Specific Binding Molecule in an amount effective for killing cancer cells." As described in more detail below, the claims require the tri-specific binding molecule to bridge immune cells with targeted cancer cells to mediate killing of these cells. The claims do not require that 100% of all cancer cells be killed nor does it require that the subject be cured of cancer.
Response to Arguments
The response does not clarify the distinction between prevention and treatment as to address this aspect for the original grounds of rejection. Whilst “therapeutically effective” is deleted from the claims (see discussion on pp. 4-5 of the OA (2/5/2026) with respect to overlapping meaning between prevention/treatment), the killing of cancer cells is not exclusive to a therapy and may occur with a prophylactic antibody albeit indirectly. Teng et al ((Cancer Res (2010) 70 (7): 2665–2674)) teaching the complexity of effector functioning of prevention in tumor models for a prophylactic antibody relating to cell killing:
“RENCA and MCA-induced fibrosarcomas are both suppressed following a variety of strategies (anti-CD4, anti-FR4, and anti-CD25) that partially deplete Tregs. Quantitatively these strategies depleted FoxP3+ T cells and triggered tumor rejection to a similar extent, but qualitatively each method revealed distinct tumor rejection mechanisms, with no single lymphocyte subset or effector molecule completely accounting for the tumor immunity in these mouse models of cancer” and
“Overall, the study presented here shows that a number of redundant effector mechanisms can potentially eradicate tumors when Treg suppression mechanisms are prophylactically abrogated. Clearly the finding that the method of Treg depletion can significantly influence the downstream immune responses raises some significant issues for the application of various Treg depletion strategies in priming immunity in the context of prophylactic vaccines or minimal residual disease.”
B. Applicants clarify that it is NOT just any of the structures shown in Figs. 4A-4G that are encompassed by the claims but only the structure for Fig. 4A.
Response to Arguments
The comments are of record, namely, that the claimed method invention is directed to the structure of Fig. 4A.
C. Applicants allege the specification is non-limiting as to the “exemplary list of suitable cancer antigens that are expressed on the cell surfaces of different cancers (see Specification, paragraph [0089]). The skilled artisan would appreciate that one can select the cancer antigen binding domain sequences based on the particular cancer being targeted from among the plethora of representative binding sequences disclosed in the instant application or use the guidance provided in the specification to prepare other sequences for binding to cancer antigens (see Specification, paragraphs [0093]- [00184]. Likewise, Applicant provides the skilled artisan with a representative number of effector cell antigen binding domain sequences (see Specification, paragraphs [00186]-[00226]) and provides a representative number of exemplary trispecific binding molecule sequences (see Specification, paragraphs [00301]-[00433]).
Response to Arguments
The list of suitable cancer antigens and effector cell antigens, while pertinent to the method invention, do not define the breadth and scope of VH and/or VL domains that bind the corresponding antigen. Possession of the invention is determined based on the invention as a whole and not individual elements (i.e., a specific antigen). MPEP 2163(II)(A)(1) AND (3).
D. Applicants allege the specification provides a more than adequate subset of suitable binding sequences to demonstrate to the skilled artisan that Applicant was in possession of the full scope of the claimed methods of treating cancer by administering Applicant's claimed trispecific binding molecule scaffold that incorporates the cancer antigen binding sequences and effector cell antigen binding sequences of interest.
Response to Arguments
Applicants alleged binding sequences have not been demonstrated in the instant claimed method with the required limitation that the “amount [is] effective for killing cancer cells” and just for any cancer much less, in vivo. As discussed herein above, Applicants have NOT rendered the claimed method invention free from being prophylactic through direct or indirect mechanisms.
Applicants have not responded to the grounds for rejection set forth under section c from the Office Action of 2/5/2026 for the identification of conventional therapeutic antibodies whether they comprise a single VH, a single VL or VH/VL pairings. The Response is incomplete.
“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”).”
E. Applicant alleges that actual reduction to practice and functionality of a representative subset of the claimed trispecific binding molecules is shown in the specification. Each of these trispecific binding molecules will have the structure shown in FIG. 4A. Applicant demonstrates that trispecific binding molecules assembled with particular cancer antigen binding domains bind to the corresponding cancer-associated cell-surface antigen (see, e.g., FIGS. 9A-9C). As shown in FIGS. 10A-10C, the trispecific binding molecules of the instantly claimed methods can be used to target CHO cells expressing various cell-surface antigens linked to cancer. FIG. 10A is a cytotoxicity study on EphA2-expressing CHO cells. As shown in FIG. 10A, the trispecific binding molecules that include an EphA2 cancer antigen-binding domain (e.g., an EphA2 x CD3 x DR5 trispecific binding molecule or a EphA2 x CD3 x gpA33 trispecific binding molecule) mediate cytotoxicity. Similarly, FIG. 10B shows that trispecific binding molecules that include a DR5 cancer antigen-binding domain (e.g., the EphA2 x CD3 x DR5 tri-specific binding molecule and the gpA33 x CD3 x DR5 trispecific binding molecule) mediate increased cytotoxicity when incubated with DR5-expressing CHO cells. FIG. 10C is a cytotoxicity study using a Du145 prostate cancer cell line that expresses EphA2 and DR5, but not gpA33. As shown in FIG. 10C, trispecific binding molecules that include both of these antigen-binding domains mediate increased cytotoxicity compared to trispecific binding molecules that include only one of the antigen-binding domains and greatly increased cytotoxicity compared to trispecific binding molecules that do not include either of these antigen-binding molecules.
Response to Arguments
Applicants have not shown that the alleged working examples meet the claimed invention as a whole, namely, the full breadth and scope of just any cancer, the cancer cell killing effect being therapeutic and/or prophylactic, the undefined VH and/or VL domains or any combination thereof possessing the immunospecific binding ability for a vast and infinite repertoire of cancer cell antigens and effector cell antigens.
“immunospecific” binding: the specification is clear that specific does not refer to exclusive bind but that certain attributes are still required to be met in order for the VH, VL or VH/VL pair to bind the corresponding antigen immunospecifically:
[0158] The Binding Domains of the Tri-Specific Binding Molecules of the present invention bind to epitopes in an “immunospecific” manner. As used herein, an antibody, diabody or other epitope binding molecule is said to “immunospecifically” bind a region of another molecule (i.e., an epitope) if it reacts or associates more frequently, more rapidly, with greater duration and/or with greater affinity with that epitope relative to alternative epitopes. For example, an antibody that immunospecifically binds to a viral epitope is an antibody that binds this viral epitope with greater affinity, avidity, more readily, and/or with greater duration than it immunospecifically binds to other viral epitopes or non-viral epitopes. It is also understood by reading this definition that, for example, an antibody (or moiety or epitope) that immunospecifically binds to a first target may or may not specifically or preferentially bind to a second target. As such, “specific binding” does not necessarily require (although it can include) exclusive binding. Generally, but not necessarily, reference to binding means “specific” binding. Two molecules are said to be capable of binding to one another in a “physiospecific” manner, if such binding exhibits the specificity with which receptors bind to their respective ligands.
Thus, at least with respect to a criterion the antibody of the invention is required to possess, namely, immunospecificity in its binding, Applicants have NOT shown that the vast repertoire of alleged antibody domains meet the definition set forth in the specification.
Finally, Applicants have not introduced the sequence structures for the whole of the claimed method invention.
F. Applicants allege the skilled artisan can reasonably predict that administration of the trispecific binding molecule to a subject with the corresponding cancer would facilitate the bridging of the immune cells with the targeted cancer cells. As one having ordinary skill in the art will appreciate, the presently claimed trispecific binding molecules can be adapted to include any combination of cancer antigen-binding domains along with an effector binding domain in order to target a cancer cell expressing one or both of the corresponding cancer associated cell-surface antigens.
Response to Arguments
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 cancer antigens or infinite genus of effector cell (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, i.e., killing of cancer cells.
The rejection is maintained.
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. The rejection of Claims 21-37 and 38-39 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 is maintained. New claims 38-39 are joined under the rejection and that limit the species otherwise shown in previously rejected claim 26.
Applicants request to hold the rejection in abeyance is granted. The response is incomplete.
8. The rejection of Claims 21-37 and 38-39 on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 10633440 is maintained. New claims 38-39 are joined under the rejection and that limit the species otherwise shown in previously rejected claim 26.
Applicants request to hold the rejection in abeyance is granted. The response is incomplete.
9. The rejection of Claims 21-37 and 38-39 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 is maintained. New claims 38-39 are joined under the rejection and that limit the species otherwise shown in previously rejected claim 26.
Applicants request to hold the rejection in abeyance is granted. The response is incomplete.
Conclusion
10. No claims are allowed.
11. THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
12. 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 A BRISTOL/Primary Examiner, Art Unit 1643
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