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 1-28 are the original claims filed 4/14/2021. In the Preliminary Amendment of 8/10/2021, Claims 1-28 are canceled and new Claims 29-67 are added. In the Response of 12/13/2023, Claims 29-67 are canceled and new Claims 68-83 are added. In the Response of 7/12/2024, Claims 68 and 77 are amended and Claim 78 is canceled. In the Response of 3/6/2025, no claims are amended, canceled or added. In the Response of 4/21/2026, claim 83 is amended. In the Response After Final Action of 9/1/2026, co claims are amended, canceled or added.
Claims 68-77 and 79-83 are all the claims under examination.
The Office Action contains new grounds for rejection in view of the properly certified IDS filed 7/16/2026.
Priority
2. USAN 17/230,240, filed 04/14/2021, and having 1 RCE-type filing herein is a Divisional of 14/340,872, filed 07/25/2014, now U.S. Patent # 11161906 and having 4 RCE-type filings therein, and 14/340,872 Claims Priority from Provisional Application 61/858,402, filed 07/25/2013.
Information Disclosure Statement
3. As of 10/3/2026, a total of seven (7) IDS are filed for this application: 4/14/2021; 1/6/2023; 6/6/2032; 12/6/2023; 12/21/2023; 11/13/2024; and 7/16/2026. The corresponding initialed and dated 1449 form is considered and of record. The IDS of 7/16/2026 is certified for entry and consideration as discussed in the interview of 9/14/2026.
Withdrawal of Rejections
Double Patenting
4. The rejection of Claims 68-77 and 79-83 79-82 on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 10669337 is withdrawn. The terminal disclaimer filed on 9/1/2026 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of U.S. Patent No. 10669337 has been reviewed and is accepted. The terminal disclaimer has been recorded.
5. The rejection of Claims 68-77 and 11802158 is withdrawn. The terminal disclaimer filed on 9/1/2026 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of U.S. Patent No. 11802158 has been reviewed and is accepted. The terminal disclaimer has been recorded.
Examiner’s Comments
6. The IDS transmittal letter filed 7/16/2026 draws specific attention from amongst five references to one that is referred to as “The enclosed reference was cited in corresponding EP communication: Summons to attend oral proceedings pursuant to Rule 115(1) EPC for EP Application No. 15745116.2 dated April 21, 2026 and a Notice of Reasons for Rejection for Japanese Patent Application No. 2022-027548, mailed June 23, 2026.” “The enclosed reference” is document 2 cited in the 1449 form of 7/16/2026.
Applicants’ interview summary of 9/29/2026 states in part that the EP Application No. 15745116.2-related reference is a summons that “relates to a totally different claim set” where the reference EP application “is a national stage entry from a later-filed PCT application WO 2016014974A2 and is not the same family…and does not claim the same invention”. Applicants do not provide a copy of the reference EP application claim set in the IDS of 7/16/2026 nor with their “Applicants Summary of Interview with Examiner” for the Office to make a reasonable comparison to the instant claim set. Applicants have not cited EP Application No. 15745116.2 in an IDS of record.
The corresponding US patent stemming from PCT WO 2016014974A2 is cited in PTO 892 form of 7/19/2023 as US 10669337. The corresponding US patent 10669337 is not prior art to the claims of the instant application, because of the terminal disclaimer filed on 9/1/2026 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of U.S. Patent No. 10669337 has been reviewed and is accepted. The terminal disclaimer has been recorded. See the above withdrawal of rejections under “Double Patenting” herein above.
The current state of the art for masking moieties, immunotherapeutics in general, and antibody synergy warrants a re-opening of the case and an analysis of the claimed invention for enablement of the full breadth and scope of making and using the method invention drawn to:
A method of delivering a multispecific activatable antibody to a subject comprising intravenously administering the multispecific activatable antibody to the subject, wherein the multispecific activatable antibody comprises: at least a first antibody or an antigen binding fragment thereof (AB1) that specifically binds a first target or epitope; a second antibody or an antigen binding fragment thereof (AB2) that specifically binds a second target or epitope; at least a first masking moiety (MM1) that inhibits the binding of the AB1 to the first target or epitope; and at least a first cleavable moiety (CM1) coupled to the AB1 and coupled to the MM1, wherein the CM1 is a substrate for a protease, wherein the CM1 is between the AB1 and the MM1, wherein the AB2 is attached to an N-terminus or a C-terminus of a heavy chain or a light chain of the AB1, wherein AB1 is a targeting antibody or antigen-binding fragment thereof that specifically binds the first target or epitope present on the surface of a tumor cell or other cell type associated with disease and AB2 is an immune cell engaging antibody or antigen-binding fragment thereof that specifically binds the second target or epitope present on the surface of an immune effector cell,and wherein the protease cleaves the CM1 in the multispecific activatable antibody when the multispecific activatable antibody is exposed to the protease.
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.
Scope of Enablement
7. Claims 68-77 and 79-83 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for 3954-1204-C225v5-OKT3m-H-N, 3954-1204-C225v5—CTLA-4 and 5342-1204-4D11v2—CTLA-4, does not reasonably provide enablement for using any multispecific, activatable antibody of claim 66 for nonspecific delivery in a subject based on antigen binding specificity alone and absent a sufficient protease environment that activates the antibody. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Factors to be considered in determining whether undue experimentation is required, are summarized in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). They include the nature of the invention, the state of the prior art, the relative skill of those in the art, the amount of direction or guidance disclosed in the specification, the presence or absence of working examples, the predictability of the art, the breadth of the claims, the quantity of experimentation which would be required in order to practice the invention as claimed.
Claim interpretation
“deliver”/ “delivering”: the administering step of the method requires a subsequent delivery or delivering of the activatable antibody that is unspecified in the claims as to where the antibody is delivered to achieve a protease-sufficient environment capable of the activation step for exposing the targeting antibody and the immune cell engaging antibody. The specification teaches delivery to specific locations at:
[0285] In addition to the elements described above, the multispecific activatable antibodies can contain additional elements such as, for example, amino acid sequence N- or C-terminal of the multispecific activatable antibodies. For example, multispecific activatable antibodies can include a targeting moiety to facilitate delivery to a cell or tissue of interest. Multispecific activatable antibodies can be conjugated to an agent, such as a therapeutic agent, an antineoplastic agent, a toxin or fragment thereof, a detectable moiety or a diagnostic agent. Examples of agents are disclosed herein.
[0307] In addition, agents may be attached via disulfide bonds (for example, the disulfide bonds on a cysteine molecule) to the AB. Since many tumors naturally release high levels of glutathione (a reducing agent) this can reduce the disulfide bonds with subsequent release of the agent at the site of delivery. In certain specific embodiments the reducing agent that would modify a CM would also modify the linker of the conjugated activatable antibody.
[0350] It will be appreciated that administration of therapeutic entities in accordance with the disclosure will be administered with suitable carriers, excipients, and other agents that are incorporated into formulations to provide improved transfer, delivery, tolerance, and the like.
“intravenous”: the specification teaches pharmaceutical compositions for intravenous administration of the moiety at
[0383] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL′ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be suitable to include isotonic agents, for example, sugars, polyalcohols such as manitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate and gelatin.
[0384] Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
“cell type associated with disease”: the scope of the diseases are unlimited therefore the antigens expressed on just any disease is more unlimited for AB1. See the specification at:
[0014] In some embodiments of an immune effector cell engaging multispecific activatable antibody, one antigen is typically an antigen present on the surface of a tumor cell or other cell type associated with disease, such as, but not limited to, any target listed in Table 1, such as, but not limited to, EGFR, erbB2, EpCAM, Jagged, PD-L1, B7H3, or CD71 (transferrin receptor), and another antigen is typically a stimulatory or inhibitory receptor present on the surface of a T-cell, natural killer (NK) cell, myeloid mononuclear cell, macrophage, and/or other immune effector cell, such as, but not limited to, B7-H4, BTLA, CD3, CD4, CD8, CD16a, CD25, CD27, CD28, CD32, CD56, CD137, CTLA-4, GITR, HVEM, ICOS, LAG3, NKG2D, OX40, PD-1, TIGIT, TIM3, or VISTA. In some embodiments, the antigen is a stimulatory receptor present on the surface of a T cell or NK cell; examples of such stimulatory receptors include, but are not limited to, CD3, CD27, CD28, CD137 (also referred to as 4-1BB), GITR, HVEM, ICOS, NKG2D, and OX40. In some embodiments, the antigen is an inhibitory receptor present on the surface of a T-cell; examples of such inhibitory receptors include, but are not limited to, BTLA, CTLA-4, LAG3, PD-1, TIGIT, TIM3, and NK-expressed KIRs. The antibody domain conferring specificity to the T-cell surface antigen may also be substituted by a ligand or ligand domain that binds to a T-cell receptor, a NK-cell receptor, a macrophage receptor, and/or other immune effector cell receptor, such as, but not limited to, B7-1, B7-2, B7H3, PD-L1, PD-L2, or TNFSF9.
The POSA could reasonably conclude that the formulation and delivery of the antibody moiety is not clearly defined in the claims as filed to enable the full use of the method as instant claimed. The POSA could reasonably conclude that any cell type associated any disease is infinite in scope and encompasses known and yet-to-be-discovered antigens or epitopes thereof.
The breadth and scope of the features of the antibody moiety were analyzed under written description in the Office Actions of 2/14/2024, 9/6/2025 and 12/22/2025. Thus, the interpretation of the meaning and scope of the claimed invention is of record.
Disclosure in the Specification
Example 4:
[0416] Panel A in FIG. 15 shows that anti-EGFR multispecific activatable antibody 3954-1204-C225v5—CTLA-4 bound to EGFR, by ELISA, with lower affinity (K.sub.d=12.8 nM) as compared to C225v5 (3 nM) or to C225v5—CTLA-4 (0.33 nM). However, once activated by uPA, anti-EGFR multispecific activatable antibody 3954-1204-C225v5—CTLA-4 bound to EGFR with similar affinity (0.45 nM) as compared to C225v5 (0.21 nM) and C225v5—CTLA4 (0.33 nM). Importantly uPA did not cleave the anti-CTLA4 scFv fused to the carboxyl terminus of the heavy chain: As illustrated in panel B of FIG. 15, uPA treatment had no effect of binding to human CTLA4.
[0417] Similarly, anti-Jagged multispecific activatable antibody 5342-1204-4D11v2—CTLA-4 bound to human Jagged 1, by ELISA, with lower affinity (15 nM) as compared to 4D11v2 (0.44 nM) or 4D11v2—CTLA4 (0.77 nM). Once activated, anti-Jagged multispecific activatable antibody 5342-1204-4D11v2—CTLA-4 bound to human Jagged 1 with similar affinity as 4D11v2 (0.54 nM) and 4D11v2—CTLA4 (0.92 nM) (FIG. 15, panel C). uPA treatment had no effect on CTLA4 binding (FIG. 15, panel D). ELISA binding measurements were performed as follows. Human Jagged 1-Fc (R&D Systems; Cat #1277-JG-050), human EGFR (R&D Systems, Cat #344-ER-050) or human CTLA4 (R&D Systems; Cat #325-CT-200/CF) were adsorbed onto wells of a 96-well ELISA plate. Three-fold dilutions, starting at 100 nM, of untreated and uPA treated antibodies, multispecific antibodies or multispecific activatable antibodies were applied to the plate and allowed to associate with plate-bound antigen for 1 hour. Following binding, the bound antibody was visualized with an anti-human IgG-HRP conjugate (Fab specific, Sigma, St Louis, Mo.; Cat #A0293-1ML) and developed with the chromogenic substrate TMB.
Example 13
[0455] [anti-EGFR] Multispecific activatable antibody 3954-1204-C225v5-OKT3m-H-N, activated multispecific activatable antibody 3954-1204-C225v5-OKT3m-H-N, and multispecific antibody C225v5-OKT3m-H-N were tested for their abilities to bind to EGFR-expressing SW480 cells.
[0458] FIG. 20A demonstrates that EGFR binding by multispecific activatable antibody 3954-1204-C225v5-OKT3m-H-N was attenuated compared EGFR binding by multispecific antibody C225v5-OKT3m-H-N, but EGFR binding of the multispecific activatable antibody was fully restored upon protease cleavage of the multispecific activatable antibody by matriptase. FIG. 20B shows that EGFR binding by antibody C225v5 and by activatable antibody 3954-1204-C225v5 were comparable to EGFR binding by multispecific antibody C225v5-OKT3m-H-N and multispecific activatable antibody 3954-1204-C225v5-OKT3m-H-N, respectively, demonstrating that the anti-CD3ε moiety present in the multispecific format did not alter the EGFR binding profile of either the multispecific antibody or multispecific activatable antibody.
Example 14
[0460] To determine if CD3ε binding had been affected by masking of the EGFR binding site of an anti-EGFR multispecific activatable antibody, a Jurkat T-cell binding assay was performed as described herein with [anti-EGFR] multispecific activatable antibody 3954-1204-C225v5-OKT3m-H-N, activated multispecific activatable antibody 3954-1204-C225v5-OKT3m-H-N, and multispecific antibody C225v5-OKT3m-H-N. Jurkat cells were incubated with a 5-fold dilution of 1000 nM of multispecific activatable antibody 3954-1204-C225v5-OKT3m-H-N, matriptase-activated multispecific activatable antibody 3954-1204-C225v5-OKT3m-H-N, or multispecific antibody C225v5-OKT3m-H-N in FACS Buffer for 1 hour at 4° C. Cells were washed 3 times and incubated with a secondary antibody, namely 1:400 of anti-human FcGamma specific AF488 (Jackson ImmunoResearch). Cells were washed 3 times, and the MFI of AF488 was read on the BD Accuri (BD Biosciences) flow cytometer. The MFI of a sample comprising only the secondary antibody control was subtracted from the experimental MFI and plotted in Prism with curve fitting analysis log(agonist) vs. response (three parameters).
[0461] FIG. 21A demonstrates that multispecific activatable antibody 3954-1204-C225v5-OKT3m-H-N and multispecific antibody C225v5-OKT3m-H-N exhibit equivalent binding to Jurkat T cells. FIG. 21B demonstrates that multispecific activatable antibody 3954-1204-C225v5-OKT3m-H-N and activated multispecific activatable antibody 3954-1204-C225v5-OKT3m-H-N exhibit equivalent binding to Jurkat T cells. These results indicate that masking of the EGFR binding moiety of the multispecific activatable antibody does not affect the ability of the multispecific activatable antibody to engage T cells.
Example 15 [0462-0464] using anti-EGFR multispecific activatable antibody 3954-1204-C225v5-OKT3m-H-N
Example 16 [0466-0469] using anti-EGFR multispecific activatable antibody 3954-1204-C225v5-OKT3m-H-N
The specification defines functional operative protypes but which do not even resemble the most generic description of the invention in generic Claim 68.
A) Masking moiety behavior or efficacy for an antigen recognition site is not highly predictable
While the general concept of masking using a peptide or domain to temporarily block an antibody’s paratope is straightforward, predicting the actual masking efficiency (how well it blocks the target in healthy tissue) and demasking kinetics (how cleanly it releases at the target site) involves complex, non-linear biophysical trade-offs (Orozoco (PTO 892)); Byondis BV WO 2023222580A1 (PTO 892)).
To completely block an antibody's complementarity-determining regions (CDRs), an affinity-based mask (like an epitope mimic or anti-idiotypic domain) needs a high on-rate (kon) and tight binding. However, if the mask binds too tightly, it will fail to dissociate even after the intervening protease linker is cleaved, because it remains trapped in a competitive equilibrium with the native antigen. (Chen (PTO 892); Escobar-Rosales (PTO 892); Orozoco (PTO 892)).
Finding the exact thermodynamic location where the mask binds tightly enough to block the antigen but weakly enough to let go post-cleavage is highly specific to each distinct antibody-antigen pair and rarely scales predictably from one construct to another. (Chen (PTO 892); Escobar-Rosales (PTO 892)).
i. Paratope Coverage and Spatial Dynamics
Effective masking requires precise physical occlusion of specific CDR loops (particularly heavy chain H3 and light chain L2). (Bloch (PTO 892)). Even a high-affinity mask may fail if the tethered linker length or configuration allows the mask to wobble, leaving a "breathing window" where the native antigen can slip in and displace it. Minor shifts in linker length or the choice of heavy vs. light chain attachment can cause a masking strategy that worked perfectly on one antibody to fail completely on a structurally similar one. (Bloch (PTO 892)) Escobar-Rosales (PTO 892)).
ii. Steric Hindrance Approaches
To bypass the custom engineering required for affinity-based masks, researchers use universal steric masks (e.g., large, disordered polymer chains like PAS, or rigid human protein domains like CaM-CBP clamps). (Maejima (PTO)). These are more predictable in terms of modular assembly. However, their actual blocking efficiency remains highly dependent on the spatial geometry and size of the specific target antigen. A steric mask might successfully block a large, recessed cell-surface receptor but fail to block a small, highly fluid soluble ligand. (Lucchi (PTO 892)).
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B) The scope of the claims must bear a reasonable correlation with the scope of enablement. See In re Fisher, 166 USPQ 19 24 (CCPA 1970). Without such guidance, the amount of in vitro and in vivo animal model testing for any given bispecific antibody much less than a multispecific, activatable bispecific antibody is unpredictable and the experimentation left to those skilled in the art is unnecessarily and improperly extensive and undue. See Amgen, Inc. v. Chugai Pharmaceutical Co. Ltd., 927 F,2d 1200, 18 USPQ 1016 (Fed. Cir. 1991) at 18 USPQ 1026 1027 and Ex parte Forman, 230 USPQ 546 (BPAI 1986). "[T]o be enabling, the specification of a patent must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation.'" Genentech, Inc. v. Novo Nordisk, A/S, 108 F.3d 1361, 1365 (Fed. Cir. 1997) (quoting In re Wright, 999 F.2d 1557, 1561 (Fed. Cir. 1993)).
“The “predictability or lack thereof” in the art refers to the ability of one skilled in the art to extrapolate the disclosed or known results to the claimed invention. If one skilled in the art can readily anticipate the effect of a change within the subject matter to which the claimed invention pertains, then there is predictability in the art. On the other hand, if one skilled in the art cannot readily anticipate the effect of a change within the subject matter to which that claimed invention pertains, then there is lack of predictability in the art. Accordingly, what is known in the art provides evidence as to the question of predictability” (citing In re Marzocchi, 439 F.2d 220, 223-24, 169 USPQ 367, 369-70 (CCPA 1971)).
“In cases involving unpredictable factors, such as most chemical reactions and physiological activity, more may be required. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) (contrasting mechanical and electrical elements with chemical reactions and physiological activity). See also In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993); In re Vaeck, 947 F.2d 488, 496, 20 USPQ2d 1438, 1445 (Fed. Cir. 1991). This is because it is not obvious from the disclosure of one species, what other species will work.”
i) Prior Art Status: Delivery of Therapeutics from In vitro to In vivo is Unpredictable
A tumor is a 3-dimensional complex consisting of interacting malignant and non-malignant cells. Vascularisation, perfusion and drug access to the tumor cells are not evenly distributed and this is an important source of heterogeneity in tumor response to drugs. Therefore, prediction of antibody effects in an animal subject based solely on in vitro cell based assays or limited in vivo assays is not reliable and further evaluation in bioassay systems is essential.
Assuming, arguendo, the intended delivery site is a cancer (by implication that the targeting antibody (AB1) binds a cell-surface cancer antigen) then in vivo animal testing may be a platform technology in a determination of enablement, whereby the complexity and difficulty of drug delivery for cancer treatment is underscored by Voskoglou-Nomikos (PTO 892). Voskoglou-Nomikos conducted a study using the Medline and Cancerlit databases as source material in comparing the clinical predictive value of three pre-clinical laboratory cancer models: the in vitro human cell line (Figure 1); the mouse allograft model; and the human xenograft model (Figures 2 and 3). Significantly when each of the cancer models was analyzed against Phase II activity, there was a negative correlation for the in vitro human cell line models being predictive of good clinical value. No significant correlations between preclinical and clinical activity were observed for any of the relationships examined for the murine allograft model. And the human xenograft model showed good tumor-specific predictive value for NSCLC and ovarian cancers when panels of xenografts were used, but failed to predict clinical performance for breast and colon cancers. Voskoglou-Nomikos suggests that “the existing cancer models and parameters of activity in both the preclinical and clinical settings may have to be redesigned to fit the mode of action of novel cytostatic, antimetastatic, antiangiogenisis or immune-response modulating agents” and “New endpoints of preclinical activity are contemplated such as the demonstration that a new molecule truly hits the intended molecular target” (p.4237, Col. 1, ¶6).
Dennis (PTO 892) also recognizes that human cancer xenograft mouse models for testing new drugs has been and will remain the industry standard or model of choice, but it is not without problems because “many more [drugs] that show positive results in mice have little or no effect in humans” (p. 740, Col. 1, ¶3). Dennis describes transgenic animal mouse models as an alternative to xenograft modeling and the general differences between mice and humans when it comes to tumor modeling: 1) cancers tend to form in different types of tissue, 2) tumors have fewer chromosomal abnormalities, 3) ends of chromosomes (telomeres) are longer, 4) telomere repairing enzyme active in cells, 5) short lifespan, 6) fewer cell divisions (1011) during life than humans (1016), 7) metabolic rate seven time higher than humans, and 8) lab mice are highly inbred and genetically similar.
Cespdes et al. (PTO 892) review the some of the examples of art-recognized animal disease model correlates for the corresponding human disease in Tables 1-3. Cespedes emphasizes the challenges in using animal models as predictive correlates for human responsiveness to therapeutics and sets forth on pp. 318-319 a list of criteria that would represent the ideal in vivo model for studying cancer therapeutics. As regards the use of xenograft modeling, Cespedes teaches:
"One limitation of the xenograft models is precisely their use of an immunocompromised host, which eliminates the possibility of studying the role of the immune system in tumor progression. Some authors also think that cancer and host cells being from different species may limit the occurrence of critical tumor-stroma interactions, leading to an inefficient signaling. The organ of implantation could also become a limitation to the system. Thus, as it has already been described, subcutaneous xenografts infrequently metastasize and are unable to predict response to drugs” (p. 325, Col. 1, ¶2).
In another thorough and detailed review of animal model testing from 2007, Talmadge et al. (PTO 892) teach “Indeed primary human tumor xenografts can be predictive of clinical cytotoxic therapy for a given tumor histiotype provided that clinically relevant pharmacological dosing parameters are used. It is noted that human tumor cell lines in contrast to human primary tumor cells have generally been cultured for years losing much of their heterogeneity. This has resulted in undifferentiated tumors lacking the histology and cellular architecture characteristic of the modeled human tumor” (p. 795, Col. 2, ¶2)...and “xenograft tumor models can effectively predict responsive tumor histiotypes; however these models need to incorporate a pharmacological and toxicological foundation to be successful. In addition, animal models can be used to resolve a specific experimental question that can be appropriately translated into clinical trials" (p. 800, Col. 1, ¶2). “In addition to a quantitative determination of anti-tumor activity, responsive preclinical tumor models cane also be used to assess preliminary ADME (adsorption, distribution, metabolism and excretion) information and toxicity" (p. 800, Col, 2, ¶1). Talmadge states that “Before clinical testing, a new drug or drug formulation should demonstrate safety and/or efficacy profile compared with current therapeutics in animal models. The comparison should incorporate rigorous animal models and not be based on highly responsive models, such as ones with rapid outcome that are convenient or with which the investigator is familiar. Furthermore, tumor and animal models should meet specific biological criteria including heterogeneity, appropriate histology, metastatic propensity, and appropriate genetic criteria depending on the targeted drug metabolism, limited immunogenicity, and potential etiology. Last, the model should have the potential to provide a correlation between therapeutic model outcome and clinical activity, optimally with previous documentation of relevance between mice and humans” (p. 800, Col. 2, ¶3).
The POSA could reasonably conclude that evidence obtained in any in vitro assay would not necessarily correlate with results expected in a correlated animal model. Thus to the extent the claims encompass an intended in vivo outcome of delivery (to an unspecified target that comprises a genus of cleavage-specific enzymes for a) of any subject, and the specification does not provide sufficient guidance using the genus of multispecific activatable antibodies in any method of delivery. Applicants were not in possession of the full scope of the invention at the time of filing.
ii) Prior Art Status: Immunotherapeutics especially cancer therapy is unpredictable
The use of antibody immunotherapy for the treatment of tumors has been shown to have limitations. Five (5) art references spanning over 25 years in the field of immunotherapeutics and recognizing the complexity of antibody delivery to tumors in vivo are Fujimori et al. (PTO 892); Beckman et al. (PTO 892)); Thurber et al. (PTO 892); Rudnick et al. (PTO 892); and Huang et al. (PTO 892).
Fujimori teaches for further understanding of Mab distribution in the tumor, one must consider as well the microscopic pharmacology: transport across the capillary wall, transport in tumor interstitium, cellular binding and metabolism. Fujimori discusses predictive models for accessing tumor antigen availability by Mab to examine the relationship between affinity and distribution. Fujimori teaches on p. 1196, Col. 2, ¶1:
“One strategy to overcome the binding-site barrier would be to increase the initial Mab dose. Even though Mab concentration in tumor does not always increase linearly as initial Mab concentration increases, a high initial plasma concentration leads to better percolation and results in more uniform distribution in tumor. Increasing Mab dose, however, decreases the specificity ratio and may cause toxicity or other side effects. For each Mab species and set of circumstances, there is an inherent balance of factors. Other causes of heterogeneous distribution include the functional and anatomical heterogeneity of tumors and their vessels..., and the elevated interstitial tissues…”
Beckman teaches on p. 175, Col. 2, ¶2-4:
“Optimizing biodistribution properties of Ab constructs depends on a large number of host and tumor variables. These include: the density and distribution of target Ag in tumors and normal tissues: the degree of target occupancy and residence tiemr equired for tumor cell kill; possible toxicities from normal tissue distribution; tumor size and vascularity; tumor interstitial pressure, convection and diffusion; and metabolism and internilzation rates for Ab-Ag constructs.
An equally large number of Ab construct and therapy variables are available for optimization, including size, charge, and valence; constant region type and glycosylation pattern; presence or absence of a radioisotope or a toxic moiety; dose, route, and schedule of administration; and use of a traditional or a pretargeting strategy. Given the complexity of the problem, systematic preclinical programs may enhance the likelihood of success in subsequent clinical studies. Such preclinical investigations should integrate both experimental and theoretical approaches.
Preclinical studies of a putative Ab-based therapeutic agent can encompass a variety of constructs, differing in molecular weight, affinity, valence, and/or other features of interest, which bind to the same epitope as demonstrated by competition experiments. The Ag density and target affinities should be known for both tumor cells and cross-reacting normal tissues, and the percent target occupancy and required residence time for tumor cell kill should ideally be investigated in vitro. Similarly, rate constants for Ab-Ag internalization should be determined, if applicable. Dose and schedule should be varied and antitumor efficacy, pharmacokinetics, overall biodistribution, homogeneity of intratumoral distribution, and tumor microvessel density and distribution ideally should be measured in tumor-bearing animals with a variety of tumor sizes.”
Studies in tumor-bearing rodents are often confounded by lack of normal tissue reactivity with Ab constructs directed toward human Ags, but studies in transgenic animal can be performed in some instances to alleviate this issue.”
Thurber teaches on p. 1431, Col 2, ¶3:
“Analyzing the fundamental rates that determine antibody uptake and distribution provides a theoretical framework for understanding and interpreting targeting experiments and improving on the limitations of uptake. It also provides a background for a more rational design of in vitro experiments, animal studies, and clinical trials. The insight gained from this type of modeling has multiple implications for imaging and therapy. For example, not all cells are exposed to the “average” concentration obtained in a tumor. A significant portion of cells can survive even if the tumor-averaged concentration is well above the LD50 in vitro. Also, the concentration that cells in a solid tumor are exposed to ([Ab]surf) is well below the plasma concentration. This means that the bulk antibody concentration in an in vitro spheroid experiment is not analogous to the plasma concentration but is actually well below it; large doses are required to overcome this poor extravasation. Knowing the rate of uptake in a tumor and clearance from the plasma and normal tissues also provides estimates of ratios between tumor and normal tissue concentrations, and these ratios are important in both imaging and therapy. These examples illustrate the utility of combining theoretical analysis also suggest ways to rationally improve uptake, and determining the limiting rates is the first step in overcoming these problems.”
Rudnick teaches on p. 155, Col. 2:
“Not strictly limited to tumor cells, target antigen is commonly expressed on normal tissue, found in circulation, and shed into the tumor interstitial space. These nontarget pools of antigens can reduce treatment effectiveness, increase systemic clearance, and increase side-effects (especially for radioimmunoconjugates) by impairing mAb specificity for the tumor.”
and on p. 158, Col. 2, last ¶ - p. 159, Col. 1:
“…antigen selection will be a critical factor for internalization and catabolism of mAbs. The relative rates of antigen recycling and dissociation are important in mAb penetration into tumors. Therefore, in applications dependent on targeting every cell of a tumor, the mAb needs to dissociate before it is internalized and degraded. In the case of ADCC, a slow internalizing antigen would be the best target. However, if one is trying to deliver a cytotoxic agent to the cytoplasm of cells in a limited region of a tumor, such as the vasculature, a mAb with slow dissociation targeting a rapidly recycling antigen would be appropriate. These are just simple examples of the interplay of affinity, avidity, and efficacy in tumor targeting.”
Huang supports and substantiates the challenges for recombinant antibodies as immunotherapeutic agents (p. 403 and 408):
“Genetic engineering has long been employed to increase the affinity of mAb to its target by altering the amino acid sequence in complementary determining region (CDR; Maynard and Georgiou 2000; Reff et al. 2002). However, high specificity must be maintained while increasing antibody affinity as it might augment cross reactivity with other nonspecific antigens, causing unwanted side effects (Hu et al. 2009). High-affinity CDR also can be suboptimal for targeting solid tumors; thus, a suitable affinity may need to be determined (Chames et al. 2009).”
“Many hurdles remain, however,due to the complexity of human immunology as demonstrated by our limited success in chronic infectious diseases and cancer. The approach to combine both active and passive immunotherapies to have synergic effects to maximize desired immune responses may lead a way for treatments of these diseases in the near future.”
Therefore, due to the unpredictability of immunotherapeutics in general and in view of the insufficient guidance and/or working examples concerning the use of the claimed multispecific activatable antibodies as immunotherapeutic agents, in vivo, one skilled in the art could reasonably conclude that the broadly claimed invention was not fully supported in the specification and thereby removing applicants from full possession of the invention.
C) Synergy is unpredictable for immunotherapy in cancer
Even assuming, arguendo, a single species of a multispecific, activatable antibody was demonstrated as synergistic (i.e., there is no prophetic or actual working example in the specification), the POSA recognizes that synergy is not often observed in the realm of immune-biotherapy.
Summary
Across every major antibody-based oncology approach from HER2 dual blockade to checkpoint combinations, costimulatory agonists, macrophage checkpoints, bispecifics, and anti-drug conjugates (ADCs), the record shows the same pattern: a strong mechanistic rationale and positive preclinical synergy do not reliably predict clinical synergy. Some rational combinations succeeded, others failed, and some were antagonistic.
Successes: pertuzumab plus trastuzumab plus docetaxel (Swain (PTO 892)); nivolumab plus ipilimumab (Wolchok (PTO 892)); nivolumab plus relatlimab (Tawbi (PTO 892)); amivantamab plus lazertinib (Romero (PTO 892)).
Failures with strong rationale: anti-TIGIT plus PD-(L)1 (Flaherty (PTO 892)); Merck (PTO 892)); durvalumab plus tremelimumab in NSCLC (Rizvi (PTO 892)); magrolimab (anti-CD47) combinations in MDS and AML (Gilead (PTO 892)); T-DM1 plus pertuzumab (Perez (PTO 892)); urelumab plus nivolumab (Khushalani (PTO 892)).
Antagonism: adding an anti-EGFR antibody to bevacizumab and chemotherapy shortened survival in colorectal cancer (Marshall (PTO 892)); Zinser-Sierra (PTO 892))).
The oncology case law accepts that synergy is generally unpredictable but asks a narrower question: did the closest prior art give a reasonable expectation of this synergy for this combination? The same trastuzumab-plus-taxane invention was held obvious in three forums (the U.K. Court of Appeal, an EPO Board, and the PTAB, affirmed by the Federal Circuit), each relying partly on published mouse xenograft synergy. The EPO revoked a cancer-vaccine plus anti-PD-1 patent despite accepting synergy because checkpoint-release synergy was mechanistically expected (CureVac (PTO 892)). By contrast, claims survived where the art predicted toxicity or failure (Phigenix v. ImmunoGen, (Feng et al (PTO 892) ) or where the claimed format was not suggested (Stanford (PTO 892)).
Definitions and Legal Standards
Synergy is always a departure from a reference model of non-interaction, and the models differ:
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The same data can be classified differently under Loewe and Bliss (Lederer (PTO 892)). In patients, much of the benefit of approved cancer combinations is explained by independent drug action, or patient-to-patient "bet hedging," rather than true interaction (Palmer (PTO 892)).
U.S. definition: a synergistic effect "exceeds the sum of the separately administered effects" (Novo Nordisk v. Caraco (Fed. Cir. 2013)). Synergism is a form of greater-than-expected result, but "a greater than additive effect is not necessarily sufficient ... because such an effect can either be expected or unexpected" (MPEP § 716.02(a)).
U.S. obviousness: "obvious to try" requires "a finite number of identified, predictable solutions" (KSR, 550 U.S. 398, 421 (2007)); in the medical arts, "potential solutions are less likely to be genuinely predictable" (Eisai v. Dr. Reddy’s, 533 F.3d 1353, 1359 (Fed. Cir. 2008)), both as quoted in Sanofi-Aventis v. Glenmark (Fed. Cir. 2014). The reasonable-expectation inquiry "must be tied to the scope of the claimed invention" (ImmunoGen v. Stewart (Fed. Cir. 2025), p. 12).
EPO: synergy requires an effect "greater than the sum of the separate effects" (T 2773/17), and the proprietor must show the sum of separate effects is inferior to the combination (T 696/19); inventive step "was often acknowledged with reference to the common general knowledge that synergism was rare and unpredictable" (T 116/18; T 1336/19), but synergy "does not deserve a special position" (T 116/18; T 1639/21) (EPO Case Law, I.D.9.9.6).]
U.K.: the test is whether the skilled person had a "fair expectation of success" (Hospira v. Genentech [2016] EWCA Civ 1185).
Foundational antibody unpredictability (non-oncology): "scientists cannot always accurately predict exactly how trading one amino acid for another will affect an antibody’s structure and function" (Amgen v. Sanofi, 598 U.S. 594, slip op. at 3 (2023)).
Oncology Approaches: Science, Clinical Record, and Case Law
Each subsection follows the same format: the scientific reason the combination effect is hard to predict, what the clinical trials showed, and how tribunals have treated synergy for that approach.
A) HER2-directed antibodies with chemotherapy and dual HER2 blockade
Science
HER2 combinations show how much depends on epitope and format. Pertuzumab and trastuzumab bind different HER2 domains, and combinations of non-competing antibodies against a receptor tyrosine kinase can cluster the receptor and drive down-regulation that neither antibody achieves alone (Friedman et al. (PTO 892)). Whether such cooperation occurs depends on the epitope pair and orientation, not merely the target (Spangler et al (PTO 892)).
Clinical record
Trastuzumab plus a taxane was the basis of first-line HER2-positive metastatic breast cancer therapy; the patent specification reported augmented efficacy without increased severe adverse events (Hospira v. Genentech [2016] EWCA Civ 1185).
Adding pertuzumab to trastuzumab plus docetaxel significantly improved PFS and OS (Swain).
However, combining pertuzumab with the ADC T-DM1 did not produce superiority: in MARIANNE, T-DM1 and T-DM1 plus pertuzumab were non-inferior but not superior to trastuzumab plus taxane (median PFS 13.7 months with trastuzumab plus taxane, 14.1 months with T-DM1, and 15.2 months with T-DM1 plus pertuzumab) (Perez). The same antibody pair that was synergistic with docetaxel added little when one partner was delivered as an ADC.
The summary is that published xenograft synergy before the priority date was decisive against the patentee in all three jurisdictions. Unpredictability arguments based on the general mouse-to-human gap did not overcome specific, encouraging preclinical data for the very combination claimed. Iancu also shows that the comparator written into the claim (untreated patient vs. monotherapy) can eliminate a synergy argument entirely.
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B) Immune checkpoint inhibitor combinations
Science
Checkpoint antibodies act on a dynamic immune network, and their effects depend heavily on Fc biology. Anti-CTLA-4 efficacy in mouse melanoma was co-defined by Fc-dependent depletion of intratumoral regulatory T cells (Simpson et al., J Exp Med 2013), whereas anti-PD-1 was stripped from T cells within minutes by tumor-associated macrophages via Fcγ receptors (Arlauckas et al. 2017, reviewed in PMC11810350). Isotype, Fc engineering, tumor FcγR expression, and mouse-versus-human receptor differences can each change the interaction.
Clinical record
Combination
Setting
Outcome
Nivolumab + ipilimumab (PD-1 + CTLA-4)
Advanced melanoma, CheckMate 067
Longer OS than either agent; grade 3–4 treatment-related AEs 59% vs 21% (nivolumab) and 28% (ipilimumab) (Wolchok et al., NEJM 2017).
Durvalumab + tremelimumab (PD-L1 + CTLA-4)
Metastatic NSCLC, MYSTIC
Did not meet primary endpoints (Rizvi et al., JAMA Oncol 2020). Same target pair as CheckMate 067, different disease and antibodies.
Nivolumab + relatlimab (PD-1 + LAG-3)
Advanced melanoma, RELATIVITY-047
Significant PFS benefit; OS improvement clinically meaningful but not statistically significant at three years (three-year analysis).
Tiragolumab + atezolizumab (TIGIT + PD-L1)
PD-L1-high NSCLC, SKYSCRAPER-01
No statistically significant PFS or OS improvement (OncLive).
Vibostolimab + pembrolizumab (TIGIT + PD-1)
NSCLC and SCLC, KeyVibe-003/-007/-008
Phase 3 trials discontinued on Data Monitoring Committee recommendation after pre-planned analyses (Merck; KeyVibe-008).
The CTLA-4 plus PD-(L)1 pair worked in melanoma but not in unselected NSCLC with different antibodies, and two independent anti-TIGIT programs failed despite similar preclinical rationale. These are strong field-specific facts for an expert declaration arguing that synergy in one checkpoint pair or tumor type does not predict synergy in another.
Case law
The most relevant decision is EPO T1639/21. In U.S. terms, a challenger would invoke the Novo Nordisk majority reasoning that artisans "would base [their] expectations upon prior art" combinations of the same classes, while the patentee would rely on Judge Newman’s dissent: "[t]he existence of synergy in some ... combinations is not predictive of synergy in the combination" at issue, and "[f]or questions of biological synergism, predictability is notoriously difficult" (Novo is a diabetes case but is the leading Federal Circuit decision on predictability of synergy). The TIGIT and MYSTIC results give concrete oncology content to the dissent’s logic.
C) Cancer vaccines combined with checkpoint antibodies
Case law: (CureVac, EPO Board 3.3.04, 13 March 2024)
Claims to an mRNA cancer vaccine combined with an anti-PD-1 antibody were revoked for lack of inventive step even though the Board accepted a synergistic effect (decision). The closest prior art (D13) already showed synergy of an mRNA vaccine with anti-CTLA-4.
Mechanism made synergy expected: the checkpoint antibody "does not have a direct effect on the tumour; it only counteracts an inhibition of the immune response" (r. 16), illustrated by the analogy that "releasing a brake alone does not move a car ... but allows a faster speed when the motor is on" (r. 18).
Prior art disclosed anti-PD-1 synergy with other cancer vaccines (FVAX, GVAX, peptide vaccines) (r. 48), so "the skilled person had a reasonable expectation that anti-PD-1 antibodies achieve a synergistic effect when combined with an mRNA vaccine" (r. 49).
The expectation "depended on the skilled person’s fundamental understanding of the mechanistic relationship ... and not on any structural elements of the compounds" (r. 68), distinguishing T 1814/11-type cases where a structural change defeats prediction.
The proprietor’s counter-example, that an anti-LAG-3 antibody did not enhance an mRNA vaccine, was post-filed and did not cast doubt on the PD-1 art (rr. 58–59). Mouse survival differences (3/6 vs 3/8 animals) were not significant "in view of the small number of test animals" (r. 13).
The summary is that in immuno-oncology, the "indirect" checkpoint-release mechanism tends to make synergy expected. A patentee needs evidence of a direct or non-obvious interaction, a class where substitution has failed (TIGIT, LAG-3 with mRNA vaccine, if available before filing), or a regimen-specific effect.
D) Costimulatory agonist antibodies (OX40, 4-1BB/CD137)
Science
Agonist combinations are especially sensitive to schedule. In a PD-1-refractory mammary carcinoma model, concurrent anti-PD-1 attenuated the benefit of agonist anti-OX40, whereas sequential dosing preserved it (Messenheimer et al (PTO 892)). The same two antibodies were synergistic or antagonistic depending only on timing.
Clinical record
First-generation 4-1BB agonist urelumab was limited by hepatotoxicity; at tolerable doses, adding it to nivolumab or cetuximab did "not indicate an evident additive benefit" (JITC 2024).
Case law
EPO T 2506/12 (ET-743 with pegylated liposomal doxorubicin): the skilled person could not "exclude the possibility that [the agents] might interact to produce unacceptable adverse effects ... before reaching the threshold of pharmacological efficacy"; a clinical trial "is not a mere screening exercise," yet "the general consideration that any clinical trial might fail [is] not sufficient to establish an inventive step" (CMS summary).
Schedule-dependent effects are more defensible when claimed: under ImmunoGen v. Stewart, the expectation-of-success inquiry is tied to what the claim actually recites, so a claim to a specific sequential regimen with data showing antagonism of the concurrent regimen presents a narrower, more defensible question.
E) Dual EGFR and VEGF antibodies in colorectal cancer, and EGFR bispecifics
Clinical record: antagonism
PACCE: adding panitumumab to bevacizumab plus oxaliplatin-based chemotherapy worsened PFS (10.0 vs 11.4 months; HR 1.27) and OS (19.4 vs 24.5 months; HR 1.43) (review of PACCE and CAIRO2).
CAIRO2: adding cetuximab to capecitabine, oxaliplatin, and bevacizumab significantly shortened PFS (9.8 vs 10.7 months; p = 0.019) (PMC3585989).
Clinical record: a successful EGFR-directed bispecific
By contrast, the EGFR x MET bispecific amivantamab combined with the EGFR inhibitor lazertinib improved overall survival versus osimertinib in EGFR-mutated NSCLC (MARIPOSA, Nat Rev Clin Oncol). The EGFR axis produced antagonism in one antibody combination and benefit in another.
Case law
U.S. law treats an expected-antagonism context as favorable to patentees: in In re Corkill, 771 F.2d 1496 (Fed. Cir. 1985), an additive result was persuasive evidence of nonobviousness "when a diminished result would have been expected" (MPEP § 716.02(a)). After PACCE and CAIRO2, a later EGFR-plus-VEGF antibody combination showing additivity or synergy in colorectal cancer could invoke Corkill. The EPO reached a similar result in T 1642/07 (oncolytic herpes simplex virus plus chemotherapy), where "uncertainty relating to the different biological mechanism of action, and the possible drug interaction" made even an additive effect enough for inventive step (CMS summary).
F) Macrophage checkpoint (CD47) antibodies with CD20 antibodies or chemotherapy
Case law: (Stanford, EPO, 24 September 2020)
The Board ordered grant of a claim to a bispecific FcR-engaging antibody against CD47 and CD20 for diffuse large B-cell lymphoma, even though the closest prior art (D1) showed synergy of separate anti-CD47 and rituximab antibodies in a mouse lymphoma model (decision). It reasoned that a bispecific has lower avidity per target but preferential binding to dual-positive cells, plausibly reducing CD47 off-target toxicity (r. 16), and that D1 alone would not have led the skilled person to construct the bispecific (r. 19). Note that the Board also found it plausible that the bispecific would "retain the synergistic effect" (r. 28); the inventive step rested on the format, not on synergy being unpredictable.
Clinical record
The CD47 class illustrates the gap between patentable preclinical synergy and clinical outcome. Gilead discontinued the phase 3 ENHANCE trial of magrolimab plus azacitidine in higher-risk MDS for futility (Gilead ), and stopped ENHANCE-3 (magrolimab plus venetoclax and azacitidine in AML (Gilead)) after it showed futility and an increased risk of death, with the FDA placing a full clinical hold on magrolimab AML and MDS studies (Gilead).
The summary is that format changes (cocktail to bispecific) can support inventive step because they alter avidity, distribution, and toxicity. The subsequent clinical failures of CD47 combinations are strong evidence that preclinical CD47 synergy did not make clinical synergy predictable.
G) Bispecific T-cell engagers
In Ex parte Vu, Appeal No. 2018-008737 (PTAB, Nov. 25, 2019), claims to a trivalent ROR1 x CD3 bispecific for ROR1-positive hematological malignancies were held obvious over prior art describing anti-CD3 and anti-ROR1 fragments (Antibody Therapeutics 2020 review). The applicant argued there were "seven hundred possible antibody fragment combinations" and that cancer treatment is unpredictable. The Board responded that "[c]onclusive proof of efficacy is not necessary ... All that is required is a reasonable expectation of success," and that the evidence did not compare the invention with the closest prior art or show "an improvement in kind versus a mere improvement by degree." It noted that only "[a]ttorneys’ argument" supported unexpectedness.
H) Antibody-drug conjugates
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Clinically, MARIANNE (Section 3.1) shows that adding a second HER2 antibody to an ADC did not reproduce the benefit seen with chemotherapy (J Clin Oncol 2017).
I) Other oncology combination decisions useful by analogy
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In antibody-based cancer therapy, synergy is unpredictable because it emerges from a specific antibody pair, format, Fc design, dose ratio, schedule, tumor type, and immune context, and because clinical outcomes repeatedly diverge from preclinical models. Tribunals accept this as a general proposition but decide cases on whether the specific prior art made the specific synergy expected. The trastuzumab-plus-taxane decisions and T 1639/21 show that a patentee’s own or others’ published preclinical synergy, or a well-understood indirect mechanism, will defeat an unpredictability argument. Phigenix v. ImmunoGen, T 0957/18, T 0790/11, and In re Corkill show that it succeeds when the art predicted failure, toxicity, or antagonism, or when the claimed format or regimen was not suggested.
Conclusion
8. No claims are allowed.
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/LYNN A BRISTOL/Primary Examiner, Art Unit 1643
