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 .
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-10, 12-22, and 24-25 are rejected under 35 U.S.C. 103 as being unpatentable over van der Berg (WO 2009/131453 A1) in view of Johnson et al, (WO 2015/048312 A1), hereinafter Johnson as evidenced by ThermoFisher Scientific ("Macrophage Cell Overview”. Thermo Fisher Scientific. Accessed: January 14, 2026).
Van der Berg discloses agents capable of inhibiting CD47-SIRPα interaction in order to reduce suppression of the cytolytic and/or phagocytic response of immune effector cells when administered for the treatment of various cancers, such as non-Hodgkin's lymphoma, breast cancer, chronic, lymphocytic leukemia, or colorectal cancer, wherein said agent is an anti-SIRPα antibody (see entire document, including Background, Examples, and Claims, in particular, preferred agents disclosed on Pages 7 – 8 and exemplary diseases on Page 10). A composition comprising the anti-SIRPα compound and a therapeutic agent (e.g. an antibody) that can trigger a host’s immune effector cells against an aberrant cell is further disclosed (Page 4, Ln. 15-25). Specifically, in the presence of 5 μg/mL of the anti-SIRPα antibody ED9 or its Fab’ fragments, rat CC531 colon carcinoma cells are readily phagocytosed by macrophage effector cells in vitro (Example 1). Given that SIRPa is a transmembrane glycoprotein (see Gene ID: 140885 for SIRPa, OA.Appendix), the anti-SIRPa antibodies disclosed by van der Berg, including clone ED9, bind to the extracellular domain of SIRPa. Thus, the anti-SIRPA antibodies of van der Berg comprise a ‘means for binding to the ECD of SIRPa’ and a ‘means for disrupting the SIRPa pathway’. The independent claim requires administration of an anti-SIRPα antibody to treat cancer in a subject; therefore, the anti-SIRPα antibody is necessarily administered at some dose. The “wherein” clauses recited in instant claims 2, 3, 5, 7, 12, 14, 15, 17, 19, and 24 do not impose any additional limitations on the dose, structure of the antibody, or administration steps and thus merely state the intended results of administration, which do not confer patentable weight. Further, per the instant claims, an anti-SIRPa antibody that binds to the ECD of SIRPa and disrupts the SIRPa pathway is minimally required to achieve the functional and therapeutic outcomes set forth in the claims. Lastly, instant claims 4, 6, 16, and 18 merely define or characterize macrophages according to the markers and cytokine profiles expressed by M1 and M2 macrophages as evidenced by Macrophage Cell Overview published by Thermo Fisher Scientific (see, in particular, Figure 3 and Tables 1-4), and thus do not carry patentable weight.
Van der berg does not teach the second therapeutic agent administered to trigger a host’s immune effector cells against an aberrant cell is an anti-PD-L1 antibody.
However, Johnson teaches methods of treating cancer using combination immunotherapy comprising an inhibitor PD-1 or PD-L1 and an inhibitor of an immune checkpoint regulator for a greater therapeutic effect (see entire document, in particular, Abstract, Summary of Invention, and Claims), wherein the inhibitor is an antibody such as a human or humanized antibody that may be further conjugated to a cytotoxic agent (e.g. a chemotherapeutic agent, biologic agent, toxin, or radioactive isotope) (Page 3, Ln. 15-18, Page 3, Ln. 4-17) and the immune checkpoint regulator includes SIRP-alpha (Page 19, Ln. 1- 9).
It would have been obvious to one of ordinary skill in the art to administer an anti-PD-L1 antibody as a second therapeutic agent in the method for treating cancers disclosed by van der Berg. One of ordinary skill in the art would have been motivated to do so since combination immunotherapy with an anti-PD-L1 antibody can achieve therapeutic benefit in the treatment of cancer as taught by Johnson. Therefore, one of ordinary skill in the art would expect that administering an anti-SIRPa antibody in combination with an anti-PD-L1 antibody can effectively treat cancer in a subject.
Response to Arguments
Applicant's arguments filed 06/22/2026 have been fully considered but they are not persuasive.
With respect to rejections made under 35 USC 103, Applicant notes that van der Berg is directed to the enhancement of antibody-mediated clearance of aberrant cells by reducing or preventing inhibitory signal transduction initiated through the CD47/SIRPa pathway (Van der Berg, p. 1, Abstract; p. 4, lines 4-13). Interference with CD47/SIRPa inhibitory signaling is proposed to enhance the antibody-mediated clearance of that target cell by increasing Antibody-Dependent Cellular Cytotoxicity (ADCC) (Van der Berg, p. 5, line 3-12). This is confirmed by the therapeutic antibodies discussed in Van der Berg. Van der Berg refers to antibodies such as rituximab, alemtuzumab, trastuzumab, cetuximab and panitumumab (Van der Berg, p. 5, lines 1-6). These are tumor-targeting antibodies. Their therapeutic role is to bind the target cell and promote effector-cell mediated mechanisms such as ADCC or ADCP. Thus, Applicant asserts that Van der Berg is not a general disclosure of combining SIRPa blockade with any cancer immunotherapy; rather, is a disclosure of a particular strategy: improving the activity of therapeutic antibodies that themselves trigger immune effector-cell responses against target cells. Applicant states the following:
First, that there is no teaching, suggestion, or motivation to combine Van der Berg with Johnson. The rejection appears to rely more on a "both are immunotherapy/checkpoint-related" rationale, rather than a reference-specific reason why a person of ordinary skill in the art would have modified Van der Berg's anti-SIRPa/CD47 ADCC-phagocytosis regimen by adding Johnson's PD-L1/PD-1 checkpoint regimen. The experimental teaching of Van der Berg confirms the same point, with all Examples being directed to tumor-targeting ADCC-mediated clearance enhanced by interference with the CD47/SIRPa inhibitory pathway. As a matter of fact, Van der Berg's mechanism is different from Johnson's mechanism. Van der Berg is directed to enhancing clearance of aberrant cells by interfering with CD47/SIRPa inhibitory signaling, particularly to improve macrophage-mediated killing, phagocytosis, and ADCC. The cited Van der Berg passages focus on enhancing cancer-cell killing "in the presence of anti-cancer cell antibodies" by blocking CD47-SIRPa signaling. See Van der Berg [0001], [0048], [0067]. That is an innate immune / macrophage effector-cell enhancement strategy.
Johnson, by contrast, is directed to checkpoint blockade combinations for hematologic cancers, specifically combinations of PD-1 or PD-L1 inhibitors with TIM-3, LAG-3, or CTLA-4 inhibitors. Johnson's actual invention is not anti-SIRPa + anti-PD-L1. The supplied Johnson passage states: "The present invention relates to methods of treating hematologic cancers using a combination of inhibitors of PD-1 or PD-L1. and TIM-3, LAG-3 or CTLA-4." That points the skilled artisan to TIM-3, LAG-3, or CTLA-4 as Johnson's combination partners-not SIRPa. Importantly, these markers, TIM-3, LAG3 or CTLA-4 are T-cell markers. A person of ordinary skill in the art would not combine teachings of van der Berg (using anti-SIRPa antibodies with tumor targeting antibodies) with Johnson, which teaches using PD-1/PD-L1 antibodies, with other checkpoint inhibitors expressed on T cells. Applicant thus states that Johnson is directed to cancer combination therapy using an inhibitor of PD-1 or PD- L1 with an inhibitor of TIM3, LAG-3 or CTLA4. This combination is said to be unexpected "given the lack of such benefit observed for inhibiting or blocking other combinations of immune checkpoint regulators." Johnson does not relate to combinations involving an anti-SIRPa antibody. Johnson lists SIRPa in a list of 32 "immune checkpoint regulators" or "immune checkpoint proteins". According to Johnson, this list is not exhaustive, since there are "many more" immune checkpoints. Notably, Johnson distinguishes this list from the list of "immune checkpoint inhibitors" which can be used in combination with each other. Moreover, Johnson refers to "the lack of such benefit observed for inhibiting or blocking other combinations of immune checkpoint regulators." (p. 2, 1. 15-16), i.e., combinations other than the combination of an inhibitor of PD-1 or PD-L1 with an inhibitor of TIM3, LAG-3 or CTLA4. This shows that Johnson does not contemplate combinations other than the disclosed combination of an inhibitor of PD-1 or PD-L1 with an inhibitor of TIM3, LAG-3 or CTLA4. The Office has also not established that the cited references render the claimed invention predictable.
In response to Applicant’s arguments, the Examiner notes that “[t]he use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain.” In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)). In other words, a reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. Merck & Co. v.Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989). Further, disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971).
Here, van der Berg contemplates the use of a composition comprising the anti-SIRPα compound and a therapeutic agent (e.g. an antibody) that can trigger a host’s immune effector cells against an aberrant cell (e.g. cancer cells).
The invention relates to the field of molecular medicine. In particular, it relates to compositions and methods to enhance the clearance of aberrant cells, e.g. cancer cells or virus-infected cells, by the host's immune system. Provided is a composition comprising (i) a therapeutic compound that can trigger a host's immune effector cells against an aberrant cell, such as a therapeutic antibody, and (ii) at least one agent capable of reducing or preventing inhibitory signal transduction initiated via SIRPalpha. (Abstract, Emphasis Added).
Further, the “therapeutic compound” is not limited to anti-cancer agents as Applicant has alleged. The selection cited by Applicant reads as follows:
One aspect of the invention therefore relates to a composition comprising (i) a therapeutic compound that can trigger a host's immune effector cells against an aberrant cell and (ii) at least one agent capable of reducing or preventing inhibitory signal transduction initiated via SIRPα. For example, an agent is used which is capable of inhibiting the interaction between SIRPα and CD47, such that the inhibitory signal via the CD47-SIRPα interaction is reduced. A host is a mammal, preferably a primate or rodent, more preferably a human subject.
The therapeutic compound is a therapeutic antibody, in particular an antibody that induces or promotes antibody-dependent cellular cytotoxicity (ADCC). As used herein, ADCC is meant to encompass antibody- dependent cellular phagocytosis (ADCP) as well. Said therapeutic antibody is capable of forming an immune complex. In one embodiment, the therapeutic antibody has a human or non-human primate IgG Fc portion. Preferably, the therapeutic antibody is a monoclonal antibody or a functional fragment or a derivative thereof, more preferably a humanized, human or chimeric antibody. Said fragment or a derivative thereof is preferably selected from a Fab fragment, a F(ab')2 fragment, a CDR and a scFv. In a particular embodiment, the therapeutic antibody is an FDA approved therapeutic antibody, such as rituximab, herceptin, trastuzumab, alemtuzumab, bevacizumab, cetuximab or panitumumab. See for example Strome et al., Oncologist 2007;12; 1084-1095.
As shown above, van der Berg presents anti-cancer antibodies, including antibodies that induce or promote ADCC, as exemplary or preferred embodiments of the broader category of therapeutic compounds that can be used in combination with anti-SIRPa antibodies, rather than defining the therapeutic compounds as being limited to ADCC-inducing anti-cancer antibodies. Therefore, the broad category of therapeutic compounds that can “trigger a host's immune effector cells against an aberrant cell” disclosed by van der Berg can encompass anti-PD-1/PD-L1 antibodies.
Johnson further discloses a method of treating a subject having cancer comprising administering to the subject a PD-1/PD-L1 inhibitor and an inhibitor of an immune checkpoint regulator and defines SIRP-alpha as an immune checkpoint regulator.
Accordingly, in one aspect, the invention features a method of treating a subject afflicted with a hematologic cancer comprising administering to the subject an inhibitor of PD-1 or PD- Ll, and an inhibitor of an immune checkpoint regulator (e.g., an inhibitor of one or more of TEVl- 3, LAG-3 or CTLA4) (Summary of Invention, 2nd para. on Page 2) (emphasis added).
As used herein, the term "immune checkpoints" or "immune checkpoint regulators" means a group of molecules on the cell surface of CD4+ and CD8+ T cells. These molecules fine-tune immune responses by down-modulating or inhibiting an immune response, e.g., an anti-tumor immune response. Immune checkpoint proteins are known in the art and include, without limitation, CTLA-4, PD- 1, VISTA, B7-H2, B7-H3, PD-L1, B7-H4, B7-H6, 2B4, ICOS, HVEM, PD-L2, CD160, gp49B, PIR-B, KIR family receptors, TIM- 1, TIM-3, TIM-4, LAG- 3, BTLA, SIRPalpha (CD47), CD48, 2B4 (CD244), B7.1, B7.2, ILT-2, ILT-4, TIGIT, LAG-3, BTLA, and A2aR (see, for example, WO 2012/177624). Immunotherapeutic agents that can act as immune checkpoint inhibitors useful in the methods of the present invention, include, but are not limited to, inhibitors of PD- 1, PD-L1, TIM-3, LAG-3 and CTLA-4 (e.g., soluble peptide inhibitors or antibodies, e.g., anti-PD- 1 antibodies, anti-PD-L1 antibodies, anti-CTLA-4 antibodies, anti-TIM-3 antibodies, and anti-LAG-3 antibodies). (Page 18, Ln. 27-30 to Page 19, Ln. 1-8)(emphasis added).
As illustrated above, the teachings of Johnson are not limited to methods of treating cancer with anti-PD-1/PD-L1 and an inhibitor of the immune checkpoint proteins TIM-3, CTLA4, and LAG3. The Examiner reiterates, as above, that patents are not limited to what the patentees describe as their own inventions or to the problems with which they are concerned; they are part of the literature of the art, relevant for all they contain. In other words, a reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments.
Moreover, while Johnson states that the combination of PD-1/PD-L1 blockade with immune checkpoint inhibitors other than TIM3, LAG-3, or CTLA-4 yields a synergistic therapeutic benefit in the treatment of cancer; it does not state that all other combinations of immune checkpoint inhibitors would fail to provide any therapeutic benefit, regardless of whether a synergistic effect was observed or not. To the extent that Applicant argues that the combination of anti-PD-L1 and anti-SIRPa would not have predictably treated cancer in a subject, it is noted that obviousness does not require absolute predictability or conclusive proof of efficacy, only a reasonably expectation of success (MPEP 2143.02). At the time the instant application was filed, it was known in the art that PD-1/PD-L1 and SIRPa/CD47 blockade can treat cancer in a subject (see, e.g. van der Berg and Johnson). Thus, artisans would reasonably expect that combined PD-L1 and SIRPa blockade as taught by the teachings of van der Berg in view of Johnson to be effective in treating cancer.
Applicant has further argued unexpected results of administering a combination of an anti-SIRPa antibody and an antibody acting on the PD-1/PD-L1 axis. In particular, Applicant contends that the combined immunotherapy leads to a very strong improvement of the survival rate (see Figures 9, 10, and examples 2.1 and 2.2, starting on page 26, line 28); and that this result is observed even when a combination of an anti-SIRPa compound and an anti-CD137 antibody is administered (see example 2.1, on page 26, lines 21-27). In view of these findings, Applicant asserts that the synergistic effect observed with these combinations is application to other combinations recited in the claims because anti-PD-1 or anti-PD-L1 antibodies block the same pathway to lead to the activation of T cells.
Additionally, Applicant provides further data showing that the administration of either an anti-SIRPα antibody (MY1) alone or an anti-PD-1 antibody (RMP1-14) improve the survival rate of mice in an orthotopic tumor model; but the combination of the anti-SIRPα antibody and anti-PD-1 leads to 100% survival in mice compared to either monotherapy. Further, tumor volume progression is almost inhibited in mice treated with a combination of an anti-SIRPα antibody and an anti-PD-L1 antibody, as compared to mice treated with a single agent.
Therefore, Applicant contends that the inventors unexpectedly show that the recited combinations exert a positive synergistic effect on cancers, since these combinations all rely on the same combination of effects: (i) acting on T cells activation through the checkpoint activation on T cells and (ii) acting on macrophages mechanism(s) of action (like polarization), leading to a favorable biological response; and that this is unexpected and could not have been predicted by one of ordinary skill in the art from the disclosures, either alone or in combination, of Van der Berg and Johnson.
In response to Applicant’s arguments, the Examiner notes that the evidence presented does not adequately support the assertion that administration of an anti-SIRPa antibody in combination with an anti-PD-1/PD-L1 antibody results in a synergistic antitumor effect. The reported tumor-volume and survival data may show that the combination tested produced greater anti-tumor activity or longer survival than either antibody alone, but an enhanced combination effect does not, by itself, establish synergy. In general, a drug combination achieves a synergistic effect when the combined effect is greater than the expected additive effects of the individual drugs (Duarte and Vale, Abstract). Synergy is evaluated using established reference models, such as the Bliss independence, Loewe additivity, and highest single agent (HAS) models. As explained by Duarte and Vale, results cannot be interpreted as synergism based solely on simple experimental comparisons; rather, the observed combination effect has to be evaluated using an appropriate reference model. Indeed, better observed-effects of a drug combination may reflect potentiation rather than synergy (see Section 3: Current limitations of the classical combination models). Thus, the greater antitumor activity or longer survival observed with the combination of anti-SIRPa antibody and anti-PD-1/PD-L1 antibody does not, by itself, establish synergy, particularly in the absence of evaluation against an appropriate reference model.
Even if, for the sake of argument, it was determined that a tested anti-SIRPa antibody and anti-PD-1/PD-L1 pair demonstrated synergy, the data does not necessarily establish that synergy can be achieved across the entire genus of anti-SIRPa blocking antibodies and anti-PD-1/PD-L1 blocking antibodies and at any dosage amount commensurate in scope of the claims. Different therapeutic antibodies that bind to the same antigen can bind to different epitopes of a target, exhibit different binding characteristics and mode of action, and produce distinct biological effects and clinical outcomes (Shim, Abstract, Introduction, and Figure 1). Further, drug dose/dose ratio is a critical determinant of synergistic effects of a drug pair, influencing both the magnitude and nature of the drug interaction. A combination that is synergistic at one set of concentrations can be merely additive or even antagonistic at another. For example, the combination of tramadol and acetaminophen is synergistic at some dose ratios and simply additive at others (Tallarida, see “Optimizing the Drug Combination Dose Ratio” section on Page 1007). As another example, for the combination of methotrexate (MTX) and cytarabine, lower doses of the two agents were considered to yield a supra-additive (or synergistic) effect, whereas as higher doses of the two agents were considered to yield a sub-additive (or antagonistic) effect (Akutsu, see “Isobologram” section on page 1810-1811 and Figure 1). Taken together, any alleged synergistic effects involving a particular antibody pair using specific dosages observed in the working examples cannot be extrapolated to the broad genus of anti-SIRPa and anti-PD-1/L1 antibodies as well as dosages recited in the claims. Indeed, as presently claimed, the dosage of the individual antibodies present in the combination are not specified; yet Applicant has not demonstrated that a synergistic effect is observed at different dosages for the combined agents.
Therefore, the rejection under 35 USC 103 is maintained.
Applicant’s arguments with respect to the rejection under 35 USC 112(a) have been fully considered and are persuasive. Further, the terminal disclaimer filed overcomes the double patenting rejections. Thus, these rejections have been withdrawn.
Conclusion
No claims are allowable.
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.
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/LIA E TAYLOR/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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