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
The amendment filed February 23, 2026 in response to the Office Action of September 29, 2025 is acknowledged and has been entered.
Claims 1 and 2 have been amended.
Claims 5, 7-9, 22-25, 28, 30, and 33 have been cancelled.
Claims 1-4, 10, and 11 are pending and under consideration.
In view of claim 9 cancellation, the Claim Objection set forth in Office Action of September 29, 2025 is hereby withdrawn.
In view of the claim amendments, and Applicant’s arguments and evidence, the 112(a) Written Description rejection is hereby withdrawn.
In view of the claim amendments and Applicant’s arguments, the 103 rejections are hereby withdrawn.
In view of the claim amendments and Applicant’s arguments, the Double Patenting rejections over Pat. 8,840,888 and Pat. 10,191,034 are hereby withdrawn.
MAINTAINED/MODIFIED REJECTION
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 § 2146 et seq. 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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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/apply/applying-online/eterminal-disclaimer.
Application No. 17/910,698
Claims 1-3, 10 and 11 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-6, 32, 33, 42, 44, 58-60 of copending Application No. 17/910,698 (hereinafter Appl. 698, of record) in view of Baeuerle (Baeuerle et al., WO 2007/068354, Publication Date: 06/21/2007, cited in IDS of 01/18/2023, of record), Li (Li et al., Sci. Transl. Med., 11, eaax8861 (2019), Publication Date: September 4, 2019, cited in IDS of 01/18/2023, of record).
The claims of Appl. 698 teach a method for treating cancer and/or for preventing, ameliorating, and/or alleviating an adverse event associated with cancer immunotherapy comprising (a) administering an antibody construct that binds selectively to a target antigen on a cancer cell and to human CD3 on the surface of a T cell, wherein the target antigen is CD19, …, and (b) administering an inhibitor or antagonist of TNF/TNFR …, wherein a first dose of the inhibitor or antagonist of TNF/TNFR … is administered before administering a first dose of the antibody construct within a first period ranging from about 5 minutes to about 7 days prior to administering the antibody construct (claim 1), wherein the inhibitor or antagonist of TNF/TNFR is etanercept (new claim 63).
The claims of Appl. 698 teach wherein the adverse event is CRS (claim 3).
The claims of Appl. 698 teach as set forth above. However, the claims of Appl. 698 does not teach that the antibody is a single chain antibody (instant claim 1), or the corticosteroid is administered prior to the administration of the single chain bispecific antibody construct (instant claims 2 and 11), or the cancer is a solid tumor or a hematological cancer (instant claim 10).
The teachings of Baeuerle and Li are described above.
One of ordinary skill in the art before the effective filing date would have been motivated to apply the patented claimed method of reducing the adverse effects of bispecific antibody (e.g. to CD19 and CD3) with an inhibitor of TNF/TNFR to patients with adverse events induced by the single chain bispecific anti-CD19/CD3 taught by Baeuerle and Li, because Baeuerle teaches: 1) CRS is associated with the single chain anti-CD19/CD3 bispecific antibody therapy; 2) the single chain anti-CD19/CD3 bispecific antibody treatment increase TNF-α level rapidly. Li teaches: 1) uncontrolled systemic cytokine release is primary challenge for all T cell-targeting therapies (e.g. CD3 bispecific antibodies), 2) TNF-α is an early trigger for cytokine productions; 3) pretreatment of anti-TNF-α agent suppresses production of various cytokines but does not impact tumor killing activity; 4) the cytokine blockade should be applied as early as possible. Based on the teachings from Baeuerle and Li, one of ordinary skill in the art would have expected that the method of Appl. 698 could prevent CRS without impact the therapeutic activity of the single chain antibody of Baeuerle. The motivation is to further minimize the risk associated with the treatment and to possibly provide a wider dosage range without increased toxicity. There is a reasonable expectation of success for reducing CRS of the single chain bispecific antibody of Baeuerle comprised of administering an inhibitor of TNF/TNFR (e.g. etanercept), because Li teaches that pretreatment of anti-TNF-α agent suppresses production of various cytokines but does not impact tumor killing activity.
Regarding claims 2 and 11, The claims of Appl. 698 further teach the method further comprising administering at least one corticosteroid (claim 32), wherein the corticosteroid is dexamethasone (claim 33). Baeuerle teaches that administering glucocorticosteroid prior to the administration of anti-CD19/CD3 bispecific single chain antibody in order to suppress cytokine release at the initial phase (page 51, and Example 5). One of ordinary skill in the art would use the administering regimen and administering corticosteroid (e.g. dexamethasone) prior to the administration of bispecific antibody, taught by Baeuerle, because the regimen has been tested and shown effectiveness. There is a reasonable expectation that administering corticosteroid (e.g. dexamethasone) prior to the administration of anti-CD19/CD3 to further control cytokine production and release.
Regarding claim 10, Baeuerle teaches treating various cancers with the bispecific antibody, such as B-cell Non-Hodgkin’s lymphoma (NHL) (Examples 3-5). Baeuerle teaches that the antibody can be used to treat a solid tumor (page 5, para. 1).
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
For the Double Patenting rejection over Appl. 698, Applicant argues:
The claims of the '698 application do not recite etanercept as the inhibitor or antagonist of TNF/TNFR. The Examiner acknowledged that the claims of the '698 application do not teach the inhibitor or antagonist recited by instant claims 8 and 9. To supply this limitation, however, the Examiner relied on Baeuerle and Li, noting that Li teaches that the inhibitor is an antibody, i.e., adalimumab. As set forth in the arguments above regarding the § 103 rejections in Section V above, the combination of Baeuerle and Li fails to teach or suggest administering etanercept as now recited by amended claim 1.
Applicant’s arguments have been fully considered but they are not persuasive. As set for above, new claims of Appl. 698 recite the inhibitor or antagonist of TNF/TNFR is etanercept. Thus, the claims of Appl. 698, Baeuerle and Li teach the instantly claimed invention. The rejection is maintained for the reasons of record.
NEW GROUNDS OF REJECTION
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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 1-3, and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Baeuerle (Baeuerle et al., WO 2007/068354, Publication Date: 06/21/2007, cited in IDS of 01/18/2023, of record), in view of Li (Li et al., Sci. Transl. Med., 11, eaax8861 (2019), Publication Date: September 4, 2019, cited in IDS of 01/18/2023, of record) and Lee (Lee et al., Blood, Vol. 124, Number 2, 188-195, Publication Date: 07/10/2014).
Baeuerle teaches that CRS is a common phenomenon observed in antibody therapy. And the pathogenesis of CRS has been attributed to the synthesis of TNF-α, IIL-6 and IL-2 (page 2, para. 2).
Baeuerle teaches that CRS has been observed in clinical study with anti-CD19/CD3 bispecific single chain antibody for a patient with B-cell derived chronic lymphatic leukemia (B-CLL)(page 3, para. 2; Example 2).
Baeuerle teaches a single chain bispecific antibody target both CD3 and CD19 (page 5, para. 2). Baeuerle teaches that the bispecific antibody can bind CD3 and target CD19 expressing cells (pages 45-46). Thus, the anti-CD19/CD3 single chain bispecific antibody read on the antibody of instant claim 1.
Baeuerle teaches that TNF-α increased significantly in a dose-dependent manner within first hour after administration of bsCD19xCD3 (page 48, para. 2; Fig. 2).
Baeuerle teaches treating various cancers with the bispecific antibody, such as B-cell Non-Hodgkin’s lymphoma (NHL) (Examples 3-5).
Baeuerle teaches that the antibody can be used to treat a solid tumor (page 5, para. 1).
Baeuerle teaches as set forth above. However, Baeuerle does not teach administering etanercept prior to administering the antibody construct to prevent or reducing an adverse event.
Li teaches that uncontrolled systemic cytokine release is primary challenge that hinders the broad use of all T cell-targeting therapies (e.g. CD3 bispecific antibodies) regardless of the target or treatment modality (page 1, col. 1, para. 1).
Li teaches that T cell-produced tumor necrosis factor-α (TNF-α) is the signal that initiates from the T cell triggering event and cause monocyte activation, which results in systemic production of toxic cytokines (page 1, col. 2, para. 2).
Li teaches that TNF-α can be effectively and specifically blocked without affecting the therapeutic activity of T cells mediated by CD3 bispecific treatment (page 1, col. 2, para. 3).
Li teaches that anti-HER2/CD3 induced cytokine release (such as IL-6, TNF-α, IL-2) is not required for T cell cytotoxic activity (Fig. 1A, Fig. 1D, and page 3, col. 1, para. 2) in MMTV.huHER2 TG mice model.
Li teaches that induction of IL-6 was correlated with TNF-α and was 69% lower when TNF-α cells were used (Fig. 3C). Genetic deletion of TNF-α had only a minor effect on T cell activation and did not impair the ability of T cells to kill target cells (Fig. 4D). In summary, bispecific antibody-activated T cells are the initial and major source of TNF-α, which is upstream of IL-6 secretion (page 7, col. 1, para. 1).
Li teaches that cotreatment of anti-TNF-α and anti-HER2/CD3 bispecific antibody reduces IL-6, IL-1β, IL-2 and INF-γ production, but does not impact on the ability of T cells to kill tumor cells (Fig. 4E); in vivo MMTV.huHER2 TG mice model, anti-TNF-α pretreatment suppressed T cell-dependent bispecific antibody (TBD)-induced IL-6 and IL-1β (Fig. 4F), but had no impact antitumor activity of TDB (Fig. 4G). Also see page 7, col. 1, para. 2.
Li teaches that TNF-α release upon initial T cell activation is the proximal trigger, indicating that preventative treatment with anti-TNF-α would be crucial for successful intervention (page 8, col. 1, para. 4). Li teaches that the cytokine blockade should be applied as early as possible and not after clinical manifestation of severe cytokine release syndrome (CRS) symptoms (page 1, col. 2, para. 3).
Li teaches that in vivo, pretreatment of anti-TNF-α prior to administering TBD. And the pretreatment does not impact activity of TDB (Fig. S9D).
Lee teaches that etanercept has been used in treating CRS. CRS symptoms resolved within hours, and vasopressor support was discontinued. Cytokine level returned to baseline within 3 weeks. Nine months after this CRS (see § Case 2: grade 3 CRS genetically unmodified cytotoxic T cells (CTL) therapy for EBV-associated lymphoma, on pages 188-189).
Lee teaches that targeted immunosuppressive agents (such as infliximab and etanercept) could provide benefit and have been used successfully for treating CRS (page 193, col. 1, para. 3).
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to combine the teachings of Baeuerle, Li and Lee and to modify the method of Baeuerle by adding a step of administering an inhibitor of TNF-α (e.g. etanercept) prior to administering the single chain bispecific antibody for preventing side effects such as CRS. Baeuerle teaches: 1) CRS is associated with anti-CD19/CD3 bispecific antibody therapy; 2) anti-human CD19/CD3 bispecific antibody treatment increase TNF-α level rapidly. Li teaches: 1) uncontrolled systemic cytokine release is primary challenge for all T cell-targeting therapies (e.g. CD3 bispecific antibodies), 2) TNF-α is an early trigger for cytokine productions; 3) pretreatment of anti-TNF-α agent (e.g. adalimumab) suppresses production of various cytokines but does not impact tumor killing activity; 4) the cytokine blockade should be applied as early as possible. Based on the teachings from Baeuerle, Li and Lee, one of ordinary skill in the art would have expected that adding a step of administering an inhibitor of TNF-α (e.g. etanercept) prior to administering the bispecific antibody could prevent CRS without impact the therapeutic activity of the antibody. The motivation is to develop a safer treatment with a well-tested therapeutic agent and to expand the application of etanercept.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Baeuerle (Baeuerle et al., WO 2007/068354, Publication Date: 06/21/2007, cited in IDS of 01/18/2023, of record), in view of Li (Li et al., Sci. Transl. Med., 11, eaax8861 (2019), Publication Date: September 4, 2019, cited in IDS of 01/18/2023, of record) and Lee (Lee et al., Blood, Vol. 124, Number 2, 188-195, Publication Date: 07/10/2014), as applied to claims 1-3, and 10 above, and further in view of Raum (Raum et al., US 2017/0218078 A1, Publication Date: 08/03/2017).
Baeuerle, Li, and Lee teach method of claim 1 as set forth above. However, the references do not teach the second domain also binds to Callithrix jacchus or Saimiri sciureus CD3 epsilon.
Raum teaches bispecific antibody comprising binding domain for CD3 and one binding domain for a tumor-associated surface antigen on target cells ([0001]).
Raum teaches a CD3 binding domain (as used clinically in AMG 103 and AMG 110) with cross-species specificity for human and Callithrix jacchus, Saimiri sciureus CD3 episilom ([0001]). Unlike other CD3 binder, this specific CD3 binding domain do not unspecifically activate T cell to the same degree as observed for the previous generation of T cell engaging antibodies. This reduction in T cell activation was connected with less or reduced T cell redistribution in patients, which was identified as a risk for side effects ([0001]).
Raum teaches that the tumor associated antigen can be CD19 ([0193]).
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to use a method of claim 1: preventing CRS in a patient by first administering etanercept and followed by administering an anti-CD19/CD3 bispecific antibody as taught by Baeuerle, Li, and Lee, as set forth above, and to modify the method by substituting the CD3 binding domain of Baeuerle by the CD3 binding domain of Raum, because the binding domain do not unspecifically activate T cell and can be used to broader subjects and Raum teaches the antibody construct of the invention exhibiting cross-species specificity described herein can be advantageously used in identical form in preclinical testing in non-chimpanzee primates and as drug in humans. See ¶ [0327] . Because the binding domain has been clinically tested, one of ordinary skilled in the art would have had a reasonable expectation that the anti-CD19/CD3 antibody with substituted CD3 binding domain would reduce toxicity associated with antibody-induced side effects, as recognized by Raum. The motivation would be to develop a better and safer therapeutic antibody and to expand the application for the bispecific antibody. There is a reasonable expectation of success for reducing CRS of the bispecific antibody (MT103) comprised of administering an inhibitor of TNF/TNFR 9 e.g. etanercept), because Li teaches that pretreatment of anti-TNF-α agent suppresses production of various cytokines but does not impact tumor killing activity.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Baeuerle (Baeuerle et al., WO 2007/068354, Publication Date: 06/21/2007, cited in IDS of 01/18/2023, of record), in view of Li (Li et al., Sci. Transl. Med., 11, eaax8861 (2019), Publication Date: September 4, 2019, cited in IDS of 01/18/2023, of record) and Lee (Lee et al., Blood, Vol. 124, Number 2, 188-195, Publication Date: 07/10/2014), as applied to claims 1-3 and 10 above, and further in view of Brandl (Brandl et al., Cancer Immuno Immunother (2007) 56: 1551-1563, Publication Date: 02/20/2007).
Baeuerle, Li and Lee teach method of claim 2 as set forth above. However, the references do not teach the corticosteroid is dexamethasone.
Brandl teaches MT103, a CD19 x CD3 single chain bispecific antibody (Abstract).
Brandl teaches that MT103 induces cytokine productions, including IL-2, TNF-α, IFN-γ, and IL-6, which potentially can lead to cytokine related side effect (the bridging paragraph of cols 1-2 on page 1552).
Brandl teaches that dexamethasone barely impact T cell proliferation (Fig. 4, and Abstract).
Brandl teaches that dexamethasone can effectively reduce production of all studies cytokines (Fig. 1, and Abstract). Importantly, dexamethasone did not inhibit the cytotoxic activity of MT103-activated T cells against cancer cells from 12 human donors (Fig. 5, and Abstract).
Brandl teaches that dexamethasone can be used in combination with bispecific antibodies for cancer (Abstract).
Brandl teaches that dexamethasone has been widely used in cancer therapies to dampen side effects (page 1552, col. 2, para. 1).
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to use a method of claim 2: preventing CRS in a patient by first administering an inhibitor of TNF/TNFR: etanercept and a corticosteroid (methylprednisolone) and followed by administering an anti-CD19/CD3 bispecific antibody as taught by Baeuerle, Li, and Lee, as set forth above, and to modify the method by substituting methylprednisolone with dexamethasone as the corticosteroid to further control cytokine production, because Brandl teaches that dexamethasone is common drug for control side effect; can reduce all tested cytokines induced by anti-CD19/CD3 bispecific antibody; barely impact T cell proliferation; and does not impact cytotoxicity of anti-CD19/CD3 bispecific antibody to cancer cell. Based on the teachings of Brandl, Baeuerle, Li, and Lee, one of ordinary skill in the art would have expected that dexamethasone would be able to further control production of cytokines and to better prevent potential CRS associated with anti-CD19/CD3 bispecific antibody therapy. The motivation would be to develop a safer treatment with a well-tested therapeutic agent and to expand the application of dexamethasone.
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 § 2146 et seq. 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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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/apply/applying-online/eterminal-disclaimer.
Patent No. 8,840,888 B2
Claims 1-4 and 10 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-34 of U.S. Patent No. 8,840,888 B2 (herein after Pat. 888, of reocrd) in view of Baeuerle (Baeuerle et al., WO 2007/068354, Publication Date: 06/21/2007, cited in IDS of 01/18/2023, of record), Li (Li et al., Sci. Transl. Med., 11, eaax8861 (2019), Publication Date: September 4, 2019, cited in IDS of 01/18/2023, of record), and Lee (Lee et al., Blood, Vol. 124, Number 2, 188-195, Publication Date: 07/10/2014), as evidenced by Raum (Raum et al., US 2017/0218078 A1, Publication Date: 08/03/2017) and Nagorsen (Nargorsen et al., Pharmacol Ther. 136(3): 334-342, Publication Date: 08/24/2012).
It is noted that the original Assignee for Pat. 888 is Micromet GmbH, but the current Assignee is Amgen Research Munich GmbH. Amgen Research Munich GmbH is one of the Assignees of the instant application.
The claims of Pat. 888 teach a method for ameliorating or preventing an adverse effect mediated by the administration of a CD19×CD3 bispecific antibody to a human patient having a B:T cell ratio of about 1:5 or lower, said method comprising (a) determining the ratio of total B cells to total T cells in a peripheral blood sample from said human patient to identify patients at risk of developing an adverse effect; (b) identifying said human patient as having an increased risk of potential adverse effects when the ratio of B:T cells is about 1:5 or less before treatment; (c) administering a first dose of said antibody for a first period of time to said patient identified in (b), and consecutively; (d) administering a second dose of said antibody for a second period of time; wherein said second dose exceeds said first dose, and wherein said CD19×CD3 bispecific antibody is MT103 (Blinatumomab). See claim 32.
As evidenced by Nagorsen, MT103, AMG 103 and blinatumomab refer to the same compound (Abstract), which is a single chain antibody construct (Fig. 1). As evidenced by Raum, the CD3 binding domain of AMG 103 has cross-species specificity for human and Callithrix jacchus, Saimiri sciureus CD3 episilom ([0001]). Thus, MT103, AMG 103 or blinatumomab reads the antibody constructs of instant claim 1 and 4.
The claim 32 of Pat. 888 is directed a method of reducing adverse effects associated with the administration of MT103 (AMG103, blinatumomab), a bispecific antibody binds to CD3 and CD19. The patented claims do not claim administering etanercept.
The teachings of Baeuerle, Li, and Lee are described above.
One of ordinary skill in the art before the effective filing date would have been motivated to modified the patented claimed method of reducing the adverse effects of MT103 to use administration of an inhibitor of TNF/TNFR (such as etanercept) prior to administration of the bispecific antibody MT103, because Baeuerle teaches: 1) CRS is associated with anti-CD19/CD3 bispecific antibody therapy; 2) anti-CD19/CD3 bispecific antibody treatment increase TNF-α level rapidly. Li teaches: 1) uncontrolled systemic cytokine release is primary challenge for all T cell-targeting therapies (e.g. CD3 bispecific antibodies), 2) TNF-α is an early trigger for cytokine productions; 3) pretreatment of anti-TNF-α agent (e.g. adalimumab) suppresses production of various cytokines but does not impact tumor killing activity; 4) the cytokine blockade should be applied as early as possible. Lee teaches using etanercept to treat CRS. Based on the teachings from Baeuerle, Li, and Lee, one of ordinary skill in the art would have expected that the modified method (adding a step of administering an inhibitor of TNF-α (e.g. etanercept) prior to administering the bispecific antibody) could prevent CRS without impact the therapeutic activity of the antibody. The motivation is to minimize the risk associated with the treatment, to develop a safer treatment with a well-tested therapeutic agent and to expand the application of etanercept.
Regarding claim 2, Baeuerle teaches that administering glucocorticosteroid prior to the administration of anti-CD19/CD3 bispecific single chain antibody in order to suppress cytokine release at the initial phase (page 51, and Example 5). One of ordinary skill in the art would use glucocorticosteroid (methylprednisolone) prior to prior to the administration of anti-CD19/CD3 to further control cytokine production and release.
Regarding claim 10, Baeuerle teaches treating various cancers with the bispecific antibody, such as B-cell Non-Hodgkin’s lymphoma (NHL) (Examples 3-5). Baeuerle teaches that the bispecific antibody targeting CD19 and CD3 can be used to treat a solid tumor (page 5, para. 1).
Claim 11 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-34 of U.S. Patent No. 8,840,888 B2 (herein after Pat. 888, of record) in view of Baeuerle (Baeuerle et al., WO 2007/068354, Publication Date: 06/21/2007, cited in IDS of 01/18/2023, of record), Li (Li et al., Sci. Transl. Med., 11, eaax8861 (2019), Publication Date: September 4, 2019, cited in IDS of 01/18/2023, of record), and Lee (Lee et al., Blood, Vol. 124, Number 2, 188-195, Publication Date: 07/10/2014), as evidenced by Raum (Raum et al., US 2017/0218078 A1, Publication Date: 08/03/2017) and Nagorsen (Nargorsen et al., Pharmacol Ther. 136(3): 334-342, Publication Date: 08/24/2012), as applied to claims 1-4 and 10 above, and further in view of Brandl (Brandl et al., Cancer Immuno Immunother (2007) 56: 1551-1563, Publication Date: 02/20/2007).
The claims of Pat. 888, Baererle, Li and Lee teach the method of instant claim 2, as set forth above. However, the references do not teach the corticosteroid is dexamethasone.
The teachings of Brandl are described above.
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to use a method of claim 2: preventing CRS in a patient by first administering an inhibitor of TNF/TNFR: etanercept and a corticosteroid (methylprednisolone) and followed by administering an anti-CD19/CD3 bispecific antibody as taught by the claims of Pat. 888, Baeuerle, Li, and Lee, as set forth above, and to modify the method by substituting methylprednisolone with dexamethasone as the corticosteroid to further control cytokine production, because Brandl teaches that dexamethasone is common drug for control side effect; can reduce all tested cytokines induced by anti-CD19/CD3 bispecific antibody; barely impact T cell proliferation; and does not impact cytotoxicity of anti-CD19/CD3 bispecific antibody to cancer cell. Based on the teachings of Brandl, Baeuerle, Li, and Lee, one of ordinary skill in the art would have expected that dexamethasone would be able to further control production of cytokines and to better prevent potential CRS associated with anti-CD19/CD3 bispecific antibody therapy. The motivation would be to develop a safer treatment with a well-tested therapeutic agent and to expand the application of dexamethasone.
Patent No. 10,191,034 B2
Claims 1-3 and 10 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 10,191,034 B2 (herein after Pat. 034, of record) in view of Baeuerle (Baeuerle et al., WO 2007/068354, Publication Date: 06/21/2007, cited in IDS of 01/18/2023, of record), Li (Li et al., Sci. Transl. Med., 11, eaax8861 (2019), Publication Date: September 4, 2019, cited in IDS of 01/18/2023, of record) and Lee (Lee et al., Blood, Vol. 124, Number 2, 188-195, Publication Date: 07/10/2014).
The claims of Pat. 034 teach a method for treating a human patient suffering from malignant CD19-positive lymphoma or leukemia, wherein the patient is at risk for potential adverse effects resulting from treatment with a CD19×CD3 bispecific antibody comprising an amino acid sequence encoded by the nucleic acid sequence set forth in SEQ ID NO: 2 or the amino acid sequence set forth in SEQ ID NO: 1, the method comprising: (a) determining …; and (b) identifying …; (c) administering the CD19×CD3 bispecific antibody (i) to the patient who is at higher risk in an incremental dosage schedule to reduce the possibility of potential adverse effects in the patient, wherein a first dose is administered for a first period of time and a second dose is consecutively administered for a second period of time, wherein said second dose is greater than said first dose, and wherein said second period of time exceeds said first period of time; or (ii) to the patient who is at lower risk in a constant dose for at least four weeks. See claim 1. Since the bispecific antibody is a single chain antibody (SEQ ID NO: 1), the antibody of Pat. 034 reads on the antibody of instant claim 1.
The claim 32 of Pat. 034 is directed a method of reducing adverse effects associated with the administration of a single chain bispecific antibody binds to human CD3 and CD19. The patented claims do not claim administering etanercept.
The teachings of Baeuerle, Li and Lee are described above.
One of ordinary skill in the art before the effective filing date would have been motivated to modified the patented claimed method of reducing the adverse effects of the bispecific antibody taught by the claims of Pat. 034 to use administration of an inhibitor of TNF/TNFR (such as etanercept) prior to administration of the bispecific antibody, because Baeuerle teaches: 1) CRS is associated with anti-CD19/CD3 bispecific antibody therapy; 2) anti-CD19/CD3 bispecific antibody treatment increase TNF-α level rapidly. Li teaches: 1) uncontrolled systemic cytokine release is primary challenge for all T cell-targeting therapies (e.g. CD3 bispecific antibodies), 2) TNF-α is an early trigger for cytokine productions; 3) pretreatment of anti-TNF-α agent (e.g. adalimumab) suppresses production of various cytokines but does not impact tumor killing activity; 4) the cytokine blockade should be applied as early as possible. Lee teaches using etanercept to treat CRS. Based on the teachings from Baeuerle, Li and Lee, one of ordinary skill in the art would have expected that the modified method (adding a step of administering an inhibitor of TNF-α (e.g. etanercept) prior to administering the bispecific antibody) could prevent CRS without impact the therapeutic activity of the antibody. The motivation is to minimize the risk associated with the treatment, to develop a safer treatment with a well-tested therapeutic agent and to expand the application of etanercept.
Regarding claim 2, Baeuerle teaches that administering glucocorticosteroid prior to the administration of anti-CD19/CD3 bispecific single chain antibody in order to suppress cytokine release at the initial phase (page 51, and Example 5). One of ordinary skill in the art would use glucocorticosteroid (methylprednisolone) prior to prior to the administration of anti-CD19/CD3 to further control cytokine production and release.
Regarding claim 10, Baeuerle teaches treating various cancers with the bispecific antibody, such as B-cell Non-Hodgkin’s lymphoma (NHL) (Examples 3-5). Baeuerle teaches that the bispecific antibody targeting CD19 and CD3 can be used to treat a solid tumor (page 5, para. 1).
Claim 11 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 10,191,034 B2 (herein after Pat. 034, of record) in view of Baeuerle (Baeuerle et al., WO 2007/068354, Publication Date: 06/21/2007, cited in IDS of 01/18/2023, of record), Li (Li et al., Sci. Transl. Med., 11, eaax8861 (2019), Publication Date: September 4, 2019, cited in IDS of 01/18/2023, of record) and Lee (Lee et al., Blood, Vol. 124, Number 2, 188-195, Publication Date: 07/10/2014), as applied to claims 1-3 and 10 above, and further in view of Brandl (Brandl et al., Cancer Immuno Immunother (2007) 56: 1551-1563, Publication Date: 02/20/2007).
The claims of Pat. 034, Baererle, Li and Lee teach the method of instant claim 2, as set forth above. However, the references do not teach the corticosteroid is dexamethasone.
The teachings of Brandl are described above.
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to use a method of claim 2: preventing CRS in a patient by first administering an inhibitor of TNF/TNFR: etanercept and a corticosteroid (methylprednisolone) and followed by administering an anti-CD19/CD3 bispecific antibody as taught by the claims of Pat. 034, Baeuerle and Li, as set forth above, and to modify the method by substituting methylprednisolone with dexamethasone as the corticosteroid to further control cytokine production, because Brandl teaches that dexamethasone is common drug for control side effect; can reduce all tested cytokines induced by anti-CD19/CD3 bispecific antibody; barely impact T cell proliferation; and does not impact cytotoxicity of anti-CD19/CD3 bispecific antibody to cancer cell. Based on the teachings of Brandl, Baeuerle, Li and Lee, one of ordinary skill in the art would have expected that dexamethasone would be able to further control production of cytokines and to better prevent potential CRS associated with anti-CD19/CD3 bispecific antibody therapy. The motivation would be to develop a safer treatment with a well-tested therapeutic agent and to expand the application of dexamethasone.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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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/CHENG LU/ Examiner, Art Unit 1642
/PETER J REDDIG/ Primary Examiner, Art Unit 1646
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