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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on February 5, 2025 has been entered.
DETAILED ACTION
The amendment filed February 5, 2025 in response to the Office Action of September 5, 2024 is acknowledged and has been entered.
Claims 2, 83, 84 and 91 have been amended.
Claims 66, 67 and 92 have been cancelled.
Claim 96 has been added.
Claims 2, 26, 27, 42, 70, 73, 83-91, 93-96 are pending.
Claims 26 and 86 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions or species, there being no allowable generic or linking claim.
Claims 2, 27, 42, 70, 73, 83-85, 87-91, and 93-96 are currently under consideration as drawn to the elected invention.
MAINTAINED/MODIFIED 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 2, 27, 70, 73, 85 and 93-95 are rejected under 35 U.S.C. 103 as being unpatentable over Berenson (Berenson, WO 2017/019496 A1, Publication Date: 2017-02-02, of record), in view of Borges (Borges et al., WO 2012/066058 A1, Publication Date: 05-24-2012, of record).
These claims are drawn to a method of treating a subject having a multiple myeloma (MM) comprising administering to the subject a combination of a multispecific antibody molecule that binds to BCMA, CD3 and a small molecule gamma secretase inhibitor (GSI), i.e. BMS-708163 (the elected species).
Berenson teaches that the presence of BCMA in the serum contributes to the pathologies of various B cell malignancies, thus, there is a need in the art for a means to reduce levels of serum BCMA (page 2, para. 3).
Berenson teaches that gamma secretase is involved in the cleavage of membrane bound BCMA and shedding of the BCMA’s extracellular domain into the serum (page 9, para. 1). Particular embodiments contemplate a model whereby gamma secretase activity promotes BCMA shedding from pathogenic B cells in a subject, which in turn contributes to immune system dysfunction in the subject. According to this model, gamma secretase activity in pathogenic B cells (e.g., multiple myeloma tumor cells) promotes BCMA shedding which releases the extracellular portion of BCMA from B cells (page 9, para. 2).
Berenson teaches gamma secretase inhibitors that can decrease, prevent or block BCMA cleavage and its shedding, including small molecule inhibitor BMS-708163 (the elected species) (page 9, paras.1-3; and page 5, line 27; Example 1; claim 14).
Berenson teaches that reducing BCMA shedding will enhance other therapies that target BCMA expressed on B cells, since if BCMA is shed, the B cell will no longer be efficiently targeted, but if the shedding is blocked or decreased more BCMA will be expressed on the surface of the B cells, thereby increasing the efficacy of the therapies that target BCMA expressed on B cells (page 42, para. 2).
Berenson teaches that using of gamma secretase inhibitors may improves the efficacy of a therapeutic agent that binds to BCMA and/or binds to cells that express BCMA. Therapeutic agents that bind to BCMA include therapeutic anti-BCMA antibodies, anti-BCMA antibody-drug conjugates (page 10, para. 2, claim 3).
Berenson teaches that the GSI is administered with proteasome inhibitors (page 31, para. 3).
Berenson teaches that the GSI and methods can be used to treat various diseases, i.e. MM (multiple myeloma) (claims 5-13; page 1, lines 18-21; page 41).
Berenson teaches as set forth above. However, Berenson does not teach that the BCMA antibody is an anti-BCMA/CD3 bispecific antibody.
Borges teaches agents and methods for the treatment of human diseases that correlate with BCMA expression, including tumor therapy, in particular the therapy of plasma cell disorders like multiple myeloma (MM), plasmacytoma and plasma cell leukemia and other B cell disorders like NHL, CLL HD, as well as autoimmune diseases (whole document, page 1 in particular).
Borges teaches that BCMA expression is highly elevated in the malignant plasma cell disorders i.e. MM, plasmacytoma and plasma cell leukemia. Expression in normal tissue is low and restricted to lymphoid tissues and colon (page 4, para. 2).
Borges teaches that a BCMA-specific antibody prevents NF-κB activation of malignant B-cells and confer ADCC to multiple MM cell lines (page 3, para. 2).
Borges teaches that BCMA-specific antibodies induce elimination of myeloma cells and long-term remission of patients (page 3, para. 3).
Borges teaches bispecific antibodies comprising the first binding domain to BCMA; and the second binding domain to CD3 (page 9, para. 2, claim 1).
Borges teaches that clustering of CD3 on T cells, e.g. by immobilized anti-CD3-antibodies, leads to T cell activation similar to the engagement of the T cell receptor (page 4, para. 5).
Borges teaches that the bispecific antibody (anti-BCMA/CD3) can pull the target cells into the complex by specifically binding to a selective target molecule present on the target cells. Formation of this complex will induce signaling in cytotoxic T cells, either on its own or in combination with accessory cells, which lead to the release of cytotoxic mediators. The agent will only induce the desired signaling in the presence of the target cell providing the surface molecules to form a signaling complex of CD3 molecule (page 2, paras 2-3).
Borges teaches that the bispecific binding agent is in the format of a bispecific antibody molecule or a fragment thereof which has at least two binding domains, comprising a first binding domain and a second binding domain, wherein said first binding domain binds to BCMA and wherein the second binding domain binds to CD3 (page 9, para. 2; and claim 1). Preferably, the first binding domain of a bispecific binding agent of the invention binds to an epitope of BCMA that is located in the extracellular domain (page 25, para. 2).
Borges teaches that the bispecific antibodies can lead to desired signaling in the presence of the target cell providing the surfaces molecules, e.g. BCMA. See page 2.
Borges teaches various methods and formats to make the anti-BCMA/CD3 bispecific antibodies (pages 9-18, claims 3-14, Example).
Borges teaches that the anti-BCMA/CD3 bispecific antibodies can be used to prevent, treat or alleviate various disease associated with BCMA expression, i.e. plasmacytoma, plasma cell leukemia, multiple myeloma, macroglobulinemia, amyloidosis, CLL (chronic lymphocytic leukemia), non-Hodgkins lymphoma (NHL), Systemic Lupus Erythematosus (SLE), multiple sclerosis (MS) and rheumatoid arthritis (RA) (page 36, claim 17).
Borges teaches that additional therapeutic agent, i.e. a proteasome inhibitor, may be administered simultaneously with, optionally as a component of the same pharmaceutical preparation, or before or after administration of the bispecific antibodies (pages 36-37).
Borges teaches that the antibodies of the invention can be multispecific. See p. 7-lines 5-6.
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to treat a disease associated with expression of BCMA such as MM with a combination of a small molecule GSI such as BMS-708163 and anti-BCMA antibody as taught by Berenson, and to use an anti-BCMA/anti-CD3 bispecific antibody in the combination, as taught by Borges, because Berenson teaches that using a GSI can improve efficacy of a BCMA-targeted therapy for MM; Borges teaches that anti-BCMA/anti-CD3 bispecific antibodies can introduce targeted cytotoxicity to BCMA-expressing cells. One of ordinary skilled in the art would have recognized that the bispecific antibody would be more specific to BCMA-expressing cancer cells and would improve efficacy and reduce adverse effects of treatment. Given that both BMS-708163 and the bispecific antibody have been well-known in the art, as evidenced by Berenson and Borges, one of ordinary skilled in the art would have had a reasonable expectation of success to reach the claimed invention. The motivation would be to develop a better treatment for BCMA-associated disease.
Regarding claims 27 and 85, Berenson teaches the bispecific antibody is a trifunctional molecule by targeting plasma cells through binding to BCMA, mediating cytotoxic T cell activity through CD3 binding and providing a fully functional Fc constant domain mediating antibody-dependent cellular cytotoxicity through recruitment of effector cells like NK cells (page 10, para. 2). The bispecific binding agent of the invention has one binding domain for the interaction with BMCA, one binding domain for binding to CD3 and the intact Fc region with its functional binding features for activating Fey receptor type I (CD64)-, Ila (Cd32a)- and III (CD16)- expressed on accessory cells. While, according to this aspect of the invention, the bispecific binding agent in the format of an intact bispecific antibody binds to the T cell with the binding arm that is specific for CD3 and activates it at the same time, co-stimulatory signals from the Fc receptor-positive cell bound to the Fc portion of the bispecific antibody can be transferred to the T cell. (page 11, para. 1). Thus, the intact Fc region binds to a third antigen such as CD64 or CD16.
Regarding claim 73, Berenson teaches that the GSI is administered with steroids, i.e. dexamethasone (page 32, para. 2).
Regarding claims 70, and 93-95, Berenson further teaches that the specific amount/dosage regimen will vary depending on the weight, gender, age and health of the individual; the formulation, the biochemical nature, bioactivity, bioavailability and the side effects of the agents and the number and identity of the agents in the complete therapeutic regimen. Therefore one of skill in the art could modify the administration regimen for the claimed combination depending upon the age and the size of a subject to be administered, target disease, conditions, route of administration, and the like to reach the specific regimens as claimed.
Response to Arguments
For the rejection of claims 2, 27, 70, 73, 85 and 93-95 under 35 U.S.C. 103, Applicant argues:
PNG
media_image1.png
187
646
media_image1.png
Greyscale
PNG
media_image2.png
271
647
media_image2.png
Greyscale
PNG
media_image3.png
373
653
media_image3.png
Greyscale
PNG
media_image4.png
740
650
media_image4.png
Greyscale
PNG
media_image5.png
186
643
media_image5.png
Greyscale
PNG
media_image6.png
242
648
media_image6.png
Greyscale
PNG
media_image7.png
243
646
media_image7.png
Greyscale
PNG
media_image8.png
243
651
media_image8.png
Greyscale
PNG
media_image9.png
407
653
media_image9.png
Greyscale
PNG
media_image10.png
517
647
media_image10.png
Greyscale
PNG
media_image11.png
188
639
media_image11.png
Greyscale
PNG
media_image12.png
185
642
media_image12.png
Greyscale
Applicant’s arguments have been fully considered but they are not persuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
As set forth above, Berenson explicitly teaches gamma secretase inhibitors that can decrease, prevent or block BCMA cleavage and its shedding in MM tumor cells, i.e. BMS-708163 (page 9, paras.1-3 and page 5, line 27, claim 14). Example 1 shows that GSI can prevent shedding of BCMA off of myeloma tumor cells. Berenson further teaches that using of gamma secretase inhibitors may improves the efficacy of a therapeutic agent that binds to BCMA (which would encompass bispecific antibodies of the instant application) and/or binds to cells that express BCMA e.g. MM cells. Therapeutic agents that bind to BCMA include therapeutic anti-BCMA antibodies, anti-BCMA antibody-drug conjugates (page 10, para. 2, claim 3). Borges explicitly teaches that the anti-BCMA/CD3 bispecific antibodies can be used to prevent, treat or alleviate various disease associated with BCMA expression, i.e. multiple myeloma. Borges teaches that additional therapeutic agent can be used in combination with the bispecific antibody. Based on the teachings of references, as set forth above, an ordinary skilled in the art would recognize that an GSI, such as BMS-708613 would have improved the efficacy of a therapeutic agent bind to BCMA, such as the BCMA x CD3 bispecific antibody, as set forth above. One of ordinary skilled in the art would have known to combine BMS-708163 from a limited number of options (claim 14 od Berenson) and multispecific antibody told by Borges to reach claimed invention.
Applicant further argues that unexpected results would overcome any prima facie obviousness. However, “Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980) (Claims were directed to a process for removing corrosion at "elevated temperatures" using a certain ion exchange resin (with the exception of claim 8 which recited a temperature in excess of 100C). Appellant demonstrated unexpected results via comparative tests with the prior art ion exchange resin at 110C and 130C. The court affirmed the rejection of claims 1-7 and 9-10 because the term "elevated temperatures" encompassed temperatures as low as 60C where the prior art ion exchange resin was known to perform well. The rejection of claim 8, directed to a temperature in excess of 100C, was reversed.). See also In re Peterson, 315 F.3d 1325, 1329-31, 65 USPQ2d 1379, 1382-85 (Fed. Cir. 2003) (data showing improved alloy strength with the addition of 2% rhenium did not evidence unexpected results for the entire claimed range of about 1-3% rhenium); In re Grasselli, 713 F.2d 731, 741, 218 USPQ 769, 777 (Fed. Cir. 1983) (Claims were directed to certain catalysts containing an alkali metal. Evidence presented to rebut an obviousness rejection compared catalysts containing sodium with the prior art. The court held this evidence insufficient to rebut the prima facie case because experiments limited to sodium were not commensurate in scope with the claims.)”. MPEP 716.02
Applicant provides additional Post-Filing Evidence to support the argument of Unexpected Results. It is acknowledged that Chen’s results with the same bispecific antibodies (e.g. ER26, BQ76, BU76) as instantly claimed (see page 2-§ Reagents and compounds) further confirmed the therapeutic activity of the combinations disclosed in the instant specification. Schjesvold and Raab also show enhanced therapeutic activity to MM with a specific combination of WVT078 (a BCMAxCD3 BsAb) + WHG626 (a GSI).
However, the claims are not limited to the bispecific antibodies disclosed in the specification and the post-filing references. The claims encompass a broad genus of multispecific antibodies, including anti-BCMA/anti-CD3 bi-specific antibodies and variants (as evidenced by claims 83, 84, 96), or tri-specific antibodies binging to an additional antigen . For combination treatment (BCMA x CD3 bispecific antibody + small molecule GSI) for MM, in vivo, only one BCMA x CD3 bispecific antibody (FP31), combined with only three small molecule GSIs (LY-450139, PF-5212362, PF-3084014), for only one BCMA+ cell line (KMS11). See Example 3, Table 5. Taken account in vitro results (Example 1), only five BCMA x CD3 bispecific antibodies (ER26, BQ76, BU76, EE11, and EM90) combined with only one small molecule GSI (DAPT) have been tested and showed enhanced results. Thus, the example is not commensurate in scope with the claimed invention and is not probative on the non-obviousness of the claimed invention.
Applicant provides additional Post-Filing Evidence to support the argument of Unexpected Results. It is acknowledged that Chen’s results with the same bispecific antibodies (e.g. ER26, BQ76, BU76) as instantly claimed (see page 2-§ Reagents and compounds) further confirmed the therapeutic activity of the combinations disclosed in the instant specification. Schjesvold and Raab also show enhanced therapeutic activity to MM with a specific combination of WVT078 (a BCMAxCD3 BsAb) + WHG626 (a GSI). Again, the examples in the references are not commensurate in scope with the claimed invention and is not probative on the non-obviousness of the claimed invention.
Furthermore, Berenson teaches that using of gamma secretase inhibitors may improves the efficacy of a therapeutic agent that binds to BCMA and/or binds to cells that express BCMA. Therapeutic agents that bind to BCMA include therapeutic anti-BCMA antibodies, anti-BCMA antibody-drug conjugates (page 10, para. 2, claim 3). Thus, the combination of a BCMA/CD3 bispecific antibody and a small molecule GSI would have been expected to have an enhanced therapeutic effect.
Applicant further argues that Berenson and Borges do not teach treating patient-derived primary multiple myeloma cells. However, this limitation was not recited by the claims. As set forth above, Berenson and Borges together teach treating MM with the claimed combinations.
Thus, Applicant’s arguments are not found persuasive for the reasons set forth above and the rejection is maintained for the reasons of record.
Claims 83, and 87-91 are rejected under 35 U.S.C. 103 as being unpatentable over Berenson (Berenson et al., WO 2017/019496 A1, Publication Date: 02-02-2017, of record) and Borges (Borges et al., WO 2012/066058 A1, Publication Date: 05-24-2012, of record), as applied to claims 2, 27, 70, 73, 85 and 93-95 above, and further in view of Algate (Algate et al., US 2013/0280280 A1, Appl. No.: 13/795,314, Publication Date: 10-24-2013, of record).
Berenson and Borges teach as set forth above, However, Berenson and Borges do not teach the anti-BCMA antibody comprise a heavy chain variable region and a light chain variable region comprising the amino acid sequence of SEQ ID NO:1118 and 1119, respectively (J6M0, BCMA antibody, Table 1, the elected species).
Algate teaches humanized BCMA antibody J6M0 ([0014]).
Algate teaches that J6M0 antibody comprises a heavy chain variable region and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 23 and 31, respectively (page 33, Table C). SEQ ID NO: 23 and 31 are identical to SEQ ID NO:1118 and 1119, respectively. Alignments shown below:
SEQ ID NO: 1118 of instant application vs. SEQ ID NO: 23 of Algate:
PNG
media_image13.png
259
573
media_image13.png
Greyscale
SEQ ID NO: 1119 of instant application vs. SEQ ID NO: 31 of Algate:
PNG
media_image14.png
197
568
media_image14.png
Greyscale
Algate teaches that J6M0 neutralizes binding of BAFF or APRIL to BCMA ([0016] and Fig. 7, Example 4), and inhibits BAFF or APRIL induced phosphorylation of NFKappaB ([0018] and Fig. 7, Example 4).
Algate teaches that J6M0 has good ADCC activity in treating BCMA expressing cells, such as ARH77 10B5 (Figs. 9 and 17, [0304]).
Algate teaches that J6M0 inhibits MM tumor cell growth in xenograft model (Fig. 19, Example 6).
Algate teaches that J6M0 can be used to treated various diseases, i.e., MM, leukaemia, CLL etc…([0129-0143], claim 13).
As set forth above, Berenson and Borges combined teach the method of claim 2. It would have been prima facie obvious to one of ordinarily skilled in the art at the time the invention was filed to relate the teachings of Berenson, Borges and Algate to use J6M0 as the anti-BCMA arm of the bispecific antibody (e.g. anti-BCMA/CD3 antibody), and to combine the bispecific antibody and a small molecule GSI (e.g. BMS-708163) to treat MM, because J6M0 has been well tested and has good binding activity and anti-tumor (MM) activity, as taught by Algate, thus, would be a good candidate for therapeutic purpose. From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed multispecific antibody. The motivation would have been to develop a better therapeutic bispecific antibody and to expand the application of J6M0.
Regarding claims 87 and 88, Algate teaches that Fc region is important for ADCC and CDC activity of an antibody ([0190]), various modifications to heavy chain constant region of antibody may be carried out depending on the desired effector property ([0192]). Algate teaches afucosylated form of J6M0 (Potelligent) ([0288]). And the afucosylated J6M0 has enhanced ADCC potency ([0318], and Fig. 17).
Regarding claims 89-91, Algate teaches antibody-drug conjugates comprising an antibody conjugated to one or more cytotoxic agents, such as a chemotherapeutic agent, a drug, a growth inhibitory agent, a toxin (e.g., a protein toxin, an enzymatically active toxin), or a radioactive isotope ([0207]). Algate teaches an antibody-drug conjugate with the structure of antibody-linker-drug ([0209])., e.g. antibodies linked by an MC linker with auristatins such as MMAE and MMAF ([0211]). Algate teaches a protease-resistant (non-cleavable) maleimidocaproxyl linker for MMAF, and a dipeptide linker for MMAE ([0214])
Response to Arguments
For the rejection of claims 83, and 87-91 under 35 U.S.C. 103, Applicant argues:
PNG
media_image15.png
49
651
media_image15.png
Greyscale
PNG
media_image16.png
244
652
media_image16.png
Greyscale
Applicant’s arguments have been fully considered but they are not persuasive. As set forth above, Berenson and Borges teach the method of claim 2. Algate teaches humanized BCMA antibody J6M0 which comprises a heavy chain variable region and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 1118 and 1119 of the instant application (Table 26), respectively. Algate teaches the antibody shows good anti-tumor activity, e.g. for MM. As set forth above, an ordinary skilled in the art would have used J6M0 in making BCMA x CD3 bispecific antibody. Based on the teachings of references, an ordinary skilled in the art would recognize that an GSI, such as BMS-708613 would have improved the efficacy of a therapeutic agent bind to BCMA, such as the BCMA x CD3 bispecific antibody such as J6M0, as set forth above.
Claims 42, 84, 87 and 96 are rejected under 35 U.S.C. 103 as being unpatentable over Berenson (Berenson et al., WO 2017/019496 A1, Publication Date: 02-02-2017, of record) and Borges (Borges et al., WO 2012/066058 A1, Publication Date: 05-24-2012, of record), as applied to claims 2, 27, 66, 67, 70, 73, 85 and 92-95 above, and further in view of Moore (Moore et al., US 2014/0322217 A1, Appl. No.: 14/155,248, Publication Date: 10-30-2014, of record).
It is noted, based on the specification: for example, under Kabat, the CDR amino acid residues in the heavy chain variable domain (VH) are numbered 31-35 (HCDRl), 50-65 (HCDR2), and 95-102 (HCDR3); and the CDR amino acid residues in the light chain variable domain (VL) are numbered 24-34 (LCDRl), 50-56 (LCDR2), and 89-97 (LCDR3). Under Chothia the CDR amino acids in the VH are numbered 26-32 (HCDRl), 52-56 (HCDR2), and 95-102 (HCDR3); and the amino acid residues in VL are numbered 26-32 (LCDRl), 50-52 (LCDR2), and 91-96 (LCDR3). By combining the CDR definitions of both Kabat and Chothia, the CDRs consist of amino acid residues 26-35 (HCDRl), 50-65 (HCDR2), and 95-102 (HCDR3) in human VH and amino acid residues 24-34 (LCDRl), 50-56 (LCDR2), and 89-97 (LCDR3) in human VL, See [0393]. Generally, unless specifically indicated, the anti-BCMA antibodies can include any combination of one or more Kabat CDRs, Chothia CDRs, combination of Kabat and Chothia CDRs, and/or IMGT CDRs, See [0395].
Based on the Chothia definition, HCDR1-HCDR2-HCDR3 and LCDR1-LCDR2-LCDR3 of scFv CD3 antibody (SEQ ID NO: 1122) are identified as: GFTFNTY-RSKYNNYA-HGNFGNSYVSWFAY and STGAVTTSNY-GTN-WYSNLW, respectively.
Berenson and Borges teach as set forth above, However, claims 42 and 84 recites specific sequences of anti-CD3 antibody, which are not taught by the references.
Moore teaches a scFv CD3 antibody (SEQ ID NO:2, XENP11874), which is 92.8% identical to SEQ ID NO: 1122 of the instant claims and have a heavy chain variable region comprising a heavy chain CDRs 1-3 and a light chain CDRs 1-3 identical to SEQ ID NO: 1122 (in Table 1). The alignment is shown below and the CDR regions are boxed:
PNG
media_image17.png
617
568
media_image17.png
Greyscale
Moore teaches multispecific antibodies that simultaneously co-engage antigens and methods of using the antibodies for therapeutic purpose ([0003])
Moore teaches using anti-CD3 scFv (XENP11874) to make bispecific antibodies (Figs. 1 and 9).
Moore teaches that the bispecific antibody with XENP11874 anti-CD3 arm has bioactivity and potently recruit T cells for B cell depletion (Fig. 10, [0302]).
Moore teaches that the antibody can be used for treatment of multiple myeloma ([0269]).
As set forth above, Berenson and Borges combined teach the method of claim 2. It would have been prima facie obvious to one of ordinarily skilled in the art at the time the invention was filed to combine the teachings of Berenson and Borges to use a combination of a multispecific antibody (e.g. anti-BCMA/CD3) and a small molecule GSI (e.g. BMS-708163) to treat MM, and further to use the specific anti-CD3 scFv (XENP11874) as the anti-CD3 antibody arm because XENP11874 has been well tested can recruit T cells and has potent therapeutic activity, as taught by Moore, thus, would be a good candidate for multispecific antibody targeting CD3. From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed multispecific antibody. The motivation would have been to develop a better therapeutic bispecific antibody and to expand the application of XENP11874.
Regarding claim 87, Moore teaches that amino acid changes within the Fc region can be added to facilitate increased ADCC or CDC ([00228]).
Regarding claim 96, Moore teaches that XENP11874 comprises a VL of SEQ ID NO: 8 (Fig. 7A and Fig. 8).
As shown below, SEQ ID NO: 8 is 95.4% identical to the VL (amino acid positions 146-254) of SEQ ID NO: 1122:
Best Local Similarity 95.4%;
Matches 104; Conservative 1; Mismatches 4; Indels 0; Gaps 0;
Qy 146 QAVVTQEPSLTVSPGGTVTLTCRSSTGAVTTSNYANWVQQKPGQAPRGLIGGTNKRAPWT 205
|||||||||||||||||||||| |||||||||||||||||||||||||||||||||||
Db 1 QAVVTQEPSLTVSPGGTVTLTCGSSTGAVTTSNYANWVQQKPGQAPRGLIGGTNKRAPGV 60
Qy 206 PARFSGSLLGDKAALTLSGAQPEDEAEYFCALWYSNLWVFGGGTKLTVL 254
|||||||||| |||||||||||||||||:||||||||||||||||||||
Db 61 PARFSGSLLGGKAALTLSGAQPEDEAEYYCALWYSNLWVFGGGTKLTVL 109
Response to Arguments
For the rejection of claims 42, 84, 87 and 96 under 35 U.S.C. 103, Applicant argues:
PNG
media_image18.png
104
645
media_image18.png
Greyscale
PNG
media_image19.png
189
634
media_image19.png
Greyscale
Applicant’s arguments have been fully considered but they are not persuasive. As set forth above, Borges and Bereson teach method of claim 2, i.e. treating MM with a combination of small molecule GSI and BCMA x CD3 bispecific antibody. Moore teaches the specific anti-CD3 scFV (XENP11874) which has the same HCDRs 1-3 and LCDRs 1-3 of the instant claimed anti-CD3 antibody (SEQ ID NO: 1122 in Table 26) and has been well tested and has potent therapeutic activity and can be used for treatment of multiple myeloma. Thus, XENP11874 would be a good candidate for bispecific antibody targeting CD3. In addition, XENP11874 comprises a VL which is 95.4% identical to the VL of SEQ ID NO: 1122. Thus, XENP11874 teach the VL of claim 96.
Thus, Applicant’s arguments are not found persuasive for the reasons set forth above and the rejection is maintained for the reasons of record.
Claims 2, 27, 70, 73, 85, 87 and 93-95 is/are alternatively rejected under 35 U.S.C. 103 as being unpatentable over Moore et al. (WO 2016/105450 A2, Publication Date: 2015-06-30, hereinafter “Moore-2”, of record), in view of Borges (Borges et al., WO 2012/066058 A1, Publication Date: 05-24-2012, of record) and Berenson (Berenson et al., WO 2017/019496 A1, Publication Date: 02-02-2017, of record).
These claims are drawn to a method of treating a subject having a BCMA associated disease comprising administering to the subject a combination of a multispecific antibody molecule that binds to BCMA, CD3, and a third antigen and a small molecule gamma secretase inhibitor (GSI), i.e. BMS-708163 (the elected species), and administration regimens.
Moore-2 teaches a tri-specific antibody which binds to CD3, CD8 and a third antigen targeting tumor. See claim 1, Figs. 3A-3E, 4A-4F, 5A-5F, 6-8.
Moore-2 teaches the third antigen targeting tumor, e.g. BCMA. See [00286].
Moore-2 teaches that treating a patient in need thereof comprising administering the trispecific antibody (claims 59).
Moore-2 teaches that the tri-specific antibody may be used to treat a related malignant condition, e.g. multiple myeloma. See [00308].
Moore-2 teaches as set forth above. However, Moore-2 does not teach a gamma secretase inhibitor (GSI) in combination with the multispecific antibody.
Borges and Berenson teach as set forth above. In particularly, Borges teaches that BCMA is highly expressed in multiple myeloma; Berenson teaches gamma secretase inhibitors that can decrease, prevent or block BCMA cleavage and its shedding; Berenson teaches that using of gamma secretase inhibitors (e.g. BMS-708163) may improves the efficacy of a therapeutic agent that binds to BCMA and/or binds to cells that express BCMA.
It would have been prima facie obvious at the time the invention was filed to combine the treatment of MM, with the trispecific antibody anti-CD3/CD8/BMCA, as taught by Moore-2, with BMS-708163 (a GSI) taught by Berenson, because Berenson teaches that using a GSI can improve efficacy of a BCMA-targeted therapy for MM and Borges teaches that BCMA is highly expressed in multiple myeloma. One of skill in the art would have been motivated to find the optimal treatment for cancers like MM, by combining the antibody treatment with additional GSI. Given that that claimed compounds, e.g. BMS-708163 and the trispecific antibodies were known in the art for cancer treatment, one of skill in the art would have had a reasonable expectation of success of using the compounds in combination.
Regarding claims 70, and 93-95, Berenson further teaches that the specific amount/dosage regimen will vary depending on the weight, gender, age and health of the individual; the formulation, the biochemical nature, bioactivity, bioavailability and the side effects of the agents and the number and identity of the agents in the complete therapeutic regimen. Therefore one of skill in the art could modify the administration regimen for the claimed combination depending upon the age and the size of a subject to be administered, target disease, conditions, route of administration, and the like to reach the specific regimens as claimed.
Response to Arguments
For the rejection of claims 2, 27, 70, 73, 85, 87 and 93-95 under 35 U.S.C. 103, Applicant argues:
PNG
media_image20.png
103
641
media_image20.png
Greyscale
PNG
media_image21.png
326
651
media_image21.png
Greyscale
PNG
media_image22.png
215
650
media_image22.png
Greyscale
Applicant’s arguments have been fully considered but they are not persuasive. As set forth above, Moore-2, Borges, and Berenson teach and suggest the method of claim 2, i.e. treating MM with a combination of GSI and BCMA x CD3 x CD8 tri-specific antibody. Moore teaches that XENP11874 anti-CD3 arm has bioactivity and potently recruit T cells for B cell depletion and can be used in MM treatment. As set forth above, one of ordinary skilled in the art would have used anti-CD3 scFv (XENP11874) as the anti-CD3 antibody arm because XENP11874 has been well tested and has potent therapeutic activity, as taught by Moore, thus, would be a good candidate for multispecific antibody targeting CD3. From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed multispecific antibody.
Furthermore, Berenson explicitly teaches that using of gamma secretase inhibitors may improves the efficacy of a therapeutic agent that binds to BCMA and/or binds to cells that express BCMA. Berenson teaches exemplary gamma secretase inhibitors, including BMS-708163 (claim 14). Berenson teaches therapeutic agents that bind to BCMA include therapeutic anti-BCMA antibodies, anti-BCMA antibody-drug conjugates (page 10, para. 2, claim 3). Thus, the combination of a BCMA/CD3/CD8 multispecific antibody and a small molecule GSI would have been expected to have an enhanced therapeutic effect.
Regarding surprising benefits of the claimed combination, “Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980) (Claims were directed to a process for removing corrosion at "elevated temperatures" using a certain ion exchange resin (with the exception of claim 8 which recited a temperature in excess of 100C). Appellant demonstrated unexpected results via comparative tests with the prior art ion exchange resin at 110C and 130C. The court affirmed the rejection of claims 1-7 and 9-10 because the term "elevated temperatures" encompassed temperatures as low as 60C where the prior art ion exchange resin was known to perform well. The rejection of claim 8, directed to a temperature in excess of 100C, was reversed.). See also In re Peterson, 315 F.3d 1325, 1329-31, 65 USPQ2d 1379, 1382-85 (Fed. Cir. 2003) (data showing improved alloy strength with the addition of 2% rhenium did not evidence unexpected results for the entire claimed range of about 1-3% rhenium); In re Grasselli, 713 F.2d 731, 741, 218 USPQ 769, 777 (Fed. Cir. 1983) (Claims were directed to certain catalysts containing an alkali metal. Evidence presented to rebut an obviousness rejection compared catalysts containing sodium with the prior art. The court held this evidence insufficient to rebut the prima facie case because experiments limited to sodium were not commensurate in scope with the claims.)”. MPEP 716.02
However, the claims are not limited to the bispecific antibodies disclosed in the specification and the post-filing references. The claims encompass a broad genus of multispecific antibodies, including anti-BCMA/anti-CD3 bi-specific antibodies and variants (as evidenced by claims 83, 84, 96), or tri-specific antibodies binging to an additional antigen . For combination treatment (BCMA x CD3 bispecific antibody + small molecule GSI) for MM, in vivo, only one BCMA x CD3 bispecific antibody (FP31), combined with only three small molecule GSIs (LY-450139, PF-5212362, PF-3084014), for only one BCMA+ cell line (KMS11). See Example 3, Table 5. Taken account in vitro results (Example 1), only five BCMA x CD3 bispecific antibodies (ER26, BQ76, BU76, EE11, and EM90) combined with only one small molecule GSI (DAPT) have been tested and showed enhanced results. Thus, the example is not commensurate in scope with the claimed invention and is not probative on the non-obviousness of the claimed invention.
Furthermore, Berenson teaches that using of gamma secretase inhibitors may improves the efficacy of a therapeutic agent that binds to BCMA and/or binds to cells that express BCMA. Therapeutic agents that bind to BCMA include therapeutic anti-BCMA antibodies, anti-BCMA antibody-drug conjugates (page 10, para. 2, claim 3). Thus, the combination of a BCMA/CD3 bispecific antibody and a small molecule GSI would have been expected to have an enhanced therapeutic effect.
Thus, Applicant’s arguments are not found persuasive for the reasons set forth above and the rejection is maintained for the reasons of record.
Claims 83, and 87-91 is/are alternatively rejected under 35 U.S.C. 103 as being unpatentable over Moore et al. (WO 2016/105450 A2, Publication Date: 2015-06-30, hereinafter “Moore-2”, of record), Borges (Borges et al., WO 2012/066058 A1, Publication Date: 05-24-2012, of record), and Berenson (Berenson et al., WO 2017/019496 A1, Publication Date: 02-02-2017, of record), as applied to claims 2, 27, 70, 73, 85, 87 and 93-95 above, and further in view of Algate (Algate et al., US 2013/0280280 A1, Appl. No.: 13/795,314, Publication Date: 10-24-2013, of record).
Moore-2, Borges and Berenson teach as set forth above, However, Moore-2, Borges, and Berenson do not teach the anti-BCMA antibody comprise a heavy chain variable region and a light chain variable region comprising the amino acid sequence of SEQ ID NO:1118 and 1119, respectively (J6M0, BCMA antibody, Table 1).
Algate teaches as set forth above.
As set forth above, Moore-2, Borges and Berenson combined teach the method of claim 2. It would have been prima facie obvious to one of ordinarily skilled in the art at the time the invention was filed to combine the teachings of Moore-2, Borges and Berenson and Algate to use a combination of a multispecific antibody (e.g. anti-BCMA/CD3/CD8 antibody) and a small molecule GSI (e.g. BMS-708163) to treat MM, taught by Moore-2, Borges and Berenson, and further to use J6M0 as the anti-BCMA antibody arm because J6M0 has been well tested and has good binding activity and anti-tumor (MM) activity, as taught by Algate, thus, would be a good candidate for therapeutic purpose. From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed multispecific antibody. The motivation would have been to develop a better therapeutic bispecific antibody and to expand the application of J6M0.
Regarding claims 87 and 88, Algate teaches that Fc region is important for ADCC and CDC activity of an antibody ([0190]), various modifications to heavy chain constant region of antibody may be carried out depending on the desired effector property ([0192]). Algate teaches afucosylated form of J6M0 (Potelligent) ([0288]). And the afucosylated J6M0 has enhanced ADCC potency ([0318], and Fig. 17).
Regarding claims 89-91, Algate teaches antibody-drug conjugates comprising an antibody conjugated to one or more cytotoxic agents, such as a chemotherapeutic agent, a drug, a growth inhibitory agent, a toxin (e.g., a protein toxin, an enzymatically active toxin), or a radioactive isotope ([0207]). Algate teaches an antibody-drug conjugate with the structure of antibody-linker-drug ([0209])., e.g. antibodies linked by an MC linker with auristatins such as MMAE and MMAF ([0211]). Algate teaches a protease-resistant (non-cleavable) maleimidocaproxyl linker for MMAF, and a dipeptide linker for MMAE ([0214]).
Response to Arguments
For the rejection of claims 83, and 87-91 under 35 U.S.C. 103, Applicant argues:
PNG
media_image23.png
322
652
media_image23.png
Greyscale
Applicant’s arguments have been fully considered but they are not persuasive. As set forth above, Moore-2, Borges, and Berenson teach and suggest the method of claim 2, i.e. treating MM with a combination of GSI and BCMA x CD3 x CD8 tri-specific antibody. Algate teaches humanized BCMA antibody: J6M0, which shows good efficacy inhibiting MM tumor cell growth in xenograft model. As set forth above, one of ordinary skilled in the art would have used J6M0 as the anti-BCMA antibody arm because J6M0 has been well tested and has good binding activity and anti-tumor (MM) activity, as taught by Algate, thus, would be a good candidate for therapeutic purpose. From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed multispecific antibody.
Furthermore, Berenson teaches that using of gamma secretase inhibitors may improves the efficacy of a therapeutic agent that binds to BCMA and/or binds to cells that express BCMA. Therapeutic agents that bind to BCMA include therapeutic anti-BCMA antibodies, anti-BCMA antibody-drug conjugates (page 10, para. 2, claim 3). Thus, the combination of a BCMA/CD3/CD8 multispecific antibody and a small molecule GSI would have been expected to have an enhanced therapeutic effect.
Thus, Applicant’s arguments are not found persuasive for the reasons set forth above and the rejection is maintained for the reasons of record.
Claims 42, 84 and 96 is/are alternatively rejected under 35 U.S.C. 103 as being unpatentable over Moore et al. (WO 2016/105450 A2, Publication Date: 2015-06-30, hereinafter “Moore-2”, of record), Borges (Borges et al., WO 2012/066058 A1, Publication Date: 05-24-2012), and Berenson (Berenson et al., WO 2017/019496 A1, Publication Date: 02-02-2017, of record), as applied to claims 2, 27, 70, 73, 85, 87 and 93-95 above, and further in view of Moore (Moore et al., US 2014/0322217 A1, Appl. No.: 14/155,248, Publication Date: 10-30-2014).
Moore-2, Borges and Berenson teach as set forth above, However, claims 42 84, and 96 recite specific sequences of anti-CD3 antibody, which are not taught by the references.
Moore teaches the sequence of XENP11874 which reads claims 42, 84 and 96, as set forth above.
Thus, Moore-2, Borges and Berenson combined teach the method of claim 2 as set forth above. It would have been prima facie obvious to one of ordinarily skilled in the art at the time the invention was filed to combine the teachings of Moore-2, Borges and Berenson to use a combination of a multispecific antibody (e.g. anti-BCMA/CD3/CD8) and a small molecule GSI (e.g. BMS-708163) to treat MM, taught by Moore-2, Borges and Berenson, and further to use the specific anti-CD3 scFv (XENP11874) as the anti-CD3 antibody arm because XENP11874 has been well tested, can recruit T cells and has potent therapeutic activity, as taught by Moore, thus, would be a good candidate for the multispecific antibody targeting CD3. From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed multispecific antibody. The motivation would have been to develop a better therapeutic bispecific antibody and to expand the application of XENP11874.
Response to Arguments
For the rejection of claims 42 and 84 under 35 U.S.C. 103, Applicant argues:
PNG
media_image24.png
325
638
media_image24.png
Greyscale
Applicant’s arguments have been fully considered but they are not persuasive. As set forth above, Moore-2, Borges, and Berenson teach and suggest the method of claim 2, i.e. treating MM with a combination of GSI and BCMA x CD3 x CD8 tri-specific antibody. Moore teaches that XENP11874 anti-CD3 arm has bioactivity and potently recruit T cells for B cell depletion and can be used in MM treatment. As set forth above, one of ordinary skilled in the art would have used anti-CD3 scFv (XENP11874) as the anti-CD3 antibody arm because XENP11874 has been well tested and has potent therapeutic activity, as taught by Moore, thus, would be a good candidate for multispecific antibody targeting CD3. From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed multispecific antibody.
Furthermore, Berenson teaches that using of gamma secretase inhibitors may improves the efficacy of a therapeutic agent that binds to BCMA and/or binds to cells that express BCMA. Therapeutic agents that bind to BCMA include therapeutic anti-BCMA antibodies, anti-BCMA antibody-drug conjugates (page 10, para. 2, claim 3). Thus, the combination of a BCMA/CD3/CD8 multispecific antibody and a small molecule GSI would have been expected to have an enhanced therapeutic effect.
Thus, Applicant’s arguments are not found persuasive for the reasons set forth above and the rejection is maintained for the reasons of record.
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-fi