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Patent Application 17264386 - DOSING REGIMEN FOR BCMA-CD3 BISPECIFIC ANTIBODIES - Rejection

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Patent Application 17264386 - DOSING REGIMEN FOR BCMA-CD3 BISPECIFIC ANTIBODIES

Title: DOSING REGIMEN FOR BCMA-CD3 BISPECIFIC ANTIBODIES

Application Information

  • Invention Title: DOSING REGIMEN FOR BCMA-CD3 BISPECIFIC ANTIBODIES
  • Application Number: 17264386
  • Submission Date: 2025-05-15T00:00:00.000Z
  • Effective Filing Date: 2021-01-29T00:00:00.000Z
  • Filing Date: 2021-01-29T00:00:00.000Z
  • National Class: 424
  • National Sub-Class: 136100
  • Examiner Employee Number: 98487
  • Art Unit: 1644
  • Tech Center: 1600

Rejection Summary

  • 102 Rejections: 1
  • 103 Rejections: 3

Cited Patents

No patents were cited in this rejection.

Office Action Text


    Detailed Action
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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 26 February 2025 has been entered.
 
Status of the claims
In Response to Non-Final dated 20 June 2024 (referred to herein as Remarks) claims 27-34 were added. Claims 1-15, 17-19, 21, 22, 24-26, and 28-35 are currently pending and under consideration.

Withdrawn Rejections
	In view of Applicant canceling claim 27 the 35 U.S.C. 112(d) rejection of claim 27 is hereby withdrawn.
	 
New Claim Rejections
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –

(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.


(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.

Claims 1, 4, 7-15, 17-19, 21, 22, 24-26, 28, 31, and 33-34 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Kufer (U.S. Patent 9,340,621, as cited on the PTO-892 dated 23 February 2024).
Kufer discloses the treatment of human tumor xenograft, NCI-H929, female NOD/SCID mice (i.e., multiple myeloma, a BCMA-positive neoplasm) with bispecific BCMA-98xCD3 or BCMA-34xCD3 by intravenous bolus (see instant claims 9 and 31) injection for 17 consecutive days (see Kufer col. 63-64, example 19; see instant claim 1). The animals were injected with 0.5 mg/kg/day which is 12.8 µg per day (see instant claim 1) given the average weight of female NOD mice at 15 weeks is 25.6±1.7g as evidenced by Jackson Laboratory (see Jackson Laboratory, weight table). It is noted, the elected species of BCMA binding domain (Seq ID Nos: 171-179) and CD3 binding domain (Seq ID Nos: 633-639, 641, and 642) recited in instant claims 12-14 part 18, 15, 17 part 18-19, 21, 22, and 24-26 corresponds to Kufer BCMA-34xCD3 (see Seq ID Nos: 337-340; see Non-Final dated 23 February 2024). Furthermore, Kufer BCMA-34xCD3 has a first and second domain in the format of a scFv and is connected via a glycine/serine linker (see Kufer Seq ID No. 340 aa 244-249, claim 6; see instant claims 11, 33, and 34). Animals that were administered BCMA-34xCD3 had significantly reduced tumor volumes starting on day 16 compared to controls (see Kufer figure 16 group 4). Kufer teaches a method of treating a BCMA positive neoplasm (i.e., MM) comprising administering a dose of 6.5-650µg/day (i.e., 12.8µg/day) of BCMA-34xCD3 (i.e., identical to instant Seq ID No: 171-179, 633-639, 641, and 642) intravenously for 17 consecutive days. Claim 1 is drawn to two cycles of administration wherein one cycle is at least 7 consecutive days. The specification defines ā€œone cycleā€ as at least seven consecutive days (see specification pg. 10, 4th para). Therefore, Kufer anticipates administration of the BCMAxCD3 bispecific construct in two cycles (i.e., back to back) of at least seven consecutive days. This is pertinent to claims 1, 4, 7-15, 17-19, 21, 22, 24-26, 28, 31, and 33-34. 

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 1-15, 17-19, 21, 22, 24-26, 28-33, and 35 are rejected under 35 U.S.C. 103 as being unpatentable over Topp (see Topp et al. Phase I dose-escalation study of BI836909, an anti-BCMA bi-specific T-cell engager, in relapsed and/or refractory multiple myeloma (RRMM). Journal of Clinical Oncology 2016, Vol. 34, No. 15), Hipp (see Hipp et al. BI836909, a novel bispecific T cell engager for the treatment of multiple myeloma induces highly specific and efficacious lysis of multiple myeloma cells in vitro and shows anti-tumor activity in vivo. Blood (2015) 126 (23):2999)and Hipp2 (see Hipp et al. A novel BCMA/CD3 bispecific T-cell engager for the treatment of multiple myeloma induces selective lysis in vitro and in vivo. Leukemia (2017) 31, 1743-1751) and Choi (see Choi et al. Reference values of hematology, biochemistry, and blood type in cynolmolgus monkeys from Cambodia origin. Lab Anim Res (2016), 32(1), 46-55).
Topp teaches administering a BCMAxCD3 (i.e., BI836909) antibody with continuous IV infusions for 4 weeks in 6 week cycles with dose escalation proceeding based on clinical findings during the first 2-4 weeks of cycle 1 allowing for up to 5 cycles of treatment and 10 cycles with ongoing clinical benefit in patients (i.e., human) with RRMM (see Topp Methods). In addition, Topp teaches the first four dose cohorts were safe and well tolerated in 9 patients (see Topp last 3 lines). However, Topp does not teach administering the BCMAxCD3 antibody with the claimed dose of 6.5µg/day-650 µg/day.
Hipp discloses the BCMAxCD3 bispecific T cell engager, BI836909, has comparable cross-reactive binding to both BCMA and CD3 epsilon of human and macaque origin with picomolar and low nanomolar affinities respectively (see Hipp 8th para). The toxicity studies in cynomolgus monkeys demonstrated doses of 135µg/kg/day via continuous intravenous infusion up to 405µg/kg/day via daily subcutaneous injection for up to 28 days were both safe and effective(see Hipp 8th para). In addition, ā€œthese pre-clinical data demonstrate that BI836909 is highly potent, efficacious and BCMA-selective T cell redirecting agent and support clinical testing of BI836909 in multiple myeloma patientsā€ (see Hipp 9th para). 
Therefore, a person of ordinary skill in the art would administer the BCMAxCD3 bispecific T cell engager, BI836909, in multiple cycles comprising periods of administration and periods without administration to patients with RRMM as taught by Topp at up to 135µg/kg/day via continuous intravenous infusion as taught by Hipp given Hipp teaches up to 135µg/kg/day  via continuous intravenous infusion for up to 28 days was safe in cynomolgus monkeys. It is noted 135µg/kg/day is about 545.4 µg/day in female cynomolgus monkeys (average wt=4.04kg) as evidenced by Choi (see Choi pg. 49, 1st col.) This is pertinent to claims 1-15, 17-19, 21, 22, 24-32, and 35.
Regarding claim 33, given both Hipp and Topp teach the BCMAxCD3 antibody construct is a BiTEĀ® connected via a peptide linker as evidenced by Hipp2 (see Hipp2 Sup Figure 1a).
Regarding claim 35 Hipp2, discloses BI836909 treatment increased survival of in L-363 xenograft models (i.e., leukemia) at doses as low as 0.005mg/kg/day and ā€œthe preclinical data presented in this manuscript show that BI 836909 selectively and potently redirects T cells to MM cells, and supports clinical testing in MM patientsā€ (see Hipp2 para spanning pgs. 1747-1748, figure 6, pg. 1750, 1st col. 4th para). Therefore, a person of ordinary skill in the art would administer BI836909 to human patients at doses as low as 0.005mg/kg/day given this dose was shown to effectively treat (i.e., increase overall survival) leukemia in preclinical models. 

Claim 34 is rejected under 35 U.S.C. 103 as being unpatentable over Topp, Hipp, and in further view of Kufer as evidenced by Hipp2.
The reasons claims 1, 11, and 33 are rejected are set forth above.
The teachings of Topp, Hipp, and Kufer as evidenced by Hipp2 are set forth above. 
Therefore a person of ordinary skill in the art would substitute the peptide linker of BI836909 with the glycine/serine linker taught by Kufer given the success disclosed by Kufer using a BCMAxCD3 BiTE linked via a glycine/serine linker in reducing tumor volumes in a method of treating MM. 

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 ā€œright to excludeā€ 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.

Claims 1-15, 17-19, 21, 22, and 24-35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 15 of U.S. Patent No. 9,598,500 B2 published 21 March 2017 (referred herein as ā€˜500 patent), Topp, Hipp, and Kufer as evidenced by Hipp2.
Claims 1-15, 17-19, 21, 22, and 24-35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 15 of U.S. Patent No. 9,340,621 B2 published 17 May 2016 (referred herein as ā€˜621 patent), Topp, Hipp, and Kufer as evidenced by Hipp2.
Claims 1-15, 17-19, 21, 22, and 24-35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 13 of U.S. Patent No. 9,150,664 B2 published 6 October 2015 (referred herein as ā€˜664 patent), Topp, Hipp, and Kufer as evidenced by Hipp2.
Claims 1-15, 17-19, 21, 22, and 24-35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 12 of U.S. Patent No. 11,419,933 B2 published 23 August 2022 (referred herein as ā€˜933 patent), Topp, Hipp, and Kufer as evidenced by Hipp2.
Claims 1-15, 17-19, 21, 22, and 24-35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 11 of U.S. Patent No. 10,752,694 B2 published 25 August 2020 (referred herein as ā€˜694 patent), Topp, Hipp, and Kufer as evidenced by Hipp2.
Claims 1-15, 17-19, 21, 22, and 24-35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 9, 10, and 17 of U.S. Patent No. 10,301,391 B2 published 28 May 2019 (referred herein as ā€˜391 patent), Topp, Hipp, and Kufer as evidenced by Hipp2.
Claims 1-15, 17-19, 21, 22, and 24-35 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 10, 18, 26, 29, 30, 31, and 40 of copending Application No. 18/026,505 (referred herein as ā€˜505 application) Topp, Hipp, and Kufer as evidenced by Hipp2.
Claims 1-15, 17-19, 21, 22, and 24-35 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, and 31-33 of copending Application No. 16/482,603 (referred herein as ā€˜603 application) Topp, Hipp, and Kufer as evidenced by Hipp2. 
The teachings of Topp, Hipp, Kufer, and as evidenced by Hipp2 are set forth above. 
Therefore, a person of ordinary skill in the art would substitute the nucleic acids encoding (i.e., ā€˜500 patent), amino acids sequences (i.e., ā€˜621 patent, ā€˜644 patent, ā€˜694 patent, ā€˜391 patent), a pharmaceutical composition (i.e., ā€˜933 patent, co-pending ā€˜603), or a method for administering to a patient with cancer (i.e., co-pending ā€˜505) comprising a BCMAxCD3 bispecific T-cell engager claimed in the U.S. Patents and co-pending applications for BI836909 in a method of treating RRMM comprising administering 135µg/kg/day in continuous intravenous in up to at least 5 cycles of 4 weeks of administration and 2 weeks with no administration.

Maintained Rejections
Claim Rejections - 35 USC § 103
Claims 1-15, 17-19, 21, 22, and 24-34 are rejected under 35 U.S.C. 103 as being unpatentable over U.S. Patent No. 9,340,621 B2 (referred to herein as Kufer, as cited on the PTO-892 dated 23 February 2024) and Yuraszeck (as cited on the PTO-892 dated 23 February 2024).
Kufer discloses the treatment of human tumor xenograft, NCI-H929, female NOD/SCID mice (i.e., multiple myeloma, a BCMA-positive neoplasm) with bispecific BCMA-98xCD3 or BCMA-34xCD3 by intravenous bolus (see instant claims 9 and 31) injection for 17 consecutive days (see Kufer col. 63-64, example 19; see instant claim 1). The animals were injected with 0.5 mg/kg/day which is 12.8 µg per day (see instant claim 1) given the average weight of female NOD mice at 15 weeks is 25.6±1.7 g as evidenced by Jackson Laboratory (see Jackson Laboratory, weight table). It is noted, the elected species of BCMA binding domain (Seq ID Nos: 171-179) and CD3 binding domain (Seq ID Nos: 633-639, 641, and 642) recited in instant claims 12-14 part 18, 15, 17 part 18-19, 21, 22, and 24-26 corresponds to Kufer BCMA-34xCD3 (see Seq ID Nos: 337-340; see Non-Final dated 23 February 2024). Furthermore, Kufer BCMA-34xCD3 has a first and second domain in the format of a scFv and is connected via a glycine/serine linker (see Kufer Seq ID No. 340 aa 244-249, claim 6; see instant claims 11, 33, and 34). Animals that were administered BCMA-34xCD3 had significantly reduced tumor volumes starting on day 16 compared to controls (see Kufer figure 16 group 4). Kufer teaches a method of treating a BCMA positive neoplasm (i.e., MM) comprising administering a dose of 6.5-650µg/day (i.e., 12.8µg/day) of BCMA-34xCD3 (i.e., identical to instant Seq ID No: 171-179, 633-639, 641, and 642) intravenously for 17 consecutive days. Kufer does not teach a continuous intravenous administration or a cyclic regimen of antibody administration.
Yuraszeck discloses the preclinical properties of blinatumomab, a CD19 and CD3 BiTE® (bispecific T-cell engagers), have been well characterized and blinatumomab is considered representative of the general characteristics of BiTE® (see Yuraszeck pg. 636, 2nd col. 2nd paragraph). Yuraszeck discloses blinatumomab has been approved to treating acute lymphoblastic leukemia (ALL), in a 4 week on and 2 week off schedule and step wise dosing in the first cycle starting with 9 µg/day continuous intravenous injection (cIV) for 7 days then 28 µg/day cIV for three weeks followed by 28 µg/day cIV for 4 weeks for subsequent cycles (see Yuraszeck pg. 641, 2nd col. 2nd paragraph, Table 2). Furthermore, six out of seven listed clinical trials for blinatumomab had flat dosing at various doses with 4 weeks on and 2 weeks off across repeated cycles with positive outcomes (see Yuraszeck Table 2). Yuraszeck teaches flat dosing has practical advantages over body surface area (BSA) based dosing such as better compliance and reduced risks of medical errors (see Yuraszeck pg. 639, 1st col. 2nd paragraph). It is noted that step dosing during the first cycle was more advantageous over flat dosing in regards to mitigating adverse events (see Yuraszeck pg. 639, 1st col. 2nd paragraph). Moreover, pretreatment with glucocorticoids could blunt the increase in cytokine levels with minimal impact on proliferation of killing of ALL cells, and thus are coadministered with other BiTE® constructs (see Yuraszeck pg. 637, 2nd col. 1st paragraph). Yuraszeck also discloses a similar BiTE®, AMG 420, directed to BCMA and CD3 being developed for myeloid and plasma cell antigens (see Yuraszeck pg. 637, 1st col. 2nd paragraph, Table 1). 
Therefore, a person of ordinary skill in the art would have combined the treatment of MM with a dose of 12.8µg/day as taught by Kufer with repeated cycles comprising periods of administration with periods without as taught by Yuraszeck with a reasonable expectation of success given Yuraszeck teaches this protocol was successful in a well characterized similar BiTE® that is representative of the general characteristics of BiTEs®. Furthermore, Yuraszeck also teaches there are additional advantages of patient compliance and reduced medical errors providing additional motivation for consistent doses across cycles. 
Regarding new claims 27-30, Kufer teaches a skilled person knows how to modify or adapt certain parameters of this study, (e.g., timelines) while still arriving at a meaningful and reproducible result (see Kufer col. 13 last para). Yuraszeck teaches therapy using BiTEĀ® antibodies with cyclic treatment comprising periods with and without treatment. Specifically, Yuraszeck teaches a six weeks cycle with 4 weeks of administration and 2 weeks without administration; thereby, arriving at the presently claimed invention (i.e., a period with or without administration of 1wk-1month).  
Applicant's Remarks filed 26 February 2025 have been fully considered but they are not persuasive. 
Applicants have argued that Examiner has not met the three prong test for establishing a prima facie case of obviousness (see Response dated 02/26/2025, referred to herein as Remarks, pg. 22 last para). Specifically, Applicant argues there was no motivation to combine Yuraszeck with Kufer because Kufer does not teach continuous administration with periods of time without administration nor the length of time recited in instant claim, while Yuraszeck discloses multiple treatment cycles comprising a period with and without administration and consistent doses across multiple cycles (see Remarks pg. 23, 2nd para). 
First claim 1 is drawn to two cycles of administration wherein one cycle of at least 7 consecutive days (see instant claim 1). The specification defines ā€œone cycleā€ of at least seven consecutive days (see specification pg. 10, 4th para). Therefore, Kufer anticipates administration of the BCMAxCD3 bispecific taught by Kufer administered for 17 days, alternatively 2 back to back cycles (see 35 U.S.C. 102 above). Thus, regarding claim 1 Applicant is arguing limitations (i.e., continuous administration, periods without administration, and consistent doses across multiple cycles) not recited in the instant claims 1, 2, 4, 7, 9-15, 17-19, 21, 22, 24-26, 28, and 31-35. 
Regarding claim 3 and dependent claims 5, 6, 29, and 30 wherein the one cycle comprises a period with and without administration, Applicant reiterates the arguments presented in the Response to Non-final received 20 June 2024 (see Response to Non-final received 06/20/2024, pg. 25, 3rd para). Applicant argues Yuraszeck is directed a different first binding domain (see Remarks pg. 23, 2nd full para). 
First, it is well known in the art that CD19 and BCMA are both expressed in B-cells (see Yuraszeck pg. 635 2nd col. 1st para; see Kufer col. 1, 3rd para). Therefore, both CD19 and BCMA are targets for B-cell neoplasms and both ALL and MM are hematological cancers involving B cells. In addition, Applicants argue that blinatumomab is directed to treatment of a different disease, in a different cell type, with a different construct and therefore there is no motivation to combine treating ALL and not a BCMA positive neoplasm (see Remarks pg. 25, 2nd para). However, as stated in the rejection above Yuraszeck teaches, ā€œThe preclinical properties of blinatumomab, the first and only approved BiTEĀ® antibody construct, have been well characterized and are representative of the general characteristics of BiTEĀ® antibody constructsā€ (see Yuraszeck pg. 636, 2nd col. 1st full para). Therefore, Yuraszeck invites a person of ordinary skill in the art to use the dosing regimen of blinatumomab as guidance for preclinical studies given its properties are well characterized and it is representative of BiTEĀ® antibody constructs. Regarding a reasonable expectation of success, MPEP § 2143.02(I) states conclusive proof of efficacy is not required to show a reasonable expectation of success, the expectation of success need only be reasonable, not absolute (see OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019); Acorda Therapeutics, Inc. v. Roxane Lab., Inc., 903 F.3d 1310, 1333, 128 USPQ2d 1001, 1018 (Fed. Cir. 2018); PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1364 (Fed. Cir. 2007); Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364, 1367–68 (Fed. Cir. 2007)).
In particular, Applicant argues
ā€œa different target cell for a different disease with a different antibody, i.e., a BiTEĀ® targeting BCMA and CD3 would require a dosing regimen different than that of blinatumomab as disclosed by Yuraszeck for targeting CD19 in the treatment of ALL or NHL… Consequently, a person of skill in the art would not have any motivation to combine Yuraszeck with Kufer or to transfer the claimed method because Yuraszeck is drawn to blinatumomab for targeting CD19 on B cells in the treatment of ALL, and Kufer is drawn to a different antibody construct for targeting BCMA on plasma cells in the treatment of plasma cell neoplasms.ā€ (see Remarks pg. 26, 2nd para). 

However, Applicant’s own specification teaches,
ā€œThe first generation of BiTEĀ® antibody constructs (see WO 99/54440 and WO 2005/040220) was brought into the clinic as AMG 103 (blinatumomab, anti- CD19 x anti-CD3) and AMG 110 (solitomab, anti-EpCAM x anti-CD3). Blinatumomab, which is approved for patients with ALL, is administered via continuous intravenous infusion, with a lower initial dose in the first period of administration and a higher dose in the remaining treatment, during the first cycle and in all subsequent cycles. In a comparison of step dosing versus constant (flat) dosing as a means to reach the target dose of blinatumomab, step dosing was found to be more effective at mitigating adverse events. In view of the positive efficacy signal and favorable safety profile, a similar administration scheme has hence been used for solitomab which was also administered with increasing doses in each cycle.ā€ (see specification pg. 2, 3rd para). 

Therefore, Applicant’s specification teaches the administration scheme of blinatumomab can be used to inform the dosing scheme of BiTEĀ® antibodies directed to different targets (i.e., EpCAM) in different cell types (i.e., solid tumors, epithelia and epithelial cells) in different diseases (i.e., gastric, lung, and ovarian cancer) as evidenced by Frankel and Baeuerle (see Frankel and Baeuerle. Targeting T cells to tumor cells using bispecific antibodies. Current Opinion in Chemical Biology 2013, 17:385-392, pg. 387 1st col.-2nd section on solitomab).  
Second, Applicants argue that Yuraszeck teaches that different BiTEsĀ® can behave differently as evidenced by the differential sensitivity of the effector functions to dexamethasone combination treatment (see Remarks pg. 25, 3rd para). However, Yuraszeck actually teaches that it is ā€œnot clear if the differential sensitivity of effector functions to dexamethasone can be generalized across the BiTEĀ® platformā€ (see Yuraszeck pg. 637, 2nd col. 1st para, last sentence). Yuraszeck is suggesting combination therapy specifically with dexamethasone may not be generalizable from one BiTEĀ® to the next. The present claims do not recite combination therapy with dexamethasone nor do they recite combination therapy broadly.  Therefore, Applicant's argument that the reference, Yuraszeck, teaches different BiTEsĀ® can behave differently, is based on a method of treatment with limitations (i.e., combination therapy with dexamethasone) that are not recited in the rejected claim(s). 
Third Applicants argue that Yuraszeck teaches the treatment regimens are determined based upon the totality of pharmacokinetic, pharmacodynamic, safety, and efficacy data for the selected dose and schedule for the patients in the trial and effective dose levels and dosing regimen are different for different diseases (see Remarks pg. 26, 1st para). In support, Applicants argue that Yuraszeck teaches the dosing regimen for NHL is different from that of ALL with the same antibody (see Remarks pg. 26, 1st para). However, a person of ordinary skill in the art would use the dose disclosed in Kufer as that dose is relevant to the specific BCMA34-CD3 antibody that is administered and is both safe and effective in treating MM (see Kufer figure 1 Group 4). The Yuraszeck reference is relied upon for teaching multiple cycles of antibody treatment with periods of administration and periods without administration. Yuraszeck teaches multiple cycles using a fixed dose of blinatumomab which comprise periods of administration and periods without administration. Yuraszeck points to Viardot (see Viardot et al.  as cited on the PTO-892 dated 08/28/2024) for the dosing regimen of diffuse large B-cell lymphoma (DLBCL) (i.e., a NHL) wherein Viardot teaches subjects were administered blinatumomab in ā€œcyclesā€ as defined by the present specification (see Yuraszeck pg. 639, 1st col. 2nd para; see Viardot pg. 1411, 1st col. 6th para). Specifically, ā€œadministered by continuous IV infusion for up to 8 weeks (cycle 1), followed by 4 treatment-free weeks. Patients with CR, partial response (PR), or stable disease could receive 4 weeks of consolidation (cycle 2). The core study included cycle 1 (8 weeks), the 4-week treatment-free interval, cycle 2 (4 weeks)ā€ and also teaches the stepwise cohort were also eligible for a ā€œ2nd cycleā€ if the patient relapsed (see Viardot pg. 1411, 1st col. 6th an 7th para). Thus, while the flat dose of blinatumomab was not effective for NHL step-wise dosing with cycles of treatment was effective. Thus, while the dosing regimen for NHL is different from ALL both regimens comprise the multiple cycles comprising periods with and without administration of the therapy. In addition, see above for discussion in regards to the applicability of the dosing regimen across different diseases.
Fourth, Applicants argue that Kufer discloses various factors to be considered for finding the appropriate dosage without teaching or suggesting any of the claimed dosage features (see Remarks pg. 25, 1st full para). Kufer teaches a ā€œskilled person knows how to modify or adapt certain parameters of this study, such as the number of injected tumor cells, the site of injection, the number of transplanted human T cells, the amount of BCMA/CD3 bispecific binding molecules to be administered, and the timelines, while still arriving at a meaningful and reproducible resultā€ (see Kufer col. 13 last para). Furthermore, Kufer teaches, ā€œThe dosage regimen will be determined by the attending physician and clinical factors. As is well known in the medical arts, dosages for any one patient depend upon many factors, including the patient's size, body surface area, age, the particular compound to be administered, sex, time and route of administration, general health, and other drugs being administered concurrentlyā€ (see Kufer col. 37, 1st para). In the instant case, Kufer has disclosed the sex of the animal, weight, the therapeutically effective amount to be administered, route of administration, the general health of the animal, and no other drugs are being administered in combination (see Kufer col. 63-64 example 19). Kufer also teaches a skilled person knows how to modify or adapt certain parameters (i.e., the timelines) and still arrive at a meaningful and reproducible result. Thus, while Kufer does teach several parameters influence dosing regimens, Kufer also discloses nearly all of those parameters in Example 19. The Remarks also argue that Kufer does not teach or suggest any of the claimed dosage features. In fact, Kufer teaches the identical therapy to be administered (i.e., BCMA34xCD3), a therapeutically effective amount within the instantly claimed range (i.e., 12.8µg/day), therapy over consecutive days (i.e., 17 days), the route of administration (i.e., parenterally or intravenously), the disease to be treated (i.e., MM, a BCMA positive neoplasm), and a constant dose.  
Therefore, a person of ordinary skill in the art would combine and/or adapt the treatment of a BCMA positive neoplasm (i.e., MM), using a dose of 12.8µg/day, intravenous injection over 10+ days (i.e., consecutive days) as taught by Kufer to include multiple cycles comprising periods of administration with periods without administration as taught by Yuraszeck given the cyclic regimen was developed in a well characterized BiTE® with similar properties targeting a similar cell type (i.e., B-cells), and the cyclic regimen is adaptable to different diseases (i.e., ALL and DLBCL) as taught by Yuraszeck. In addition, Kufer teaches a person skilled in the art would know how to modify the timeline of administration to get a meaningful result. 
Fifth, Applicant argues a person of ordinary skill in the art could not have predicted complete responses observed in human patients with doses as low as 6.5µg/day-400µg/day based on xenograft model described by Kufer (see Remarks pg. 26, 1st para). However, these alleged unexpected results are drawn to a particular BCMAxCD3 (i.e., AMG420) in a particular BCMA neoplasm (i.e., MM) while the claims are drawn to genera of BCMAxCD3 bispecific antibodies and BCMA neoplasms. In addition, the claims are not limited to human subjects, the particular doses administered (e.g., 400µg/day), or the number of cycles (i.e., 4 cycles) (see specification pg. 57, 1st full para). Therefore, Applicant is arguing limitations not recited in at least instant claim 1. Furthermore, Kufer discloses administering 12.8 µg per day of BCMA-34xCD3 starting on day 13 resulted in decreased tumor volumes starting one day later (i.e., 99.2%) and 4 days later (i.e., 68.2%) ultimately resulting in 0% tumor volume at 14 days (i.e., day 26) (see Kufer col. 64, 2nd para, Table 12 and Figure 16). Kufer teaches 50% tumor reduction at day 3 of treatment (i.e., 52.3% on day 16) and 0% tumor volumes 14 days after starting treatment (see Kufer col. 64, 2nd para, Table 12 and Figure 16). Thus, Applicant’s allegedly unexpected results is entirely expected. 
The 35 U.S.C. 103 rejection is therefore maintained. 

Maintained Double Patenting

Claims 1-11, 13, 19, 21, 22, 24, and 25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 15 of U.S. Patent No. 9,598,500 B2 published 21 March 2017 (referred herein as ā€˜500 patent) and Yuraszeck.
Claims 1-15, 17-19, 21-22, and 24-26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 15 of U.S. Patent No. 9,340,621 B2 published 17 May 2016 (referred herein as ā€˜621 patent) and Yuraszeck.
Claims 1-11, 13, 19, 21, 22, 24, and 25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 13 of U.S. Patent No. 9,150,664 B2 published 6 October 2015 (referred herein as ā€˜664 patent) and Yuraszeck.
Claims 1-15, 17-19, 21-22, and 24-26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 12 of U.S. Patent No. 11,419,933 B2 published 23 August 2022 (referred herein as ā€˜933 patent) and Yuraszeck.
Claims 1-15, 17-19, 21-22, and 24-26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 11 of U.S. Patent No. 10,752,694 B2 published 25 August 2020 (referred herein as ā€˜694 patent) and Yuraszeck.
Claims 1-13, 15, 19, 21-22, and 24-25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 9, 10, and 17 of U.S. Patent No. 10,301,391 B2 published 28 May 2019 (referred herein as ā€˜391 patent) and Yuraszeck.
Claims 1-15, 17-19, 21-22, and 24-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 10, 18, 26, 29, 30, 31, and 40 of copending Application No. 18/026,505 (referred herein as ā€˜505 application) in view of Yuraszeck and US Patent ā€˜621 (referred herein as Kufer). 
Claims 1-15, 17-19, 21-22, and 24-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, and 31-33 of copending Application No. 16/482,603 (referred herein as ā€˜603 application) in view of Yuraszeck and Kufer. 

Applicant's arguments filed 26 February 2025 have been fully considered but they are not persuasive. 
Applicants argue that for the reasons stated in above in 35 U.S.C. 103 rejection with Kufer and Yuraszeck applies to the rejections for nonstatutory double patenting and therefore ā€œthere was no motivation to combine Yuraszeck with the patents and patent applications asserted by the Officeā€ (see Remarks pg. 29, 1st para). 
For the reasons stated above the nonstatutory double patenting rejections are maintained. 

Conclusion
No claim allowed.
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/H.A.P./               Examiner, Art Unit 1644                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        /AMY E JUEDES/Primary Examiner, Art Unit 1644                                                                                                                                                                                                        


    
        
            
        
            
        
            
        
            
        
            
        
            
        
            
        
            
        
            
        
            
        
            
        
            
        
            
        
            
        
            
        
            
        
            
        
            
        
            
    


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