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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 July 24, 2025 has been entered.
DETAILED ACTION
The amendment filed July 24, 2025 in response to the Office Action of March 24, 2025 is acknowledged and has been entered.
Claims 1, 22 and 24 have been amended.
Claim 28 has been cancelled.
Claim 51 has been added.
Claims 1, 3-5, 8, 13, 16, 17, 19, 20, 22, 24, 29, 31, 38, 50 and 51 are pending.
Claims 38 and 50 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions or species, there being no allowable generic or linking claim.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 1, 3-5, 8, 13, 16, 17, 19, 20, 22, 24, 29, 31 and 51 are currently under consideration as drawn to the elected invention.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on July 24, 2025 has been entered and considered.
MAINTAINED/MODIFIED REJECTIONS
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, 3-5, 8, 13, 16, 17, 19, 20, 22, 29, 31 and 51 are rejected under 35 U.S.C. 103 as being unpatentable over Wright (Wright et al., Clin. Cancer Res., 16(16), 4094-4104, Publication Date: 08/15/2010, cited by IDS of 06/02/2021, of record) in view of Hutchinson (Hutchinson et al., Molecular Immunology 67 (2015): 89-94, Publication Date: 05/08/2015, cited by IDS of 04/13/2023, of record) and Richardson (Richardson et al., J Clin Oncol., 27(34); 5713-5719, Publication Date: 09/28/2009, of record), as evidenced by Spencer (Spencer et al., Blood Cancer Journal, (2019) 9:58, Publication Date: 07/31/2019, of record).
Wright teaches that bortezomib (the elected proteasome inhibitor) has been approved by the USFDA for multiple myeloma (MM) (page 4904, col. 2, para. 1).
Wright teaches that bortezomib through inhibition of the 26S proteasome and subsequent effect on multiple key cellular pathways, has shown increased and/or synergistic activity with several novel targeted agents, indicating its potential to substantially enhance the clinical activity of those novel therapies (page 4904, col. 2, para. 1).
Wright teaches that combinations of bortezomib and novel targeted therapies may act synergistically to increase antitumor activity and overcome specific cellular resistance and/or anti-apoptotic mechanisms (page 4095, col. 1, para. 3).
Wright teaches that various of combinations of bortezomib and other novel agents, including antibodies, have been tested in ongoing clinical trials for MM (Table 1).
Wright teaches that synergistic/enhanced activity have been observed combining bortezomib with elotuzumab (antibody targeted CS1), or with CNTO328 (antibody to IL-6), or mapatumumab (antibody to R1 receptor); or G6.31 (antibody to VEGF), or trastuzumab (antibody to HER2) (page 4100, § Other novel targeted therapies).
Wright teaches that several studies are evaluating bortezomib in combination with immunomodulatory drugs (IMiD), such as thalidomide or lenalidomide. The rationale for these combinations is provided by preclinical studies showing that IMiDs potentiate the proapoptotic effect of bortezomib on MM cells through multiple mechanisms of action involving caspase-8 activation; MM cell sensitization to Fas-mediated apoptosis; downregulation of the caspase-8 inhibitors, cellular inhibitor of apoptosis protein-2 (cIAP-2) and FLICE inhibitory protein (FLIP); and downregulation of NF-κB activity, among other anti-MM effects. The efficacy of combining bortezomib and lenalidomide has been shown in a phase I study in patients with relapsed and/or refractory MM, which reported the combination to be well tolerated and to have promising activity with durable responses. Bortezomib-lenalidomide combinations are subsequently under study in the phase II and III settings (page 4100, col. 2, para. 3).
Wright teaches as set forth above, Wright does not teach bortezomib in combination with an anti-KMA antibody or treat refractory MM.
Hutchinson teaches a chimeric mAb MDX-1097 (Abstract). As evidenced by Spencer, MDX-1097 is also called KappaMab which is used as the exemplary anti-KMA antibody in the instant application. Based on paras. [0054] and [0056] of instant publication US 2022/0031849 A1, KappaMab (MDX-1097) reads on antibodies of claims 1, 5-8 and 10.
Hutchinson teaches that MDX-1097 binds membrane κFLC on MM cells (page 91, col. 2, para. 1).
Hutchinson teaches that MDX-1097 can recruit effector cells and kill target MM cells via ADCC (page 91, col. 2, para. 2).
Hutchinson teaches that in a phase I clinical trial MDX-1097 was well tolerated at all tested doses with no dose limiting toxicities or serious adverse events (page 92, col. 1, para. 1).
Hutchinson teaches that MDX-1097 has a good serum half-life and show some encouraging efficacy signs (page 92, col. 1, para. 1).
Hutchinson teaches that in a phase IIa clinical trial MDX-1097 showed good efficacy. Among 19 patients, one had very good partial response and two had partial responses, three had marginal response based on a reduction of serum κFLC or M-protein. Furthermore, ten patients had stable disease six months after the initial infusion (page 92, col. 1, para. 1).
Hutchinson teaches MDX-1097 in combination with other standard drugs for MM is warranted. Therapeutic oncology mAbs often show synergistic activity when used in combination with chemotherapies (page 92, col. 1, para. 1).
Hutchinson teaches that in vitro testing of MDX-1097 showed that it can recruit effector cells and kill target MM cells via ADCC. This effect is further enhanced in the presence of lenalidomide, a MM therapy, which is well known to enhance effector functions of immune cells as well as increase the efficacy for a number of mAb therapies being tested in the clinic (page 91, col. 2, para. 3).
Richardson teaches that lenalidomide plus bortezomib was well tolerated and showed promising activity with durable responses in patients with relapsed and relapsed/refractory MM, including patients previously treated with lenalidomide, bortezomib, and/or thalidomide (§Abstract-Conclusion).
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to use bortezomib in combination with other targeted anti-tumor agents (such as Elotuzumab) to treat MM as taught by Wright, and substitute antibody with MDX-1097, because 1) MDX-1097 has cytotoxicity to MM; 2) MDX-1097 has been tested in clinical trial and showed promising results; 3) MDX-1097 is well tolerated at all tested doses with no dose limiting toxicities or serious adverse events, as taught by Hutchinson. In addition both bortezomib and MDX-1097 are used for treating MM and good candidates for combination therapy for MM, as suggested by Wright and Hutchinson. Given the teachings of Wright and Hutchinson, one of ordinary skilled in the art would have had a reasonable expectation of success to reach the claimed method. The motivation would have been to develop a better treatment for MM, and to expand applications of MDX-1097 and bortezomib. And to further add lenalidomide in the combination for treating refractory MM to lenalidomide, bortezomib, and/or thalidomide, because lenalidomide may augment the activity of MDX-1097 through the enhancement of effector cell function, as well as by increasing the amount of mκFLC on the surface of MM cells, as taught by Hutchinson (page 91, col. 2, para. 3); lenalidomide may also potentiate the effect of bortezomib on MM cells, as taught by Wright; lenalidomide plus bortezomib are effective to refractory MM to lenalidomide, bortezomib, and/or thalidomide as taught by Richardson (§ Abstract -Conclusion). Given the teaching of Richardson, one of ordinary skilled in the art would have a reasonable expectation that the bortezomib + MDX-1097 + lenalidomide would be effective to bortezomib refractory MM. Because all three components have been well tested in combination setting, as evidenced by the references, one of ordinary skilled in the art would have had a reasonable expectation of success to reach the claimed method. The motivation would have been to develop a more effective treatment for MM refractory to at least one proteasome inhibitor.
Regarding claim 13, Hutchinson teaches MDX-1097 was assess at four doses (0.3, 1, 3 and 10 mg/kg) (page 92, col. 1, para. 1). In a phase IIa trial patients demonstrating stable disease for three months or more, were treated with 10mg/kg dose of MDX-1097 (page 92, col. 1, para. 1).
Regarding claim 16, Wright teaches dosage of bortezomib in various combinations, e.g. 1 mg/m2 in combination with sorafenib (page 4097, col. 1, para. 5), 1.6 mg/m2 in combination with temsirolimus (page 4097, col. 2, para. 1), 1.3 mg/m2 in combination with tipifarnib (page 4099, col. 2, para. 1).
In addition, optimum suitable ranges may be obtained by routine experimentation, absent a showing of criticality or unexpected results. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05(II)(A).
Regarding claim 17, 19, 20, and 51, Hutchinson teaches that in vitro testing of MDX-1097 showed that it can recruit effector cells and kill target MM cells via ADCC. This effect is further enhanced in the presence of lenalidomide, a MM therapy, which is well known to enhance effector functions of immune cells as well as increase the efficacy for a number of mAb therapies being tested in the clinic. However, in the case of MDX-1097, lenalidomide was also found to increase the levels of mκFLC on the cell surface. Therefore lenalidomide may augment the activity of MDX-1097 in two ways; through the enhancement of effector cell function, as well as by increasing the amount of mκFLC on the surface of MM cells (page 91, col. 2, para. 3).
Wright teaches that several studies are evaluating bortezomib in combination with immunomodulatory drugs (IMiD), such as thalidomide or lenalidomide. The rationale for these combinations is provided by preclinical studies showing that IMiDs potentiate the proapoptotic effect of bortezomib on MM cells through multiple mechanisms of action involving caspase-8 activation; MM cell sensitization to Fas-mediated apoptosis; downregulation of the caspase-8 inhibitors, cellular inhibitor of apoptosis protein-2 (cIAP-2) and FLICE inhibitory protein (FLIP); and downregulation of NF-κB activity, among other anti-MM effects. The efficacy of combining bortezomib and lenalidomide has been shown in a phase I study in patients with relapsed and/or refractory MM, which reported the combination to be well tolerated and to have promising activity with durable responses. Bortezomib-lenalidomide combinations are subsequently under study in the phase II and III settings. One of ordinary skill in the art would have a reasonable expectation that the combination of Bortezomib + lenalidomide + MDX-1097 would be effective in treating MM refractory to proteasome inhibitor, such as bortezomib.
Regarding claim 22, simultaneously or sequentially would have been obvious to one of skill in the art because those are the only two possible options for administering drugs in combination, i.e. together or separately. One of skill in the art would have been motivated to administer MDX-1097 and bortezomib simultaneously or sequentially to find the optimal order of administration of MDX-1097 and bortezomib to provide maximum benefit to patients.
Regarding claim 29, Hutchinson teaches many combinations comprising bortezomib have been developed for relapsed and/or refractory MM (Table 1 lists about 15 combinations). Hutchinson further teaches bortezomib and lenalidomide show promising results for relapsed and/or refractory MM in a phase I study (page 4100, col. 2, para. 3). One of ordinary skilled in the art would have had a reasonable expectation that the combination of bortezomib + MDX-1097 + lenalidomide would be effective treating relapsed and/or refractory MM.
Regarding claim 31, Hutchinson teaches that MDX-1097 recognizes both cell surface-associated and soluble kappa FLCs raises concerns that the latter may represent a soluble antigen sink that has the potential to reduce the level of binding of MDX-1097 to target cells. Thus, one of ordinary skill in the art would have expected that MDX-1097 would be better target to MM cells in the patients with low serum kappa FLC (e.g. <250 mg/ml) and be more effective to the patient population. The motivation would have been to identify a suitable MM population for treatment comprising MDX-1097.
Response to Arguments
For the rejection of claims 1, 3-5, 8, 13, 16, 17, 19, 20, 22, 29, 31 and 51 under 35 U.S.C. 103, Applicant mainly argues:
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Applicant’s arguments have been considered, but have not been found persuasive. Applicant argues surprising and unexpected results about KappaMab (i.e. MDX-1097) in decreasing serum cytokine levels in MM patients who are refractory to a proteasome inhibitor (see paragraphs [0155], [0156], Table 9 and Figure 4). However, the amended claims do not recite decreasing serum cytokine levels in MM patients refractory to a proteasome inhibitor. Importantly, the examples of the instant specification do not show any “superior and unexpected” result for treating multiple myeloma refractory to the proteasome inhibitor, such as bortezomib. For instance, all results of Example 2 is based on KappaMab monotherapy. The specification does not show any comparison between KappaMab monotherapy and claimed combination therapy.
In addition, Hutchinson teaches that in vitro testing of MDX-1097 showed that it can recruit effector cells and kill target MM cells via ADCC. This effect is further enhanced in the presence of lenalidomide, a MM therapy, which is well known to enhance effector functions of immune cells as well as increase the efficacy for a number of mAb therapies being tested in the clinic. Richardson teaches that lenalidomide plus bortezomib was well tolerated and showed promising activity with durable responses in patients with relapsed and relapsed/refractory MM (rrMM), including patients previously treated with lenalidomide, bortezomib, and/or thalidomide. As set forth above, one of ordinary skill in the art would have expected that the triple combination would be effective for rrMM and would have reached the claimed invention even without knowing the decreasing serum cytokine levels caused by the antibody.
In addition, contrary to Applicant’s argument, [0155], [0156], Table 9 and Figure 4 only teach that cytokines showed changes in expression with respect to KappaMab dose (Table 9), [0155], [0156], Table 9 and Figure 4 do not teach that the expressions of these cytokines are associated with MM resistance to a proteasome inhibitor. Paragraph [0156] disclose: The dysregulation of the HGF/MET signaling pathway in myeloma correlates with aggressive disease, drug resistance, and increased lytic bone lesions. … While the cytokines described here have a broad range of immune effects, they all play a role in B cell trafficking and potential homing from secondary lymphoid organs to the BME. However, the specification has not established that the increased cytokine levels is the cause for the MM resistance to a proteasome inhibitor, or reducing cytokine levels is sufficient to overcome MM resistance to a proteasome inhibitor.
Applicant further cites Rocci to supports the position that HGF is both a biomarker and a driver of resistance to proteasome inhibitors such as bortezomib. However, Rocci also teaches that although MET (a tyrosine kinase receptor) mRNA expression identified patients with worse outcome enrolled in both trials. No correlation or differences were observed in PFS and OS with regard to HGF (Hepatocyte Growth Factor) mRNA expression (§ MET mRNA expression and response to therapy and § MET and HGF mRNA expression and clinical outcome on pages 844-845). Thus, Rocci does not establish that high serum cytokines (such as HGF) is the cause for resistance to proteasome inhibitors such as bortezomib in MM patients. In addition, Rocci teaches only bortezomib-based treatments. However, the instant claims encompass a broad genus of proteasome inhibitors. No results related to other proteasome inhibitors have been provided.
Applicant further argues:
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Applicant’s arguments have been considered, but have not been found 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, although none of the references teaches reducing cytokines such as HGF by KappaMab, the limitation is not cited in the claims. In addition, as set forth above, one of ordinary skill in the art would be able to reach the claimed method without knowing the specific property of the KappaMab.
Applicant argues that Richardson is not relevant to the claimed therapy. However, as evidenced by the newly added claim 51, the triple combination therapy (bortezomib + MDX-1097 + lenalidomide) would read on the claimed method. Richardson provides motivation to make the triple combination as set forth above.
Furthermore, it would have prima facie been obvious to one of ordinarily skilled in the art to use bortezomib in combination with an antibody to treat MM as taught by Wright, and to substitute the antibody with MDX-1097, because 1) MDX-1097 has cytotoxicity to MM; 2) MDX-1097 has been tested in clinical trial and showed promising results; 3) MDX-1097 is well tolerated at all tested doses with no dose limiting toxicities or serious adverse events, as taught by Hutchinson. In addition both bortezomib and MDX-1097 are used for treating MM and good candidates for combination therapy for MM, as suggested by Wright and Hutchinson and to further add lenalidomide in the combination for treating refractory MM to bortezomib, because lenalidomide may augment the activity of MDX-1097 through the enhancement of effector cell function, as well as by increasing the amount of mκFLC on the surface of MM cells, as taught by Hutchinson (page 91, col. 2, para. 3); lenalidomide may also potentiate the effect of bortezomib on MM cells, as taught by Wright; lenalidomide plus bortezomib are effective to refractory MM to lenalidomide, bortezomib, and/or thalidomide as taught by Richardson (§ Abstract -Conclusion). Given the teaching of Richardson, one of ordinary skilled in the art would have a reasonable expectation that the bortezomib + MDX-1097 + lenalidomide would be effective to bortezomib refractory MM. Because all three components have been well tested in combination setting, as evidenced by the references, one of ordinary skilled in the art would have had a reasonable expectation of success to reach the claimed method. The motivation would have been to develop a more effective treatment for MM refractory to a proteasome inhibitor such as bortezomib.
Applicant further argues:
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Applicant further argues no reasonable expectation of success and cites four combinations which failed to enhance efficacy of treatments.
First, contrary to applicant’s argument, for Elotuzumab and bortezomib combination trial (NCT00726869), Jakubowiak (Jakubowiak et al., J Clin Oncol 30: 1960-1965, Publication Date: 01/20/2012) presents the results for clinical trial NCT00726869 (page 1961, col. 1, paras. 4-6). Jakubowiak teaches: “The objective response rate (ORR; less than or equal to a PR) was 48% by the EBMT criteria, and 63% of patients achieved a minor response (MR) or better. Responses observed among patients with prior bortezomib treatment, those with bortezomib-refractory disease, those with prior lenalidomide, those with lenalidomide-refractory disease, and those refractory to their most recent treatment were consistent with those observed in the overall study population. Notably, two of three patients refractory to bortezomib responded to this regimen. Patients with high-risk cytogenetics exhibited an ORR of 70% (seven of 10) including one patient with CR” (the bridging paragraph of cols. 1-2 on page 1963). Jakubowiak concludes: the combination of elotuzumab and bortezomib was generally well-tolerated and showed encouraging activity in patients with relapsed/ refractory MM.
Palumbo (Palumbo et al., N Engl J MED, 375: 8, 754-766, Publication Date: 08/25/2016) teaches: “Among patients with relapsed or relapsed and refractory multiple myeloma, daratumumab in combination with bortezomib and dexamethasone resulted in significantly longer progression-free survival than bortezomib and dexamethasone alone and was associated with infusion-related reactions and higher rates of thrombocytopenia and neutropenia than bortezomib and dexamethasone alone. (Funded by Janssen Research and Development; ClinicalTrials.gov number, NCT02136134)”. See § Abstract—CONCLUSIONS.
Zhang (Zhang et al., Chemotherapy, 2015 June; 5(2), Publication Date: 03/31/2015) teaches that the combination (anti-β2M mAbs + bortezomib) treatment offered a much higher anti-MM effects than either agent alone, and anti-β2M mAbs enhanced bortezomib-induced apoptosis in MM cells and in mouse models. Mechanistic studies showed that anti-β2M mAbs could overcome bortezomib resistance by inhibiting bortezomib -induced nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling and autophagy activation (Abstracts; and pages: 8570-8571).
These references and references cited by applicant indicate that some combinations work for refractory multiple myeloma, some combinations do not work. Even with some negative results from clinical trials, the efforts to make/test new antibody-bortezomib combination never stop. In the field of biological technology, no invention has absolute certainty of success before experimental tests. Thus, only a reasonable expectation of success (not absolute) would have motivated an artisan to make the claimed fusion protein. Given the teachings from references, an ordinary skilled in the art would have would have had a reasonable expectation of success in producing the claimed invention.
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.
U.S. Patent No.: 7,344,715
Claims 1, 3-5, 8, 13, 16, 17, 19, 20, 22, 29, 31, and 51 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 of U.S. Patent No.: US7,344,715 B2 (hereinafter Pat. 715, corresponding to application 10/481,212, of record), in view of Wright (Wright et al., Clin. Cancer Res., 16(16), 4094-4104, Publication Date: 08/15/2010, cited by IDS of 06/02/2021, of record), Hutchinson (Hutchinson et al., Molecular Immunology 67 (2015): 89-94, Publication Date: 05/08/2015, cited by IDS of 04/13/2023, of record), and Richardson (Richardson et al., J Clin Oncol., 27(34);5713-5719, Publication Date: 09/28/2009, of record), as evidenced by Spencer (Spencer et al., Blood Cancer Journal, (2019) 9:58, Publication Date: 07/31/2019, of record).
The claims of Pat. 715 teach:
1. A method for the treatment of kappa-type multiple myeloma in a subject, the method comprising administering to the subject in need thereof an effective amount of an antibody which is not conjugated to a toxin or a cytolytic agent, wherein the antibody comprises a VH region set forth in SEQ ID NO:1 and a VL region set forth in SEQ ID NO:3 or binds the same epitope of kappa myeloma antigen (KMA) as an antibody comprising a VH region set forth in SEQ ID NO:1 and a VL region set forth in SEQ ID NO:3, wherein said administering is effective to kill KMA-bearing myeloma cells.
2. A method as claimed in claim 1 which further comprises the step of treating the subject to reduce the levels of free kappa light chains present in the fluid of the subject prior to administration of the antibody.
3. A method as claimed in claim 2 wherein the levels of free kappa light chains are reduced by plasmapheresis.
4. The method of claim 1, wherein the antibody is a monoclonal antibody.
5. The method of claim 1, wherein the antibody comprises the CDR loops (CDR1, CDR2 and CDR 3) of the heavy and light chains of a K121 antibody as shown in FIG. 9a.
6. The method of claim 1, wherein the antibody is a chimeric antibody or a humanized antibody.
As shown below, SEQ ID NO: 1 and SEQ ID NO: 3 of the reference claims comprise HCDRs of SEQ ID NOs: 6-7-8, and LCDRs of SEQ ID NOs: 9-10-11, respectively:
US-10-481-212-1
Query Match 89.3%; Score 203.5; Length 119;
Best Local Similarity 45.8%;
Matches 38; Conservative 0; Mismatches 0; Indels 45; Gaps 2;
Qy 1 GFNIKDTYMHW-------------RIDPANGNTKYDPKFQG------------------- 28
||||||||||| |||||||||||||||||
Db 26 GFNIKDTYMHWVKQRPEQGLEWIGRIDPANGNTKYDPKFQGKAAIIADTSSNTAYLQLSS 85
Qy 29 -------------GVYHDYDGDY 38
||||||||||
Db 86 LTSEDTAVYYCARGVYHDYDGDY 108
US-10-481-212-3
Query Match 82.6%; Score 117.3; Length 107;
Best Local Similarity 36.5%;
Matches 27; Conservative 0; Mismatches 0; Indels 47; Gaps 2;
Qy 1 KASQNVGTNVA---------------STSYRYS--------------------------- 18
||||||||||| |||||||
Db 24 KASQNVGTNVAWYQQKPGQSPKALIYSTSYRYSGVPDRFTGSGSGTDFTLTISNVQSEDL 83
Qy 19 -----QQYNSYPYT 27
|||||||||
Db 84 AEYFCQQYNSYPYT 97
The claims of Pat. 715 teach as set forth above. The claims of Pat. 715 do not teach the combination with bortezomib as instantly claimed, or the specific VH and VL of SEQ ID NO: 1 and SEQ ID NO: 2, or further comprising lenalidomide, or subject is relapsed or refractory MM, such as refractory to bortezomib.
Wright, Hutchinson, and Richardson teach as set forth above. Hutchinson furth teaches chimeric mAb MDX-1097, featuring the murine K121 VL and VH regions. MDX-1097 showed a stronger affinity (4nM) to mκFLC on MM cells (page 91, 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 anti-KMA antibody K121 to treat MM as taught by the claims of Pat. 715, and substitute K121 with MDX-1097, because MDX-1097 has better binding property than its parent antibody K121 and has been well tested and has showed good therapeutic activity for MM, as taught by Hutchinson, and to treat MM with a combination of MDX-1097 and bortezomib as taught by Wright and Hutchinson as set forth above, and to further add lenalidomide in the combination, because lenalidomide may augment the activity of MDX-1097 through the enhancement of effector cell function, as well as by increasing the amount of mκFLC on the surface of MM cells, as taught by Hutchinson (page 91, col. 2, para. 3); lenalidomide may also potentiate the effect of bortezomib on MM cells (e.g. bortezomib refractory MM), as taught by Wright and Richardson; lenalidomide plus bortezomib are effective to refractory MM to lenalidomide, bortezomib, and/or thalidomide as taught by Richardson (§ Abstract -Conclusion). Given the teaching of Richardson, one of ordinary skilled in the art would have a reasonable expectation that the bortezomib + MDX-1097 + lenalidomide would be effective to bortezomib refractory MM. Because all three components have been well tested in combination setting, as evidenced by the references, one of ordinary skilled in the art would have had a reasonable expectation of success to reach the claimed method. The motivation would have been to develop a more effective treatment for MM refractory to at least one proteasome inhibitor.
U.S. Patent No.: 7,838,041
Claims 1, 2, 3, 5-8, 10, 13, 17, 19, 20, 22, 26, 29 and 51 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No.: US7,838,041 B2 (hereinafter Pat. 041, corresponding to application 12/016,462, of record), in view of Wright (Wright et al., Clin. Cancer Res., 16(16), 4094-4104, Publication Date: 08/15/2010, cited by IDS of 06/02/2021, of record), Hutchinson (Hutchinson et al., Molecular Immunology 67 (2015): 89-94, Publication Date: 05/08/2015, cited by IDS of 04/13/2023, of record), and Richardson (Richardson et al., J Clin Oncol., 27(34);5713-5719, Publication Date: 09/28/2009, of record), as evidenced by Spencer (Spencer et al., Blood Cancer Journal, (2019) 9:58, Publication Date: 07/31/2019, of record).
The claims of Pat. 041 teach:
1. A method for autologous hematopoietic cell transplantation in a subject, the method comprising: transplanting a hematopoietic progenitor cell population into the subject,
wherein the hematopoietic progenitor cell population has been obtained from the subject and has been treated with an antibody, wherein the antibody is not conjugated to a toxin or a cytolytic agent, and wherein the antibody comprises a VH region set forth in SEQ ID NO:1 and a VL region set forth in SEQ ID NO:3 or binds the same epitope of kappa myeloma antigen (KMA) as an antibody comprising a VH region set forth in SEQ ID NO:1 and a VL region set forth in SEQ ID NO:3, wherein the antibody is effective to kill KMA-bearing myeloma cells.
2. The method of claim 1 wherein, the method further comprises intravenous infusion of an antibody into the subject.
3. The method of claim 1 wherein the method of autologous transplantation is performed on the subject during or after cytoreductive therapy.
4. The method of claim 1, wherein the antibody is a monoclonal antibody.
5. The method of claim 1, wherein the antibody binds the same epitope of kappa myeloma antigen (KMA) as an antibody comprising a VH region set forth in SEQ ID NO:1 and a VL region set forth in SEQ ID NO:3 and comprises the CDR loops (CDR1, CDR2 and CDR 3) of the K121 antibody as shown in FIG. 9 a.
6. The method of claim 1 wherein the antibody is a chimeric antibody or a humanized antibody.
10. The method of claim 5, wherein the antibody is a monoclonal antibody.
11. The method of claim 5, wherein the antibody is a chimeric antibody or a humanized antibody.
As shown below, SEQ ID NO: 1 and SEQ ID NO: 3 of the reference claims comprise HCDRs of SEQ ID NOs: 6-7-8, and LCDRs of SEQ ID NOs: 9-10-11, respectively:
US-12-016-462-1
Query Match 89.3%; Score 203.5; Length 119;
Best Local Similarity 45.8%;
Matches 38; Conservative 0; Mismatches 0; Indels 45; Gaps 2;
Qy 1 GFNIKDTYMHW-------------RIDPANGNTKYDPKFQG------------------- 28
||||||||||| |||||||||||||||||
Db 26 GFNIKDTYMHWVKQRPEQGLEWIGRIDPANGNTKYDPKFQGKAAIIADTSSNTAYLQLSS 85
Qy 29 -------------GVYHDYDGDY 38
||||||||||
Db 86 LTSEDTAVYYCARGVYHDYDGDY 108
US-12-016-462-3
Query Match 82.6%; Score 117.3; Length 107;
Best Local Similarity 36.5%;
Matches 27; Conservative 0; Mismatches 0; Indels 47; Gaps 2;
Qy 1 KASQNVGTNVA---------------STSYRYS--------------------------- 18
||||||||||| |||||||
Db 24 KASQNVGTNVAWYQQKPGQSPKALIYSTSYRYSGVPDRFTGSGSGTDFTLTISNVQSEDL 83
Qy 19 -----QQYNSYPYT 27
|||||||||
Db 84 AEYFCQQYNSYPYT 97
The claims of Pat. 041 teach as set forth above. The claims of Pat. 041 do not teach, the combination with bortezomib as instantly claimed to treat MM, or the specific VH and VL of SEQ ID NO: 1 and SEQ ID NO: 2, or further comprising lenalidomide, or subject is relapsed or refractory MM, such as refractory to bortezomib.
Wright, Hutchinson, and Richardson teach as set forth above. Hutchinson furth teaches chimeric mAb MDX-1097, featuring the murine K121 VL and VH regions. MDX-1097 showed a stronger affinity (4nM) to mκFLC on MM cells (page 91, 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 generate anti-KMA antibody K121 as taught by the claims of Pat. 041, and further make/use a chimeric antibody of K121: MDX-1097 to treat MM, because MDX-1097 has better binding property than its parent antibody K121 and has been well tested and has showed good therapeutic activity for MM, as taught by Hutchinson, and further to treat MM with a combination of MDX-1097 and bortezomib as taught by Wright and Hutchinson as set forth above, and to further add lenalidomide in the combination, because lenalidomide may augment the activity of MDX-1097 through the enhancement of effector cell function, as well as by increasing the amount of mκFLC on the surface of MM cells, as taught by Hutchinson (page 91, col. 2, para. 3); lenalidomide may also potentiate the effect of bortezomib on MM cells (e.g. bortezomib refractory MM), as taught by Wright and Richardson; lenalidomide plus bortezomib are effective to refractory MM to lenalidomide, bortezomib, and/or thalidomide as taught by Richardson (§ Abstract -Conclusion). Given the teaching of Richardson, one of ordinary skilled in the art would have a reasonable expectation that the bortezomib + MDX-1097 + lenalidomide would be effective to bortezomib refractory MM. Because all three components have been well tested in combination setting, as evidenced by the references, one of ordinary skilled in the art would have had a reasonable expectation of success to reach the claimed method. The motivation would have been to develop a more effective treatment for MM refractory to at least one proteasome inhibitor.
U.S. Patent No.: 7,556,803
Claims 1, 2, 3, 5-8, 10, 13, 17, 19, 20, 22, 26, 29 and 51 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No.: US7,556,803 B2 (hereinafter Pat. 803, corresponding to application 12/016,470, of record), in view of Wright (Wright et al., Clin. Cancer Res., 16(16), 4094-4104, Publication Date: 08/15/2010, cited by IDS of 06/02/2021, of record), Hutchinson (Hutchinson et al., Molecular Immunology 67 (2015): 89-94, Publication Date: 05/08/2015, cited by IDS of 04/13/2023, of record), and Richardson (Richardson et al., J Clin Oncol., 27(34);5713-5719, Publication Date: 09/28/2009, of record), as evidenced by Spencer (Spencer et al., Blood Cancer Journal, (2019) 9:58, Publication Date: 07/31/2019, of record).
The claims of Pat. 803 teach:
1. A method for killing cells bearing kappa myeloma antigen (KMA) in a mixed population of cells, the method comprising: contacting the mixed population of cells with an antibody, wherein the antibody is not conjugated to a toxin or a cytolytic agent, and wherein the antibody comprises a VH region set forth in SEQ ID NO:1 and a VL region set forth in SEQ ID NO:3 or binds the same epitope of kappa myeloma antigen (KMA) as an antibody comprising a VH region set forth in SEQ ID NO:1 and a VL region set forth in SEQ ID NO:3; wherein said contacting is effective to kill cells bearing kappa myeloma antigen (KMA).
2. The method of claim 1 wherein the KMA bearing cells are kappa-type myeloma cells.
3. The method of claim 1 wherein the antibody is a monoclonal antibody.
4. The method of claim 1 wherein the antibody is a chimeric antibody or a humanized antibody.
5. The method of claim 1, wherein the mixed population of cells is in vivo in a subject.
6. The method of claim 5 wherein chemotherapy is administered to the subject.
7. The method of claim 6, wherein the chemotherapy is administered to the subject in conjunction with administration of the antibody.
8. The method of claim 5, wherein chemotherapy is administered to the subject prior to administration of the antibody.
9. The method of claim 8, wherein the radiotherapy is administered to the subject.
10. The method of claim 5, wherein the KMA bearing cells are kappa-type myeloma cells.
11. The method of claim 5 wherein the antibody is a monoclonal antibody.
12. The method of claim 5 wherein the antibody is a chimeric antibody or a humanized antibody.
13. A method as claimed in claim 5 which further comprises the step of treating the subject to reduce the levels of free kappa light chains present in the fluid of the subject prior to administration of the antibody.
14. A method as claimed in claim 13 wherein the levels of free kappa light chains are reduced by plasmapheresis.
15. The method of claim 1, wherein the antibody comprises the CDR loops (CDR1, CDR2 and CDR3) of the heavy and light chains of a K121 antibody as shown in FIG. 9 a.
16. The method of claim 5, wherein the antibody comprises the CDR loops (CDR1, CDR2 and CDR3) of the heavy and light chains of a K121 antibody as shown in FIG. 9a.
As shown below, SEQ ID NO: 1 and SEQ ID NO: 3 of the reference claims comprise HCDRs of SEQ ID NOs: 6-7-8, and LCDRs of SEQ ID NOs: 9-10-11, respectively:
US-12-016-470-1
Query Match 89.3%; Score 203.5; Length 119;
Best Local Similarity 45.8%;
Matches 38; Conservative 0; Mismatches 0; Indels 45; Gaps 2;
Qy 1 GFNIKDTYMHW-------------RIDPANGNTKYDPKFQG------------------- 28
||||||||||| |||||||||||||||||
Db 26 GFNIKDTYMHWVKQRPEQGLEWIGRIDPANGNTKYDPKFQGKAAIIADTSSNTAYLQLSS 85
Qy 29 -------------GVYHDYDGDY 38
||||||||||
Db 86 LTSEDTAVYYCARGVYHDYDGDY 108
US-12-016-470-3
Query Match 82.6%; Score 117.3; Length 107;
Best Local Similarity 36.5%;
Matches 27; Conservative 0; Mismatches 0; Indels 47; Gaps 2;
Qy 1 KASQNVGTNVA---------------STSYRYS--------------------------- 18
||||||||||| |||||||
Db 24 KASQNVGTNVAWYQQKPGQSPKALIYSTSYRYSGVPDRFTGSGSGTDFTLTISNVQSEDL 83
Qy 19 -----QQYNSYPYT 27
|||||||||
Db 84 AEYFCQQYNSYPYT 97
The claims of Pat. 803 teach as set forth above. The claims of Pat. 803 do not teach, the combination with bortezomib as instantly claimed to treat MM, or the specific VH and VL of SEQ ID NO: 1 and SEQ ID NO: 2, or further comprising lenalidomide, or subject is relapsed or refractory MM, such as refractory to bortezomib.
Wright, Hutchinson, and Richardson teach as set forth above. Hutchinson furth teaches chimeric mAb MDX-1097, featuring the murine K121 VL and VH regions. MDX-1097 showed a stronger affinity (4nM) to mκFLC on MM cells (page 91, 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 generate anti-KMA antibody K121 as taught by the claims of Pat. 803, and further make/use a chimeric antibody of K121: MDX-1097 to treat MM, because MDX-1097 has better binding property than its parent antibody K121 and has been well tested and has showed good therapeutic activity for MM, as taught by Hutchinson, and further to treat MM with a combination of MDX-1097 and bortezomib as taught by Wright and Hutchinson as set forth above, and to further add lenalidomide in the combination, because lenalidomide may augment the activity of MDX-1097 through the enhancement of effector cell function, as well as by increasing the amount of mκFLC on the surface of MM cells, as taught by Hutchinson (page 91, col. 2, para. 3); lenalidomide may also potentiate the effect of bortezomib on MM cells (e.g. bortezomib refractory MM), as taught by Wright and Richardson; lenalidomide plus bortezomib are effective to refractory MM to lenalidomide, bortezomib, and/or thalidomide as taught by Richardson (§ Abstract -Conclusion). Given the teaching of Richardson, one of ordinary skilled in the art would have a reasonable expectation that the bortezomib + MDX-1097 + lenalidomide would be effective to bortezomib refractory MM. Because all three components have been well tested in combination setting, as evidenced by the references, one of ordinary skilled in the art would have had a reasonable expectation of success to reach the claimed method. The motivation would have been to develop a more effective treatment for MM refractory to at least one proteasome inhibitor.
U.S. Patent No.: 11,305,011
Claims 1, 2, 3, 5-8, 10, 13, 17, 19, 20, 22, 26, 29 and 51 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No.: US11,305,011 B2 (hereinafter Pat. 011, corresponding to application 15/568,271, of record), in view of Wright (Wright et al., Clin. Cancer Res., 16(16), 4094-4104, Publication Date: 08/15/2010, cited by IDS of 06/02/2021, of record), Hutchinson (Hutchinson et al., Molecular Immunology 67 (2015): 89-94, Publication Date: 05/08/2015, cited by IDS of 04/13/2023, of record), and Richardson (Richardson et al., J Clin Oncol., 27(34);5713-5719, Publication Date: 09/28/2009, of record), as evidenced by Spencer (Spencer et al., Blood Cancer Journal, (2019) 9:58, Publication Date: 07/31/2019, of record).
The claims of Pat. 011 teach:
1. A chimeric antigen receptor (CAR) comprising one or more intracellular signaling domains and an extracellular antigen binding domain, wherein the extracellular antigen binding domain comprises a single chain variable fragment (scFv) that specifically binds kappa myeloma antigen (KMA) and does not bind immunoglobulin (Ig) kappa light chain associated with an Ig heavy chain, wherein the scFv comprises the VL chain and VH chain from KappaMab, wherein the VL chain comprises the VL chain of SEQ ID NO: 2 and the VH chain comprises the VH chain of SEQ ID NO: 1.
2. A chimeric antigen receptor (CAR) comprising one or more intracellular signaling domains and an extracellular antigen binding domain, wherein the extracellular antigen binding domain specifically recognizes kappa myeloma antigen (KMA), wherein the extracellular binding domain comprises a single chain variable fragment (scFv) that specifically recognizes KMA, wherein the scFv comprises the VL chain and VH chain from KappaMab wherein the VL chain comprises the VL chain of SEQ ID NO: 2 and the VH chain comprises the VH chain of SEQ ID NO: 1.
16. A method for producing a genetically modified T cell comprising introducing into a T cell an expression vector encoding a CAR comprising one or more intracellular signaling domains and an extracellular antigen binding domain, wherein the extracellular antigen binding domain specifically recognizes kappa myeloma antigen (KMA), wherein the extracellular binding domain comprises a single chain variable fragment (scFv) that specifically recogni