DETAILED ACTION
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Applicant’s reply filed on 8/14/2026 is acknowledged. Claims 1-3, 5-10, 12-17, 19-20 and 22-25 are pending. Claims 4, 11, 18 and 21 are canceled. Claims 1, 2, 7-9, 14-16 and 22 have been amended.
3. Claims 1-3, 5-10, 12-17, 19-20 and 22-25 are under examination.
Information Disclosure Statement
4. The information disclosure statement (IDS) submitted on 8/14/2026 has been considered by the examiner.
Objection Withdrawn
5. The objection to claims 1-3, 5-10, 12-17 and 19-25 for reciting “at a sensitivity of 0.01%, 0.001%, or 0.0001%” is withdrawn in view of applicant’s amendments.
Rejections Withdrawn
6. The rejection of claims 1-3, 5-10, 12-17 and 19-25 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for reciting “high risk” is withdrawn in view of applicant’s persuasive arguments.
7. The rejection of claims 7, 14, 21 and 22 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form is withdrawn in view of applicant’s amendments.
8. The rejection of claims 1-3, 5-10, 12-17 and 19-25 under 35 U.S.C. 103 as being unpatentable over Dimopoulos et al. (N. Engl. J. Med., 2016, Oct 6, 375(14): 1319-1331), in view of Rajkumar et al (Mayo Clin Proc, 2016, 91(1): 101-119) is withdrawn in view applicant’s amendments to claims 2, 9 and 16 to delete specific chromosomal abnormalities.
9. The provisional rejection of claim 1-3, 5-10, 12-17 and 19-25 on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of copending Application No. 19/418,900 (reference application) is withdrawn in view of applicant’s submission of a terminal disclaimer.
Rejections Maintained
Claim Rejections - 35 USC § 102
10. 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.
11. Claims 1-3, 5-10, 12-17, 19-20 and 22-25 remain rejected under 35 U.S.C. 102(a)(1) as being anticipated by Dimopoulos et al (N. Engl. J. Med., 2016, Oct 6, 375(14): 1319-1331).
The rejection has been modified in view of applicant’s amendments.
Regarding claims 1, 3, 5, 8, 10, 12, 14-15, 17, 19, as well as amended claims 2, 9 and 16, Dimopoulos et al teaches a method of treating relapsed or refractory multiple myeloma in human patients, the method comprising administering to the patients daratumumab (an anti-CD38 antibody), lenalidomide, and dexamethasone, wherein the patients included those having high risk cytogenetic profile (Table 1), wherein 22.4% of the patients had results below the threshold for minimal residual disease (1 tumor cell per 105 white cells, or 1 tumor cell per 106 white cells) (abstract and page 1326, column 1)), wherein the minimal residual disease status was evaluated by means of a next-generation sequencing assay of bone marrow obtained from patients who had a suspected complete response (page 1321, column 2, para 2). The antibody daratumumab inherently comprises the VH and VL amino acid sequences recited in instant claims 1, 8 and 15, the heavy and light chain amino acid sequences recited in instant claims 5, 12 and 19, as evidenced by instant specification (see paragraph [0072]).
Regarding the limitation “the subject achieves a negative minimal residual disease status at a sensitivity threshold of 0.0001% (10-6)” recited in claims 1, 8 and 15, Dimopoulos et al. discloses “consistent with the higher rates of deeper responses in the daratumumab group, the rate of results below the threshold for minimal residual disease was significantly higher in the daratumumab group than in the control group (by 3 to 5 times) at all evaluated thresholds (1 tumor cell per 104, 105, and 106 white cells)” (page 1326, column 1 and Fig. S4 in the Supplementary Appendix), indicating that some subjects have achieved a negative minimal residual disease (MRD) status at a sensitivity of 10-6 and these subjects would have reduced risk of relapse and/or disease progression.
Regarding claims 7 and 22, Dimopoulos et al teaches that the minimal residual disease status was evaluated by means of a next-generation sequencing assay of bone marrow obtained from patients who had a suspected complete response (page 1321, column 2, para 2).
Regarding claims 6, 13 and 20, Dimopoulos teaches that daratumumab is intravenously administered at a dose of 16 mg/kg weekly on days 1, 8, 15, and 22 for 8 weeks during cycles 1 and 2 (treatment cycle is 28 days) (same as once per week in a 28-day cycle), once every 2 weeks on days 1 and 15 for 16 weeks (cycles 3 through 6) (same as in a 28-day cycle during cycles 3 through 6), and every 4 weeks thereafter, lenalidomide is administered orally at a dose of 25 mg on days 1 to 21 of each cycle if the creatinine clearance was more than 60 ml per minute (or a dose of 10 mg daily if the creatinine clearance was 30 to 60 ml per minute) and dexamethasone at a dose of 40 mg weekly (patients older than 75 years of age or whose body-mass index less than 18.5 received dexamethasone at a dose of 20 mg weekly at the discretion of their physician) (page 1321, column 1).
Regarding claims 23-25, Dimopoulos et al teaches that the method increases progression-free survival compared to administering lenalidomide and dexamethasone without the anti-CD38 antibody (Fig. 1). Dimopoulos et al. teaches that the rate of progression-free survival at 12 months was 85.7% (95% CI, 80.9 to 89.4) in the daratumumab group, as compared with 63.2% (95% CI, 57.1 to 68.8) in the control group (page 1324, column 2). Dimopoulos et al. teaches “The addition of daratumumab to lenalidomide and dexamethasone significantly lengthened progression-free survival among patients with relapsed or refractory multiple myeloma.” The patients included those having high risk cytogenetic profile (Table 1).
Applicant’s Arguments
The response states that Dimopoulos does not disclose a subject having high-risk multiple myeloma who achieves a negative minimal residual disease (MRD) status at a sensitivity threshold of 0.0001% (10-6) (hereinafter "the MRD limitation"). The MRD limitation of independent claims 1, 8, and 15 is entitled to patentable weight at least because it is an express limitation of the claims and is not drafted as part of the preamble. The MRD Limitation Is Not Explicitly Disclosed in Dimopoulos and the Office Therefore bears the burden of establishing inherency. Here, the Office does not assert that Dimopoulos explicitly discloses a subject having high-risk multiple myeloma who achieves a negative MRD status at a sensitivity threshold of 0.0001% (10-6). Indeed, Dimopoulos does not report an analysis of MRD outcomes based on cytogenetic risk ("[c]omplete cytogenetic data were not available at the clinical cut-off date, and a prospective, centralized analysis of cytogenetic data is ongoing." Supplementary Appendix, at 25). Dimpoulos only establishes that among the intent-to-treat patients, some (10%) achieved a negative MRD status at a sensitivity of 10-6. See, Figure S4 (reproduced below). Dimopoulos teaches treating high risk relapsed or refractory multiple myeloma (citing Table 1). However, the evidence only establishes that among the intent-to-treat patients of the Daratumumab Group (DRd), some (15.4%) have a high-risk cytogenetic profile. Accordingly, the extrinsic evidence does not support the conclusion that the MRD limitation is inherently disclosed by Dimopoulos. As illustrated by the Table below:
(i) Dimopoulos does not establish that all high-risk patients treated with DRd achieved a negative MRD status at a sensitivity threshold of 10-6; indeed, the reported MRD negative rate and cytogenetic profile are consistent with the possibility that some high-risk patients did not achieve the claimed outcome; and
(ii) Dimopoulos does not establish that even one high-risk patient treated with DRd achieved a negative MRD status at a sensitivity threshold of 10-6.
The fact that Dimopoulos and the instant specification report results from the same clinical trial does not mean that every result reported by the specification was disclosed in Dimopoulos. Here, the relevant question for inherency is whether the MRD limitation was necessarily disclosed by Dimopoulos-not merely whether the underlying clinical trial necessarily produced the claimed result. An unreported clinical outcome does not become a necessarily disclosed limitation merely because it was generated by the same clinical trial. As Apotex and Sandoz illustrate, the possibility that some patients treated with the claimed method achieve a claimed clinical outcome does not, without more, establish inherency.
Response to Arguments
Applicant’s arguments have been carefully considered but are not persuasive. Dimopoulos et al. teaches treating same patients (high risk relapsed or refractory multiple myeloma) (Table 1) using same drugs (daratumumab, lenalidomide and dexamethasone) at same doses and same schedules. Because the method of the prior art is identical to the method of instant claims, practicing the method of prior art would inherently or necessarily lead to the same results. Furthermore, both Dimopoulos et al. and the instant specification describe the results of the same clinical trial (i.e. treating same patient populations using same treatment schedule), the results would necessarily be identical. Applicants arguments that not all high-risk patients achieves a negative minimal residual disease status at a sensitivity threshold of 0.0001% are not persuasive because at least some high-risk patients in the trial of Dimopoulos in fact achieved a negative minimal residual disease status at a sensitivity threshold of 0.0001%, as evidenced by later analysis of the clinical results. Because at least some high-risk patients included in the trial of Dimopoulos achieved a negative minimal residual disease status at a sensitivity threshold of 0.0001, Dimopoulos et al. anticipates instant invention.
Furthermore, the intended results “achieves a negative minimal residual disease status at a sensitivity threshold of 0.0001%” does not differentiate the instant method from the prior art. Before treatment starts, one of ordinary skill in the art would not be able to identify/select a patient who will achieve a negative minimal residual disease status at a sensitivity threshold of 0.0001%.
For the foregoing reasons, the rejection is maintained.
Double Patenting
12. 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 §§ 706.02(l)(1) - 706.02(l)(3) 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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
13. Claims 1-3, 5-10, 12-17, 19-20 and 22-25 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 203-210, 212-214, 234-236, and 304-320 of copending Application No. 16/797,301 (reference application), in view of Rajkumar et al (Mayo Clin Proc, 2016, 91(1): 101-119).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The claims of reference application disclose a method of treating a subject with newly diagnosed multiple myeloma, comprising administering to the subject daratumumab as a combination therapy comprising: about 16 mg/kg daratumumab administered once a week on weeks 1 to 8, once in two weeks on weeks 9 to 24 and thereafter once in four weeks, b) about 25 mg lenalidomide administered daily on days 1 to 21 of repeated 4-week cycles, and c) about 20 mg to about 40 mg dexamethasone administered per week, wherein daratumumab is administered intravenously, lenalidomide is administered orally and dexamethasone is administered intravenously or orally,
wherein the method achieves an improved clinical efficacy endpoint when compared to a clinical efficacy endpoint achieved if the subject were administered a combination of lenalidomide and dexamethasone, wherein the improved clinical efficacy endpoint is an increased likelihood of achieving a complete response (CR), an increased likelihood of achieving a negative status for minimal residual disease (MRD), a reduced risk of progression of multiple myeloma or death, wherein the subject with newly diagnosed multiple myeloma is ineligible for high dose chemotherapy (HDC) and autologous stem cell transplant (ASCT).
The claims of copending application do not tech treating relapsed, refractory or relapsed and refractory multiple myeloma having the chromosomal abnormalities recited in claims 2, 9 and 16.
Rajkumar et al teaches that stage III multiple myeloma is characterized by high-risk cytogenetics t(4;14), t(14;16), or del17p (Table 5), and approximately 40% of MM cases are characterized by the presence of trisomies in the neoplastic plasma cells (trisomic MM), while most of the rest have a translocation involving the immunoglobulin heavy chain (IgH) locus on chromosome14q32 (IgH translocated MM) (page 102, last paragraph), including t(4;14)(p16;q32), t(14;16)(q32;q23), or del17p (Table 2). Rajkumar et al. teaches that in a phase 2 trial, daratumumab as a single agent produced a response rate of approximately 30% in heavily pretreated patients (page 113, column 2). Rajkumar et al. disclose that lenalidomide plus dexamethasone is an effective regimen in treating high-risk MM (page 106, column 2, para 3, page 112, column 1, para 3).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used the method of copending application to treat high risk relapsed and refractory multiple myeloma comprising t(4;14)(p16;q32), t(14;16)(q32;q23), or del17p chromosomal abnormality in view of Rajkumar et al. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success because the claims of reference application disclose that the method can be used to treat newly diagnosed MM and Rajkumar et al teaches that daratumumab as a single agent produced a response rate of approximately 30% in heavily pretreated patients (page 113, column 2), Rajkumar et al. disclose that lenalidomide plus dexamethasone is an effective regimen in treating high-risk MM (page 106, column 2, para 3, page 112, column 1, para 3), and stage III multiple myeloma is characterized by high-risk cytogenetics t(4;14), t(14;16), or del17p (Table 5), and approximately 40% of MM cases are characterized by the presence of trisomies in the neoplastic plasma cells (trisomic MM), while most of the rest have a translocation involving the immunoglobulin heavy chain (IgH) locus on chromosome14q32 (IgH translocated MM) (page 102, last paragraph), including t(4;14)(p16;q32), t(14;16)(q32;q23), or del17p (Table 2).
Applicant’s Arguments
The response states that MPEP states, "If a provisional nonstatutory double patenting rejection is the only rejection remaining in an application having the earlier patent term filing date, the examiner should withdraw the rejection in the application having the earlier patent term filing date and permit that application to issue as
a patent, thereby converting the provisional nonstatutory double patenting rejection in the other application into a nonstatutory double patenting rejection upon issuance of the patent." See § 804.I.B.1.(b)(i).
Here, the instant application has an earlier effective U.S. filing date, October 31, 2017 (2017-10-31), compared with that of 16/797,301 (February 22, 2019 (2019-02-22)). As such, once this provisional nonstatutory double patenting rejection is the only rejection remaining in the application, reconsideration and withdrawal of the rejection are respectfully requested.
Response to Arguments
Applicant’s arguments have been carefully considered but are not persuasive because the rejection is not the only rejection remaining in the application at this time.
Conclusion
14. No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
15. Any inquiry concerning this communication or earlier communications from the examiner should be directed to HONG SANG whose telephone number is (571)272-8145. The examiner can normally be reached on Monday-Friday 8am-5pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Gregory Emch can be reached on 571-272-8149. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/HONG SANG/Primary Examiner, Art Unit 1643
