DETAILED ACTION
Notice of Pre-AIA or AIA Status
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 6/30/2026 is acknowledged. New claim 14 has been added. Claims 1-14 are pending. Claims 1, 5 and 12 have been amended.
3. Claims 1-14 are under examination.
Information Disclosure Statement
4. The information disclosure statement filed on 6/30/2026 fails to comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609 because the date for Cite Nos. 10 and 78 is not provided. It has been placed in the application file, but the information referred to therein has not been considered as it pertains to these items.
37 C.F.R. 1.98 (b)(5) Each publication listed in an information disclosure statement must be identified by publisher, author (if any), title, relevant pages of the publication, date, and place of publication.
Rejections Withdrawn
5. The rejection of claims 5 and 12 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for reciting “an early relapse” is withdrawn in view of applicant’s amendments.
6. The rejection of claims 1-13 on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5-10, 12-17 and 19-25 of copending Application No. 18/175,345 (reference application) is withdrawn in view of applicant’s submission of a terminal disclaimer.
Rejections Maintained
Claim Rejections - 35 USC § 102
7. 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.
8. Claims 1-13 and new claim 14 remian/are 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).
Regarding claim 1, Dimopoulos et al teaches a method of treating relapsed or refractory multiple myeloma in human patients, the method comprising administering to the patients daratumumab, lenalidomide, and dexamethasone, wherein 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, which is four weeks) (which is same as once per week for cycles 1 and 2), once every 2 weeks on days 1 and 15 for 16 weeks (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), wherein the patients had progressive disease during or after the receipt of their last regimen and they had received and had a response to one or more lines of previous therapy (abstract, page 1321, column 1, page 1320, last paragraph). Dimopoulos et al. teaches that patients had 1-11 lines of previous therapy (Table 1), including two lines of previous therapy (page 1321, column 1, para 2, “ …and stratified according to the number of lines of previous therapy (1 vs. 2 or 3 vs. >3)).
Dimopoulos et al teaches that at a median follow-up of 13.5 months, a higher rate of complete response or better was observed in the daratumumab than in the control group (43.1% vs. 19.2%, p<0.001), and in the daratumumab group, 22.4% of the patients had results below the threshold for minimal residual disease (MRD) (1 tumor cell per 105 white cells), as compared with 4.6% of those in the control group (p<0.001), (abstract and page 1326, column 1)). In the absence of a specific definition for MRD negative, below the threshold for minimal residual disease (1 tumor cell per 105 white cells) meets the limitation MRD negative.
Regarding claims 2 and 9, Dimopoulos et al. teaches that 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) (Fig. S4 in the Supplementary Appendix) (page 1326, column 1).
Regarding claims 3 and 10, Dimopoulos 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 4 and 11, 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.”
Regarding claims 5 and 12, Dimopoulos et al teaches that the patients had progressive disease during or after the receipt of their last regimen (abstract, page 1321, column 1, page 1320, last paragraph)n
Regarding claim 6, Dimopoulos teaches that the patients included those having high risk cytogenetic profile (Table 1).
Regarding claims 7 and 8, Dimopoulos teaches that the patients include 25 patients having del17p (Table S1).
Regarding claims 1, 13 and new claim 14, Dimopoulos teaches treating same patients (relapsed or refractory multiple myeloma patients who have received two prior lines of treatment, or who have received two prior lines of treatment and have del17p chromosomal abnormality) using same drugs (daratumumab, lenalidomide and dexamethasone) at same doses and using same schedule. Practicing the method of prior art would inherently or necessarily lead to the same results (i.e. the subject is minimal residual disease (MRD) negative at least 6 months after achieving a complete response recited in claim 1, at the time of achieving a complete response recited in claims 13-14).
Applicant’s Arguments
The response states that Dimopoulos does not disclose any analysis of MRD data stratified by number of prior lines therapy for multiple myeloma. Dimopoulos only discloses MRD data of the overall patient population of Daratumumab Group (received daratumumab, lenalidomide, and dexamethasone (DRd)) and the overall patient population of Control Group (received lenalidomide and dexamethasone without daratumumab (Rd)). Furthermore, the Protocol does not disclose future plans of stratifying MRD data by number of prior lines therapy for multiple myeloma. This is in contrast to some other end points, such as progression-free survival (PFS), time to disease progression (TTP), overall response rate, and overall survival, where number of prior lines therapy is a stratification factor to be used. See "Redacted Statistical Analysis Plan for Journal Use" (the final section of the Protocol) at pages 15-19 (pages 99-103 of the Protocol). Simply put, Dimopoulos does not disclose any analysis of MRD data stratified by number of prior lines therapy for multiple myeloma. Accordingly, Dimopoulos does not disclose MRD status in a subject who had received at least two prior lines of therapy for multiple myeloma, let alone daratumumab-mediated
improvement of MRD negativity in this subgroup of subjects.
The response states that none of the main paper, Supplementary Appendix, or Protocol of Dimopoulos discloses data on MRD status at 6 months after achieving a CR. Neither the main paper nor Supplementary Appendix discloses evaluating MRD status at 6 months post CR.
Response to Arguments
Applicant’s arguments have been carefully considered but are not persuasive.
Dimopoulos et al. teaches that patients had 1-11 lines of previous therapy (Table 1), including two lines of previous therapy (page 1321, column 1, para 2, “ …and stratified according to the number of lines of previous therapy (1 vs. 2 or 3 vs. >3)). This is further evidenced by Avet-Loiseau et al. (J Clin Oncol, 39:1139-1149, 2021, IDS 6/30/2026) submitted by applicant in the reply. Avet-Loiseau reports the results of the same clinical trial Pollux as Dimopoulos. Avet-Loiseau’s method and patient population are identical to Dimopoulos’s (see page 1140, last paragraph, which mentions Dimopoulos, see citation 17). Avet-Loiseau discloses that the patients in Pollux included those who had two line of previous therapy, see the Table under subheading 2.10 Definition of Subgroups, reproduced below:
PNG
media_image1.png
846
1100
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Greyscale
Although Dimopoulos does not teach that the subject is minimal residual disease (MRD) negative at least 6 months after achieving a complete response recited, and at the time of achieving a complete response, these are considered inherent property of the method of Dimopoulos. Dimopoulos teaches treating same patients (relapsed or refractory multiple myeloma patients who have received two prior lines of treatment, or who have received two prior lines of treatment and have del17p chromosomal abnormality) using same drugs (daratumumab, lenalidomide and dexamethasone) at same doses with same schedule. Practicing the method of prior art would inherently or necessarily lead to the same results. This is further evidenced by Avet-Loiseau et al. Avet-Loiseau discloses that higher MRD negativity rates were achieved in ≥ CR (complete response) patients in POLLUX (D-Rd, 57.4%; Rd, 29.2%; P=0.0001, and more patients in the ITT (intent to treat) population achieved sustained MRD negativity ≥ 6 months with D-Rd versus Rd (20.3% v 2.1%; P< .0001) (abstract and Table 1).
For the foregoing reasons, the rejection is deemed proper and is therefore maintained.
Claim Rejections - 35 USC § 103
9. 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.
10. Claims 1-13 and new claim 14 remain/are rejected 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).
The teachings of Dimopoulos et al have been set forth above as they apply to claims 1-13.
Dimopoulos et al teaches treating patients having high risk cytogenetic profile and stage III MM patients including those have cytogenetic profile Del17p, t(4;14) and t(14;16) (Table 1, and Table S1).
Dimopoulos et al does not specifically disclose that the high risk cytogenetic profile comprises a chromosomal abnormality t(4;14)(p16;q32), or t(14;16)(q32;q23).
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).
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 Dimopoulos to treat multiple myeloma comprising t(4;14)(p16;q32), or t(14;16)(q32;q23) chromosomal abnormality in view of Rajkumar et al. One of ordinary skill in the art would have been motivated to do so because Dimopoulos et al teaches treating patients having high risk cytogenetic profile and stage III MM patients (Table 1) including those have cytogenetic profile Del17p, t(4;14) and t(14;16) (Table S1), and 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). One of ordinary skill in the art would have had a reasonable expectation of success because Dimopoulos et al teaches treating patients having high risk cytogenetic profile and stage III MM patients including those have cytogenetic profile Del17p, t(4;14) and t(14;16) (Table 1, Table S1), Rajkumar et al teaches that carfilzomib, lenalidomide and dexamethasone (KRD) has been used clinically to treat high-risk myeloma (page 106, column 2).
Applicant’s Arguments
The response as discussed above, Dimopoulos does not teach or suggest at least two elements of claim 1: (i) MRD negativity in a subject who had received at least two prior lines of therapy for multiple myeloma, and (ii) MRD negativity at 6 months after achieving a CR. Rajkumar also does not teach or suggest either claim element. Accordingly, Rajkumar does not remedy the deficiencies in Dimopoulos' teaching, and a prima facie case of obviousness is not established.
Applicant submits the following evidence of nonobviousness, including unexpected results. At the priority date of the present application, available therapies for multiple myeloma had a complete response rate as low as approximately 5%, and the disease relapsed in nearly all patients, creating a need for therapies capable of achieving deeper levels of response. See, e.g., paragraph [0008] of the specification as filed. At the priority date of the present application, it was also known that: (i) in general, a subject is expected to have a decreased treatment response as the number of prior lines of therapy increases, and (ii) MRD negativity is associated with improved PFS and OS for multiple myeloma. Accordingly, a skilled person would have expected MRD negativity rate to decrease as the number of prior line increases. Specifically, a skilled person would have expected a lower MRD negativity rate in subjects who had received at least two prior lines of therapy of multiple myeloma than those who had received only one prior line of therapy. Contrary to treatment with Isa-Kd, Kd, or Rd, among others, the stratified MRD data in the DRd Group was unexpectedly higher in subjects who had received at least two prior lines of therapy than in subjects who had received one prior line of therapy. Furthermore, unexpectedly, the addition of daratumumab to Rd confers a greater improvement in MRD negativity in subjects who had received at least two prior lines of therapy for multiple myeloma than subjects who had received only one prior line of therapy. In summary, the skilled person would not have arrived at the claimed subject matter from Dimopoulos and Rajkumar. It is without doubt that the remarkable efficacy of the claimed method of treating multiple myeloma in a subject who had received at least two prior lines of therapy for multiple myeloma by administering a combination dosing regimen comprising daratumumab, lenalidomide, and dexamethasone is far beyond any effect that could have reasonably been expected from Dimopoulos and Rajkumar.
The Application as filed assessed MRD at the time of suspected CR, and at 3 and 6 months post-suspected CR for subjects who maintained this response. The Application as filed shows that a large number of subjects, the majority of which were in the DRd group, reached MRD negative state at a time of suspected complete response and maintained it over time (paras. [0021], [0022], and [00273], and FIGs. 6A and 6B). The Application as filed further shows that some subjects showed rapid clinical response as well as a strong reduction in the clone frequency, but did not reach MRD negativity at first evaluation at the time of suspected CR. These subjects required more time to reach MRD negativity, but did eventually become MRD negative at later time points (paras. [0029], [0030], and [00276], and FIGs. 9A and 9B). Avet-Loiseau et al. evaluated sustained MRD negativity and outcomes by assessing MRD at suspected CR, 3 and 6 months following confirmed CR, and every 12 months post-CR.
Among subjects who achieved complete response or better (> CR), significantly more subjects achieved sustained MRD negativity in the D-Rd group (see, e.g., Table 1):
- >6 months with D-Rd versus Rd (35.8% v 9.2%; P < .0001); and
- >12 months with D-Rd versus Rd (28.4% v 6.2%; P = .0001). An improvement in daratumumab-mediated sustained MRD negativity was not suggested in, and
could not have been predicted from, the combination of Dimopoulos and Rajkumar. Furthermore, sustained MRD negativity was associated with prolonged progression-free
survival (PFS) (see, e.g., Avet-Loiseau et al., Abstract (p. 1139), RESULTS (p. 1142, right column), and FIGs. 2A and 3A (reproduced below)). Accordingly, a subject who is MRD negative at 6 months after achieving a complete response, as currently claimed, is expected to have a much better survival outcome than a subject who is not.
Response to Arguments
Applicant’s arguments have been carefully considered but are not persuasive for the reasons discussed in 102(a)(1) rejection.
Applicant’s arguments of unexpected results are not persuasive as these results are inherent property of the method of Dimopoulos. Dimopoulos teaches treating same patients (relapsed or refractory multiple myeloma patients who have received two prior lines of treatment, or who have received two prior lines of treatment and have del17p chromosomal abnormality) using same drugs (daratumumab, lenalidomide and dexamethasone) at same doses with same schedule. Practicing the method of prior art would inherently or necessarily lead to the same results.
The 103 rejection was made for the limitation “the high risk cytogenetic profile comprises a chromosomal abnormality t(4;14)(p16;q32), or t(14;16)(q32;q23)”. Applicant did not show unexpected results that are related to this limitation.
For the foregoing reasons, the rejection is deemed proper and is therefore maintained.
Conclusion
12. 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.
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/HONG SANG/Primary Examiner, Art Unit 1643
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