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 .
DETAILED ACTION
The Amendment filed 2/6/2026 in response to Office Action of 8/8/2025, is acknowledged and has been entered. Claims 27-53 are now pending. Claim 27 is amended. Claims 27-53 are currently being examined.
Maintained Rejection
(Arguments Addressed)
Claim Rejections - 35 USC § 103
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.
Claim(s) 27-53 remain rejected under 35 U.S.C. 103 as being unpatentable over Study: NCT02541383 (Published: 05/31/2016l of record), in view of Cavo et al. (“Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study.” Lancet. 376,9758, 2010; of record), NCT03143036 (Published 05/03/2017; of record), van Beurden-Tan et al (Journal of Clinical Oncology 35, no. 12 (April 20, 2017) 1312-1319; of record), Mateos et al (Published 02/08/2018; of record) (N Engl J Med 2018; 378:5 18- 528) and Moreau et al (Blood (2014) 124 (21): 176; of record).
NCT02541383 teaches a method of treating newly diagnosed multiple myeloma in a subject comprising administering daratumumab, bortezomib, thalidomide, dexamethasone (or prednisone) (DVTd) combination therapy to the subject, wherein: (a) the subject is eligible for autologous stem cell transplant (ASCT), and (b) the DVTd combination therapy comprises daratumumab 16 mg/kg. NCT02541383 teaches that the purpose of the clinical trial is to demonstrate whether this combination increases progression free survival in patients with newly diagnosed multiple myeloma. NCT02541383 teaches measuring PFS as a primary and secondary outcome of the method. [Arm B, Part 1; Outcome Measures]
However, NCT02541383 does not explicitly teach: (1) the instantly claimed dosing regimen of components in each phase, including the consolidation phase, (2) the subject achieves progression free survival (PFS) of at least 30 months, (3) Claim 28 that the administration of DVTd increases the likelihood of achieving a negative status for minimal residual disease (compared to administration of the VTd combination therapy) or reduces risk of progression, (4) Claim 32-33 the dosing regimen comprises HDC, and (5) Claim 37 that dexamethasone is administered as a premedication to daratumumab.
Cavo teaches a method of treating newly diagnosed multiple myeloma in a subject, comprising administering bortezomib, thalidomide and dexamethasone (VTd) combination therapy to the subject, wherein: (a) the subject is eligible for autologous stem cell transplant, and (b) 1.3 mg/m2 bortezomib, 100 mg thalidomide, and 40 mg of dexamethasone. [Figure 1] Cavo teaches that the VTd combination therapy comprises an induction phase, a high dose chemotherapy (HDC), and autologous stem cell transplant (ASCT), and a consolidation phase. [Figure 1] Cavo teaches that the induction phase comprises the following: (a) 1.3 mg/m2 bortezomib administered twice a week on weeks 1 and 2, (b) 100 mg thalidomide daily; and (d) 40 mg dexamethasone administered at least twice a week. Cavo teaches that the induction phase is followed by high dose chemotherapy and ASCT, wherein the HDC comprises melphalan, 200 mg/m2. Cavo teaches that the HDC and ASCT is followed by the consolidation phase, wherein the consolidation comprises 2 cycles comprising: (a) 1.3 mg/m2 bortezomib administered twice a week on weeks 1 and 2, (b) 100 mg thalidomide daily; and (d) 40 mg dexamethasone administered on days 1, 2, 8, 9, 15 and 16. [Figure 1, Trial Design] Cavo teaches that patients who received VTd had higher responses and associated with significantly improved of complete or near complete responses. [Discussion]
NCT03143036 teaches a method of treating cancer, multiple myeloma, comprising administering daratumumab IV 16 mg/kg weekly weeks 1 to 8, followed by 16 mg/kg once every two weeks on weeks 9-16, thalidomide 100 mg daily administered orally, dexamethasone 40 mg administered once weekly orally. [pg 6, Arms and Assigned Interventions] NCT03143036 teaches that immunomodulatory drugs, such as thalidomide and lenalidomide, has been shown to augment NK cell activity, which are important mediators of antibody dependent cellular cytotoxicity and that the combination of daratumumab and thalidomide may improve efficacy of treatment. NCT03143036 teaches that the addition of daratumumab to an immunomodulatory drug and dexamethasone or bortezomib and dexamethasone significantly improved response and progression free survival, including a high minimal disease (MRD) negative rate of more than 20%. [pgs 3-5, Brief Summary and Detailed Description]
Van Beurden-Tan teaches a method of treating multiple myeloma comprising the administration of daratumumab, lenalidomide and dexamethasone. van Beurden-Tan teaches that this combination is the most favorable in terms of progression-free survival. [Abstract, Conclusion]
Mateos teaches a method of treating newly diagnosed multiple myeloma in a subject, comprising daratumumab, bortezomib, melphalan, and prednisone. Mateos teaches the following combination therapy:
daratumumab 16 mg/kg
subQ bortezomib dose was 1.3 mg/m2 administered twice weekly on weeks 1, 2, 4, and 5 of cycle followed by once weekly on weeks 1, 2, 4, and 5 of cycles 2 through 9
oral melphalan: 9 mg/m2 once daily on days 1 – 4 of each cycle
oral prednisone 60 mg once daily days 1-4 of each cycle or dexamethasone can be substituted at a dose of 20 mg
Mateos teaches that the most approved regimens for elderly patients are lenalidomide plus dexamethasone, as well as melphalan, prednisone and thalidomide, and melphalan, prednisone, and bortezomib. Mateos teaches that the regimens are associated with a progression-free survival of 18 months to 2 years. Mateos teaches that Mateos, an anti-CD38 antibody, has direct anti-tumor effects and an immunomodulatory component that results in depletion of immunosuppressive cells and clonal expansion of cytotoxic T cells. Mateos further teaches that the daratumumab plus the approved regimens, standard of care such as bortezomib-dexamethasone, for multiple myeloma significantly prolonged progression-free survival and induced higher response, as well as reducing the risk of disease progression or death by more than 60%. Mateos teaches that this combination increased the likelihood of achieving negative status for minimal residual disease (MRD) in subjects with newly diagnosed myeloma. Mateos teaches that patients were administered dexamethasone as pre-medication on daratumumab administration days in order to mitigate infusion reactions. [Supplementary Appendix] [Abstract, Methods, Discussion]
Moreau teaches that daratumumab in combination with lenalidomide and dexamethasone has also shown encouraging early efficacy and tolerability in multiple myeloma. Moreau teaches the safety, tolerability and dosing regimen of daratumumab with other multiple myeloma backbone treatments, including bortezomib-thalidomide-dexamethasone (VTD). Moreau teaches that patients in this arm were newly diagnosed multiple myeloma patients. Moreau teaches various daratumumab doses including daratumumab 16 mg/kg every week for two cycles followed by every 2 weeks for 4 cycles. Moreau teaches that the addition of daratumumab in these backbone therapies were tolerated and did not add any additional toxicity. [Whole abstract]
It would have been prima facie obvious to one of ordinary skill at the time the invention was filed to treat newly diagnosed multiple myeloma comprising administering combination therapy, DVTd, at the instantly claimed dosing regimen in both the induction phase and the consolidation phase, wherein the subject achieves progression free survival of at least 30 months. One would have been motivated to because: (1) NCT02541383 and Moreau teach a method of treating multiple myeloma comprising the combination of daratumumab, bortezomib, thalidomide, and dexamethasone (DVTd), (2) Cavo teaches a method of treating newly diagnosed multiple myeloma comprising an induction phase, ASCT, and a consolidation phase, and teaches instantly claimed doses of components VTd, and (3) NCT03143036 teaches the known dosing of daratumumab, thalidomide and dexamethasone (DTd) in the treatment of multiple myeloma. One would have had a reasonable expectation of success, because: (1) Cavo successfully demonstrates treating multiple myeloma by administering VTd and that this combination slows the disease progression and prolongs survival, and (2) the prior art all teach methods of treating multiple myeloma comprising known doses and dosing regimens, and teach that these combinations are most favorable in terms of improves responses and efficacy. NCT02541383 recognizes the need in the art to treat newly diagnosed myeloma comprising administering DVTd combination therapy. Given the recognized need to treat newly diagnosed multiple myeloma, and given the known methods of administering the combination therapy at the instantly claimed dosing and known dosing regimens, one of skill in the art could have pursued administering DVTd at the instantly claimed dosing regimen to treat newly diagnosed multiple myeloma in the method of NCT02541383, with a reasonable expectation of success.
Those of skill in the art recognize that DTd and DVd, are known to successfully improve progression free survival in patients with multiple myeloma, and could have been combined by known methods, and that in combination, each combination of the composition merely would have performed the same function as they did separately, and one of ordinary skill in the art would have recognized that the results of the combination would predictably improve progression-free survival and have additive effects through the combination of the agents.
As stated in the above rejection, each of these combinations had been taught by the prior art to be effective in improving progression-free survival in subjects with multiple myeloma, the instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that: “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition which is to be used for the very same purpose. In re Susi, 58 CCPA 1074, 1079-80, 440 F.2d 442, 445, 169 USPQ 423, 426 (1971); In re Crockett, 47 CCPA 1018, 1020-21, 279 F.2d 274, 276-77, 126 USPQ 186, 188 (1960). As this court explained in Crockett, the idea of combining them flows logically from their having been individually taught in the prior art.” In the instant case, it is prima facie obvious to combine the two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition which is to be used for the very same purpose of improving progression free survival in subjects with newly diagnosed multiple myeloma.
Is it noted that claim 32, 33, 46, and 47 require the method to include high dose chemotherapy, melphalan at a dose of 200 mg/m2. This limitation would have been obvious to those of ordinary skill in the art because: (1) Mateos teaches the treatment of newly diagnosed multiple myeloma comprising administering daratumumab, bortezomib, melphalan, and prednisone, and (2) Cavo teaches a method of treating multiple myeloma comprising a HDC melphalan 200 mg/m2. One of ordinary skill in the art would have a reasonable expectation of success because Mateos teaches that the combination led to a significantly prolonged PFS and higher responses. Those of skill in the art recognized that these agents (DVTd and melphalan) are all known to successfully, pharmaceutically treat newly diagnosed multiple myeloma, and could have been combined by known methods, and that in combination, each agent of the combination therapy would have performed the same function as they did separately, and one of ordinary skill in the art would have recognized that the results of the combination would predictably treat newly diagnosed multiple myeloma and have additive affects through the combination of all of these agents.
As stated in the above rejection, each of these agents had been taught by the prior art to be effective in treating newly diagnosed multiple myeloma, thus the instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that: “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition which is to be used for the very same purpose. In re Susi, 58 CCPA 1074, 1079-80, 440 F.2d 442, 445, 169 USPQ 423, 426 (1971); In re Crockett, 47 CCPA 1018, 1020-21, 279 F.2d 274, 276-77, 126 USPQ 186, 188 (1960). As this court explained in Crockett, the idea of combining them flows logically from their having been individually taught in the prior art.” In the instant case, it is prima facie obvious to combine this combination of agents, each of which is taught by the prior art to be useful for the same purpose, which is to be used for the very same purpose of treating subjects with newly diagnosed multiple myeloma.
It is noted that claim 37 and 51 require the method to administer dexamethasone as a pre-medication to daratumumab. This limitation would have been obvious to those of ordinary skill in the art because: (1) Mateos teaches the treatment of newly diagnosed multiple myeloma comprising administering daratumumab, bortezomib, melphalan, and prednisone, and (2) Mateos teaches the administration of dexamethasone as a pre-medication to daratumumab, in order to mitigate infusion reactions. Given the recognized need to treat infusion reactions caused by daratumumab and given the known methods of pre-treatments using dexamethasone, one of skill in the art could have pursued administering dexamethasone as a premedication to daratumumab, with a reasonable expectation of success.
It is noted that claim 41, 42 and 51 require the method to administer DVTd to increase the likelihood of achieving a negative status for MRD and that the likelihood is 33% or higher or to reduce risk of progression of multiple myeloma by about 53%. This limitation would have been obvious to those of ordinary skill in the art because: (1) NCT02541383 and Moreau teaches the method of treating multiple myeloma comprising the combination of DVTd, (2) Cavo teaches that VTd had higher responses and associated with significant responses, (3) NCT03143036 teaches that the addition of daratumumab to approved agents that treat multiple myeloma significantly improved responses and progression free survival; including MRD of more than 20%, and (4) Mateos teaches that daratumumab plus approved regimens for multiple myelomas significantly improved prolonged PFS and high responses; and reduced risk of disease progression by more than 60%.
Response to Relevant Arguments
Applicant argues that none of the cited references discloses a method of treating newly diagnosed multiple myeloma in a subject eligible for ASCT with DVTd, where PFS Is assessed as an outcome of the method. NCT02541383: Applicant argues that this reference discloses no data and does not teach or suggest the claimed dosing regimen, the subject achieving PFS of at least 30 months, or the method achieving an 19-month PFS rate of 92% or more. Moreau: Applicant argues that Moraeu does not disclose dosing regimen of VTd and discloses a different dosing regimen.
Applicant’s arguments have been considered but are not persuasive. The claim is drawn to a method of treatment of newly diagnosed multiple myeloma comprising administering DVTd combination therapy. As stated in prior office actions, the Examiner relied on the combination of references cited above to provide a reasonable expectation of success for the method of NCT02541383 to result in improved PFS.
The use of these agents in this specific patient population has already been demonstrated by the primary reference. The primary reference, NCT02541383, teaches this method for this specific patient population: newly diagnosed multiple myeloma comprising administering DVTd, wherein the subject is eligible for ASCT. Although the primary reference does not disclose the results of the method, it teaches the objective (motivation) of the method is to measure PFS as a primary and secondary outcome and measure of success. Applicants argue that none of the cited references can be combined due to their differing objectives and/or combinations. Examiner outlines the purpose of each reference:
Cavo demonstrates a method of treating the same instantly claimed patient population, and teaches the known doses of each individual agent. Cavo teaches that this combination slows the disease progression and prolongs survival. The combination, DVTd, is already taught and known. The efficacy of daratumumab is taught in NCT03143036 (teaches that addition of daratumumab to an immunomodulatory drug and dexamethasone or bortezomib and dexamethasone significantly improved response and progression free survival), and Matoes (Mateos further teaches that the daratumumab plus the approved regimens, standard of care such as bortezomib-dexamethasone, for multiple myeloma significantly prolonged progression-free survival and induced higher response, as well as reducing the risk of disease progression or death by more than 60%).
NCT03143036: NCT03143036 explicitly teaches that addition of daratumumab to an immunomodulatory drug and dexamethasone or bortezomib and dexamethasone significantly improved response and progression free survival.
Van Beurden-Tan: teaches a method of treating multiple myeloma comprising administering daratumumab, an immunomodulatory drug, and dexamethasone (DTd), and that this combination is most favorable in terms of progression free survival. Van Beurdan teaches the use of an immunomodulatory drug, whether that is lenalidomide or thalidomide.
Mateos: As noted above, the combination of DVTd was already taught in the primary reference, the purpose of Matoes is to teach and demonstrate a method of treating newly diagnosed multiple myeloma comprising DVd and high dose chemotherapy. Mateos teaches that this method significantly improved progression-free survival. Mateos also teaches that bortezomib-dexamethasone are approved regimens for the treatment of multiple myeloma. Mateos teaches known combination regimens for the treatment of multiple myeloma.
Moreau: As noted prior, the purpose of this reference is to teach known combination of DTd and that this combination shows encouraging early efficacy
It is the combination of the references that render the claims obvious. DVTd is known in the art for the treatment of newly diagnosed multiple myeloma. The secondary references all demonstrate known methods of treating multiple myeloma, including subpopulation of newly diagnosed multiple myeloma, and further teach the known success of increasing progression free survival of using combinations of daratumumab, bortezomib, thalidomide, and/or dexamethasone. Combinations including DTd and DVd are known in the art, and are known to increase progression free survival in patients with multiple myeloma, including newly diagnosed multiple myeloma. Further, as taught by NCT03143036 and Mateos, the addition of daratumumab to approved regimens of multiple myeloma, whether that is Td or Vd, is known to improve efficacy and PFS. Based on the cited references, one of skill in the art would reasonably expect that the combination, DVTd will have additive effects and improve progression free survival, even compared to VTd.
Conclusion
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SARAH A ALSOMAIRY whose telephone number is (571)272-0027. The examiner can normally be reached Monday-Friday 7:30 AM to 5:30 PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Gregory Emch can be reached at (571) 272-8149. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/SARAH A ALSOMAIRY/Examiner, Art Unit 1646
/Zachariah Lucas/Supervisory Patent Examiner, Art Unit 1600