DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 23 December 2025, has been entered.
Status of Application, Amendments and/or Claims
Applicant’s arguments, filed 23 December 2025, have been entered in full. The Tsuji Declaration under 37 CFR 1.132, filed 23 December 2025, has been entered in full. Claims 7 and 12 are pending and under examination.
Information Disclosure Statement
The information disclosure statement(s) (IDS) (filed 26 January 2026) was received and complies with the provisions of 37 CFR §§1.97, 1.98 and MPEP § 609. It has been placed in the application file and the information referred to therein has been considered as to the merits. However, it is noted that reference number 28 has not been considered by the Examiner because the reference is not legible.
Applicant is advised that the date of any re-submission of any item of information contained in this information disclosure statement or the submission of any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the statement, including all certification requirements for statements under 37 CFR 1.97(e). See MPEP § 609.05(a).
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 7 and 12 remain rejected under 35 U.S.C. 103 as being unpatentable over Lee et al. (Efficacy and Safety of Romiplostim in patients with Aplastic Anemia in Refractory to immunosuppressive therapy: 1-year interim Analysis of Phase 2 Clinical Trial. BLOOD. Vol. 128/No. 22, ABSTRACT NUMBER 3910; DEC 2016).
The basis for this rejection is set forth at pages 2-11 of the previous Office Action (24 June 2025).
Lee et al. teach subjects with aplastic anemia (AA) treated with romiplostim (RMP). Lee et al. teach AA subjects were randomized to four treatment groups wherein the groups were subcutaneously administered 1, 3, 6, or 10 ug/kg of RMP once weekly for 8 weeks. Lee et al. teach after 8 weeks of treatment, platelet response counts from the subjects were measured. Lee et al. teach that a platelet response is defined as increases by > 20x109/L above baseline or increases > 10x109 and by 100% from baseline.
Lee et al. teach adjusting the dose of RMP from 1 to 20 ug/kg to maintain a subject’s platelet response. Lee et al. teach that the primary endpoint is the platelet response rate after 8 weeks. Lee et al. teach the platelet response was 0% (0/7 subjects), 0% (0/7 subjects), 33.3% (3/9 subjects) and 70.0% (7/10 subjects) for the RMP subcutaneous administered amounts of 1, 3, 6 and 10 ug/kg, respectively and that the platelet response was dose dependent.
In summary, Lee et al. teach subcutaneously administering RMP at 10 ug/kg/week for 8 weeks to aplastic anemia subjects, measuring platelet counts from the subjects, and then adjusting the administered RMP dose from 1 to 20 ug/kg to maintain the subject's platelet response.
Lee et al. do not teach subcutaneously administering RMP at 10 ug/kg/week for 4 weeks to aplastic anemia subjects, then measuring platelet counts from the subjects, and adjusting the administered RMP dose by 5 ug/kg in subjects with no platelet response. Lee et al. do not teach assessing the subject’s platelet responsiveness every 4 weeks and adjusting the RMP dose in an increment of 5 ug/kg/week based on the results of the assessment.
However, it would have been obvious for one of ordinary skill in the art before the effective filling date to modify the method of Lee et al., to make the instant invention. One of ordinary skill in the art before the effective filing date, would have been motivated to make such modifications and expect success for the following reasons:
Optimization of doses or a dosage regimen is considered routine and is well within the ordinary level of skill in the art, and is thus obvious absent evidence of 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 M.P.E.P. § 2144.05.
In the instant case, both Lee and the instant claims teach the same subject population of aplastic anemia. Both Lee and the instant claims teach initially subcutaneously administering RMP at 10 ug/kg/week. Both Lee and the instant claims teach the same parameters for how a subject’s patient response is defined (i.e. platelet count increases by > 20x109/L above baseline or increases > 10x109 and by 100% from baseline). Both Lee and the instant claims teach a maximum RMP dose of 20 ug/kg/week.
The only difference between Lee and the instant claims is:
Lee et al. teach subcutaneously administering RMP at 10 ug/kg/week for 8 weeks before measuring the subject’s platelet response and adjusting the administered RMP dose from 1 to 20 ug/kg to maintain a subject's platelet response with a maximum dose being 20 ug/kg of RMP.
The instant claims teach subcutaneously administering RMP at 10 ug/kg/week for 4 weeks before measuring the subject’s platelet response and adjusting the administered RMP dose by 5 ug/kg to a subject with no platelet response and continuing to assess the responsiveness every 4 weeks wherein RMP is administered in increments of 5 ug/kg/week depending on the results of assessing platelet response of the subject, with a maximum dose being 20 ug/kg of RMP.
See Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382; (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”). It is well within the skilled artisan's knowledge to discern the most favorable pharmaceutical dosage because these modifications are deemed a matter of judicious selection and routine optimization.
APPLICANT’S ARGUMENTS: Applicant argues that the claimed regimen, featuring a 4-week fixed dose period and a 5 ug/kg increment starting at Week 5, produces unexpectedly superior and sustained efficacy, as shown in the evidence submitted in the attached Rule 132 Declaration.
Applicant maintains that while the earlier benefit was expected due to reaching the maximum dose sooner than Lee (at Week 9 vs. Week 17), the sustained clinical difference was surprising. Applicant states that it was predicted that efficacy would lessen once the Lee group also reached the maximum dose (starting Week 17), but the claimed regimen maintained superior efficacy (platelet, hemoglobin, and neutrophil levels) up to Week 53.
Applicant argues that quantitatively, the tri-lineage response at Week 53 was 32% (8/25 subjects) in the claimed group, significantly exceeding the 10.0% (1/10 subjects) in Lee. Applicant argues that the aggressive, early dosing of RMP was also counterintuitive given the risk of promoting clonal evolution to MDS or AML.
The Tsuji Declaration under CFR 1.132: The Declaration states that the claimed invention relates to a method for treating aplastic anemia using Romiplostim (RMP), which includes administering RMP at 10ug/kg/week for 4 weeks, assessing responsiveness at the end of Week 4, selecting a subject that has no platelet response, and increasing the dose by 5 ug/kg from Week 5.
The Declaration states that the present application originally included Figures 1-3, which compared the results of the Ph2/3 trial (Study 531-002) against the prior art Ph2 trial (KR001, 10µg/kg group). The Declaration stated that the previous Office Action expressed concern regarding the original presentation of the Ph2/3 data (Study 531-002) in Figures 1-3, noting that the data represented an average of all 31 subjects.
The Declaration stated that the previous Office Action indicated that the Figures included data for subjects who were not included in the claims, such as subjects who maintained the 10µg/kg dose of RMP during Weeks 5-8. The Office Action discussed the possibility of separating out those subjects who had no platelet response for 4 consecutive weeks and were administered the increase of Romiplostim by 5µg/kg from Week 5.
Data Revision and Clarification: The Declaration states that in response to the Office Action's concerns and in order to ensure the data accurately reflects the effects of the dose adjustment regimen claimed in claim 7, Figures 1-3 have been revised.
The Declarations states that the data corresponding to the Ph2/3 trial (Study 531-002), which originally represented all 31 cases, has been modified.
The revised Ph2/3 data now includes only the 25 cases in which the dose was increased to 15ug/kg at Week 5 (excluding the six subjects who did not receive the dose increment at Weeks 5). The data corresponding to the Ph2 trial (KR001, 10/g/kg group, N=10) remains unchanged in the revised figures.
Significance of the Revised Data: The Declaration states that the revision ensures that the data shown in Figures 1-3 for the Ph2/3 trial accurately reflect the claimed method of treating aplastic anemia, specifically the regimen that involves early selection and dose escalation. The claimed Ph2/3 regimen, reflected in the data of the 25 subjects, is characterized by a shorter initial fixed dose period (4 weeks compared to 8 weeks in Lee/Ph2) and a larger dose increment (5ug/kg/week). The Declaration states that the claimed regimen allows subjects to reach the maximum dose of 20µg/kg earlier (at least 9 weeks) compared to the Ph2 trial (17 weeks).
The Declaration states that by including only the patients who followed the claimed dose escalation criteria (receiving 15µg/kg from Week 5), the revised Figures 1-3 demonstrate the benefit of the claimed regimen compared to the prior art. The revised Figures support the unexpected superior efficacy obtained specifically through this claimed regimen.
The Declaration states that on page 4-11 of the previous Office Action, the Office asserts that if the Ph2/3 Group utilized an earlier dose adjustment and a larger increment (e.g., 15µg/kg from Week 5), better efficacy compared to the Ph2 Group would be obvious. The Declaration states that the Examiner appears to view the benefits resulting from earlier and larger dose increments as merely routine optimization. The Declaration states that the data confirms that the results achieved are unexpectedly superior and sustained.
Unexpected Superior Efficacy Data: The Declaration states that the evidence comparing the claimed regimen (Ph2/3 trial data focusing on subjects fitting the claims) to the prior art (Lee Ph2, 10 µg/kg group) demonstrates an unexpected improvement in outcomes for aplastic anemia (AA) patients.
1. Superior Tri-Lineage Hematopoietic Response: The Declaration states that as argued in the Response filed on March 18, 2025, the claimed regimen achieved a significantly and unexpectedly higher rate of tri-lineage response (Table 4 from the instant specification for all 31 cases) compared to the prior art.
The Declaration states that even in the claimed regimen, tri-lineage response positive subjects were measured at:
Week 53: 32.0% (8/25 subjects) in the claimed Ph2/3 regimen, compared to 10.0% (1/10 subjects) in the Lee Ph2 (10 µg/kg group). Week 27: 28.0% (7/25 subjects) in the claimed Ph2/3 regimen, compared to 0% (0/10 subjects) in the Lee Ph2 (10 µg/kg group).
2. Sustained Superiority: The claimed regimen utilized a faster dose escalation schedule (dose increase starting at Week 5, maximum dose of 20 µg/kg reached at least by Week 9) compared to Lee (dose increase starting at Week 9, maximum dose reached earliest at Week 17).
The Declaration states that it was expected that the claimed regimen would achieve an earlier, higher effect simply by reaching the optimal dose sooner. The Declaration states that it was predicted that as the difference in the administered dose between the two groups diminished (i.e., once the Lee group also reached the maximum dose starting at Week 17), the overall difference in efficacy would also lessen, or the results would converge.
The Declaration, however, states that the data demonstrated that the superior therapeutic effect (the difference in clinical metrics like platelet, hemoglobin, and neutrophil levels) was not diminished after Week 17. The Ph2/3 group maintained superior efficacy up to Week 53.
The Declaration concludes by stating that this continued, excellent improvement effect, even after both treatment groups had the opportunity to reach the maximum dosage, was surprising and unexpected. The sustained clinical advantage confirms that the specific decision to shorten the fixed-dose period to 4 weeks and implement a 5 µg/kg increment starting at Week 5 was a critical therapeutic choice that achieved outcomes beyond what could be anticipated from simple, routine optimization of the known Lee regimen.
Applicant’s arguments have been fully considered but are not persuasive. The Tsuji Declaration under 37 CFR 1.132, filed 23 December 2025, is insufficient to overcome the rejection of claim 7 and 12 based upon 35 U.S.C. 103 as being unpatentable over Lee et al. (Efficacy and Safety of Romiplostim in patients with Aplastic Anemia in Refractory to immunosuppressive therapy: 1-year interim Analysis of Phase 2 Clinical Trial. BLOOD. Vol. 128/No. 22, ABSTRACT NUMBER 3910; DEC 2016), as set forth in the last Office action because of the following reasons:
1. The arguments regarding the Tri-lineage response in Table 4 from the instant specification of Trial Ph2 and the instant invention Trial Ph2/3 and the Tri-lineage response of the 25 cases from Trial Ph2/3 are not commensurate in scope with the instant claims.
This is because the instant claims recite “assessing the responsiveness of the subject to Romiplostim administration….based on measured platelet counts..” The claims further recite, “wherein the platelet response is defined as one of following conditions….”.
The instant specification teaches “tri-lineage response or tri-lineage response positive is defined as achieving platelet response, erythroid response and neutrophil response all together” (specification at paragraph 0118). Therefore, the arguments regarding Tri-lineage response is not commensurate in scope with the claims, as currently recited.
The Examiner also notes that the Lee reference teaches a tri-lineage response at week 52 of 33.3% (see 2nd page, 3rd full paragraph of Lee et al.), not 10.0% as stated by the Declaration.
2. Secondly, Applicant and the Declaration state that Lee teaches a dose increase starting at Week 9, with a maximum dose (20 ug/kg) reached earliest at Week 17.
The Examiner is unclear where this teaching is found in the cited Lee reference.
The Examiner reminds Applicant that the Lee reference is the applied art.
The Lee reference teaches that after the 8-week treatment of 10 ug/kg/week of RMP, the dose of RMP was adjusted from 1 to 20 ug.kg to maintain their platelet response.
The Examiner does not see a teaching in Lee et al. wherein a maximum dose of 20 ug/kg of RMP was reached earliest at Week 17.
Therefore, the arguments that it was predicted that as the difference in the administered dose between Ph2/3 (instant invention) and Ph2 (Lee) diminished (i.e., once the Lee group also reached the maximum dose starting at Week 17), the overall difference in efficacy would also lessen, but the superior therapeutic effect of Ph2/3 did not diminish after Week 17 and stayed superior up to Week 53., is not found persuasive.
3. Lastly, even if the Lee reference taught administering a maximum dose of 20 ug/kg of RMP at week 17, the results discussed by Applicant and the Declaration would be obvious and expected for the following reasons:
The instant invention (Ph2/3) has a head start/advantage of 12 weeks, wherein the subjects are at a higher dose of administered RMP (i.e. dose of 10 ug/kg from week 1 to week 4, a dose of 15 ug/kg from week 5 to week 9; a maximum dose of 20 ug/kg from week 9 to week 17). Compared to Ph2 (i.e. dose of 10 ug/kg from week 1 to week 8, reaching a maximum dose of 20 ug/kg at week 17).
But as was stated above, Lee does not teach that 20 ug/kg was administered at week 17, nor does Lee teach that 20 ug/kg was consistently administered during week 17 to week 53.
The scientific reasoning and evidence indicates that the rejection should be maintained.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to REGINA M DEBERRY whose telephone number is (571)272-0882. The examiner can normally be reached M-F 9:00-6:30 pm (alt Fri).
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/R.M.D/Examiner, Art Unit 1647 4/23/2026
/BRIDGET E BUNNER/Primary Examiner, Art Unit 1647
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