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 .
Claim Status
Applicant’s submission filed 09/11/2025 has been received and entered. Claims 2, 12, 15, 17 and 58 have been cancelled, claims 1, 13, 14, 48 and 56 have been amended. Accordingly, claims 1, 3-4, 6, 13-14, 16, 19, 30, 47-48, 53-56 are pending and under current examination.
Status of Prior Rejection/Response to Arguments
The objection to the title is withdrawn:
Applicant’s amendment to the title obviates the current objection on record. Therefore, the objection is withdrawn.
The objection to the Abstract is withdrawn:
Applicant’s submission of separate page of Abstract obviates the current objection on record. The objection is withdrawn.
The objection to claim 48 is withdrawn:
Applicant’s amendment to claim 48 obviates the current objection on record. The objection is withdrawn.
The objection to claims 1-4, 6, 12-17, 19, 30, 47-48 and 53-56 under 35 U.S.C. §112(a) is withdrawn:
Applicant’s amendment to claim 1 limit the diseases in the scope of a non-malignant blood disorder, a metabolic disorder or an immunodeficiency disorder obviates the current objection on record. The objection is withdrawn.
The rejection to claims 1-3, 56 and 58 under 35 U.S.C. §102(a)(1) and (a)(2) over Marsh et al. is withdrawn:
Applicant’s amendment to claim 1 adds the limitation “about 8 mg/m2 - about 12mg/m2 alemtuzumab is administered to the subject”. Marsh et al. do not teach this limitation. Therefore the amendment is effective to obviate the current rejection on record. The rejection is withdrawn.
The rejection to claims 1-4, 6, 12-17, 19, 56 and 58 under 35 U.S.C. §103 over Marsh et al. is maintained:
The rejection to claims 1-4, 6, 12-17, 19, 30, 47, 53-56 and 58 under 35 U.S.C. §103 over Marsh et al. in view of Fukuda et al. is maintained:
Applicant amends claim 1, and asserts that instant application has unexpected results that dosing of alemtuzumab based on body surface area (BSA, mg/m2) in the claimed concentration range decreases the percentage of patients with alemtuzumab concentrations above 0.6 µg/ml substantially (e.g., compared to dosing per kg), without significantly increasing the percentage of patients with alemtuzumab concentrations below 0.15 µg/ml (Remarks, p10).
Applicant’s argument is fully considered but found not persuasive. Claim 1 is directed to a method of treating a non-malignant blood disorder, a metabolic disorder or an immunodeficiency disorder in a subject comprising transplanting allogeneic hematopoietic cells into the subject; wherein the subject has a blood concentration of alemtuzumab in a range of about 0.15 µg/mL - about 0.6 µg/mL on day 0. While Applicant shows the unexpected results is decreasing the percentage of patients with alemtuzumab concentrations above 0.6 µg/ml substantially but not the change in the claimed range. Therefore applicant is arguing a limitation not presented in instant claims. The rejection is maintained and modified necessitated by the amendments of the claims.
Modified 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.
Claims 1, 3-4, 6, 13-14, 16, 19 and 56 stand rejected under 35 U.S.C. 103 as being unpatentable over Marsh et al. (BLOOD, 2016, V127, NO 4, published in 2016, as cited in IDS). The rejection is modified necessitated by Applicant’s amendment.
Marsh et al. collected data from 105 patients to examine the influence of peritransplant alemtuzumab levels on acute GVHD, mixed chimerism, and lymphocyte recovery (Abstract).
Regarding claim 1, Marsh et al. teach reduced intensity conditioning regimens (RIC) containing alemtuzumab, fludarabine, and melphalan have shown promise for the allogeneic hematopoietic cell transplantation (HCT) of pediatric and young adult patients with nonmalignant diseases including non-malignant blood disorders (e.g., Hematologic Cytopenias), metabolic disorders (e.g., Hurler’s syndrome syndrome) or immunodeficiency disorders (e.g., primary immunodeficiency)(see p503, left column, as well as the cited references of the paragraph). Marsh et al. collected data from 105 patients with nonmalignant diseases to illuminate the significant influence of peritransplant alemtuzumab levels (day 0 ± 72 hours) on the early outcomes of acute GVHD, mixed chimerism, and lymphocyte recovery (p504, right column). Table 1 (p504, left column) shows the types of nonmalignant diseases, and the characteristics of patient and transplant. This teaching reads on a method of treating a non-malignant blood disorder, a metabolic disorder or an immunodeficiency disorder (which needs hematopoietic cells transplantation) comprising transplanting allogeneic hematopoietic cells into the subject. Marsh et al. teach targeting alemtuzumab levels for patients receiving T cell–replete grafts from bone marrow or peripheral blood mononuclear cell graft donors to achieve levels between 0.2 and 0.4 µg/mL on day 0 to achieve a lytic level at the time of graft infusion to protect against the development of acute GVHD, but allow for quick clearance by day 130 after, to optimize lymphocyte recovery (p511, left column). This teaching reads on “the subject has a blood concentration of alemtuzumab in a range of about 0.2 µg/mL - about 0.4 µg/mL on day 0; wherein day 0 is the day, or a planned day, when the transplanting of the allogeneic hematopoietic cells into the subject occurs”, wherein the range of about 0.2 µg/mL - about 0.4 µg/mL is in the range of 0.15 µg/mL - about 0.6 µg/mL as recited in instant claim. Marsh et al. also teach patients were classified as having received distal, intermediate, or proximal alemtuzumab schedules. Distal alemtuzumab schedules were given as a dose escalation schedule of 3/10/15/20 mg alemtuzumab over days -22 to -19. Patients weighing ,10 kg received 3/10/10/10 mg. Intermediate alemtuzumab schedules were given as 1 mg/kg alemtuzumab divided over days -14 to -10 (0.2 mg/kg/dose). Proximal alemtuzumab schedules were given starting on day -12 or closer to day 0, as either the dose escalation schedule above or as a cumulative 1 mg/kg dose divided over 5 days (p505, right column). This teaching reads on ”administering to the subject alemtuzumab starting at a day between day -22 and day -8” in instant claim.
Marsh et al. do not teach about 8 mg/m2 - about 12 mg/m2 alemtuzumab is administrated to the subject. ). Instead Marsh et al. teach the intermediate alemtuzumab schedule (day -14 to day -10) last 5 days, with a dose of 1 mg/kg (0.2 mg/kg/dose for 5 doses). For Patients weighing <10 kg, the dose is limited to less than 10 mg/dose (see distal alemtuzumab schedules, p505, right column). However, 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 modify the schedule of Marsh et al., change and optimize the alemtuzumab administration dose, as long as making sure the alemtuzumab levels achieve levels between 0.2 and 0.4 µg/mL on day 0. It is not considered inventive to find optimal workable ranges by routine experimentation. Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[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." See Jn re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Regarding claim 3, Marsh et al. teach the intermediate alemtuzumab schedules were given as 1 mg/kg alemtuzumab divided over days -14 to -10 (0.2 mg/kg/dose) (p505, right column).
Regarding claims 4 and 6, Marsh et al. do not teach the administering comprises administering alemtuzumab to the subject over two days starting at day -14 (day -14 and day -13, claim 4), or the administering comprises administering alemtuzumab to the subject over three days starting at day -14 (day -14, -13 and -12, claim 6). Instead Marsh et al. teach the schedule of using alemtuzumab: patients were classified as having received distal, intermediate, or proximal alemtuzumab schedules. The intermediate alemtuzumab schedules were given as 1 mg/kg alemtuzumab divided over days -14 to -10 (0.2 mg/kg/dose) (see p505, right column). However, 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 modify the schedule of Marsh et al., and shorten the administration of alemtuzumab from 5 days consecutively to 2 or 3 days consecutively, as long as the alemtuzumab level can achieve the level between 0.2 and 0.4 µg/mL on day 0, based on the advantage of the level of alemtuzumab taught by Marsh et al.. The only difference between instant claim and Marsh et al.’s intermediate alemtuzumab schedules is instant claim administers alemtuzumab for 2 or 3 days consecutively, given that both schedules would achieve the result that the alemtuzumab level can achieve the level between 0.2 and 0.4 µg/mL on day 0, one of ordinary skill in the art would have substitute the 5 days schedule of alemtuzumab administration, and use 2-3 days schedule of alemtuzumab administration. This simple substitution of one known element (2-3-day schedule of the alemtuzumab administration) for another known element (5-day schedule of the alemtuzumab administration) is likely to be obvious when predictable results are achieved. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (see MPEP § 2143, B.).
Regarding claims 13-14 and 16, Marsh et al. do not teach about 10 mg/m2 alemtuzumab is administered to the subject (claim 13), do not teach alemtuzumab is administered to the subject over the three days of day -14, day -13 and day -12 (claim 14), and do not teach a test dose of about 3 mg of alemtuzumab on day -14 for a subject weights equal to or more than about 15 kg (claim 16). Instead Marsh et al. teach the intermediate alemtuzumab schedule (day -14 to day -10) last 5 days, with a dose of 1 mg/kg (0.2 mg/kg/dose for 5 doses). However, 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 modify the schedule of Marsh et al., change and optimize the alemtuzumab administration schedule as well as the dose, and adjust and optimize the dose for patients with a low weight, as long as making sure the alemtuzumab levels achieve levels between 0.2 and 0.4 µg/mL on day 0. It is not considered inventive to find optimal workable ranges by routine experimentation. Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[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." See Jn re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Regarding claim 19, Marsh et al. teach for patients enrolled on the prospective pharmacokinetic study, they used alemtuzumab levels obtained within 8 hours of graft infusion for analyses. For the remaining patients, they used the alemtuzumab level from the stored sample closest to day 0: drawn on day 0 (n=26), day -1 or +1 (n=27), day -2 or +2 (n=15), or day -3 or +3 (n=17) (p504, right column, also see figure 1), do not teach determining alemtuzumab concentration levels in the subject before the first dose on day -14; determining alemtuzumab concentration levels in the subject 8 hours and 24 hours after administration of alemtuzumab on day -12; and determining alemtuzumab concentration levels in the subject daily until day 0. However, 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 modify Marsh et al.’s time point to determine the level of alemtuzumab in order to, e.g., study the metabolism or pharmacokinetics of alemtuzumab. The only difference between instant claim and Marsh et al.’s time point to determine the level of alemtuzumab is instant claim collects more information of the levels of alemtuzumab on day -14 and -12. Given that both methods are intended to determine the level of alemtuzumab while only the time points for determination are different, one of ordinary skill in the art would have substitute determining the level of alemtuzumab at the time point close to day 0, and determine the level of alemtuzumab at different time points, such as day -14 and -12, depends on the research interest. This simple substitution of one known element (determining the level of alemtuzumab at different time points, such as day -14 and -12) for another known element (determining the level of alemtuzumab at the time point close to day 0) is likely to be obvious when predictable results are achieved. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (see MPEP § 2143, B.).
Regarding claim 56, Marsh et al. collected data from 105 patients with nonmalignant diseases to illuminate the significant influence of peritransplant alemtuzumab levels (day 0 ± 72 hours) on the early outcomes of acute GVHD, mixed chimerism, and lymphocyte recovery (p504, right column). Table 1 (p504, left column) shows the age of patient: medium age 4.7 years, ranges from 0.3 year -27.2 years, reads on the subject is a pediatric patient or a young adult patient afflicted with the non-malignant blood disorder, a metabolic disorder or an immunodeficiency disorder needs HCT, as recited in instant claim.
Claims 1, 3-4, 6, 13-14, 16, 19, 30, 47, 48 and 53-56 stand rejected under 35 U.S.C. 103 as being unpatentable over Marsh et al. (BLOOD, 2016, V127, NO 4, published in 2016, as cited in IDS) in view of Fukuda et al. (Blood, 2016, 128 (22): 2203, published in 2016, as cited in IDS). The rejection is modified necessitated by Applicant’s amendment.
The teaching of Marsh et al. is set forth above.
Regarding claims 30, 47, 48 and 53, Marsh et al. teach administering to a subject alemtuzumab starting at day -14 (p504, right column), but do not teach the “determining”, “modeling” and “predicting” step, as well as the “top-up dose” on day -3, day -2 or day -1, as recited in instant claim 30; the carrying out of pharmacokinetic modeling as recited in claim 47, the further limited “top-up dose” as recited in claims 48 and 53. However, such is prima facie obvious in view of Fukuda et al..
Fukuda et al. conducted a prospective 'intensive sampling' pharmacokinetics (PK) study of
subcutaneous alemtuzumab in pediatric patients undergoing HCT. PK data showed a large inter-individual variability in alemtuzumab exposure and D0 levels (p1, Introduction).
Regarding claims 30, 47, 48 and 53, Fukuda et al. teach their group (same group as Marsh et al.) showed that the risks of acute graft vs host disease (GVHD) and the development of mixed chimerism following this regimen are determined by the peritransplant levels of alemtuzumab, and recommended a potential optimal Day 0 (D0) alemtuzumab level in the range of 0.2-0.4 μg/mL (p1, Introduction). In order to support targeted precision dosing of alemtuzumab in a prospective clinical trial, they have developed a population PK (PPK) model for Bayesian adaptive control (p2. L2-3). To develop the pharmacokinetic modeling, Alemtuzumab was subcutaneously administered starting on Day -14 at a dose of 0.2 mg/kg/day for 5 days (total dose of 1 mg/kg). Alemtuzumab plasma concentrations were quantified by validated flow cytometric assay. The plasma concentrations at pre-dose, 30 minutes, and 8 hours after each dose, followed by daily levels until Day 0 were used for PPK analysis (p2, Methods). Fukuda et al. teach visual predictive check of alemtuzumab PK model (p3, figure 1), as well as population PK model predicted vs. Individual prediction of alemtuzumab concentration-time profile (p4, figure 2), which can be used for prediction of the level of Alemtuzumab. Fukuda et al. teach their model can be used for Bayesian estimation of individual PK to support alemtuzumab precision dosing in pediatric patients undergoing allogeneic HCT using the alemtuzumab, fludarabine, and melphalan containing RIC. Precision dosing of alemtuzumab will in turn optimize transplant outcomes for these high risk patients, by minimizing acute GVHD and mixed chimerism, along with improving post-HCT immune reconstitution (p2, Conclusion). This teaching reads on the “determining”, “modeling” and “predicting” steps in instant claim 30. In addition, the pharmacokinetic modeling can be carried out on any day between day -10 to day 0 (e.g., day -5 as recited in instant claim 47) with the data collected, knowing that more real data collected, more actuate the PPK modeling would be.
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 modify Marsh et al.’s method of administering alemtuzumab while determining the level of alemtuzumab close to day 0, and measure the levels of alemtuzumab at different time points to develop a population PK (PPK) model for alemtuzumab, as taught by Fukuda et al.. The skilled artisan would have been motivated to develop a population PK (PPK) model for alemtuzumab to support targeted precision dosing of alemtuzumab in a prospective clinical trial (p2. L2-3), calculate, evaluate and predict the schedule of administering alemtuzumab, as well as adding extra alemtuzumab accordingly (variable “top-up dose” as needed, as recited in instant claim) on different time points (e.g., day -2 or day -3) to rescue the level of alemtuzumab on day 0 to achieve the best effect of treatment. There would be a reasonable expectation of success of measuring the level of alemtuzumab at different time point to develop a population PK (PPK) model for alemtuzumab, since Fukuda et al. teach the method of building the PPK model as well as the analysis software (PPK analysis was performed using nonlinear mixed effects modeling (NONMEM, version 7.2). Bayesian estimation was conducted using MW/Pharm software (version 3.6), see p2, Methods).
Regarding claims 54 and 55, Marsh et al. do not teach the administration route of alemtuzumab. However, Fukuda et al. teach alemtuzumab was subcutaneously administered (p2, Methods).
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 modify Marsh et al.’s administration route of alemtuzumab, and subcutaneously administer alemtuzumab as taught by Fukuda et al.. The only difference between instant claim and Marsh et al.’s method of administering alemtuzumab is instant claim uses subcutaneous administration, while Marsh et al. do not specify the administration route. Given that Fukuda et al. teach alemtuzumab can be subcutaneously administered successfully, one of ordinary skill in the art would have select subcutaneous administration of alemtuzumab, no matter Marsh et al.’s administration route. This simple substitution of one known element (subcutaneously administering alemtuzumab) for another known element (Marsh et al.’s administration route of alemtuzumab) is likely to be obvious when predictable results are achieved. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (see MPEP § 2143, B.).
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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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/Q.G./Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633