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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 04/28/2026 has been entered.
Claim Status
In the submission filed 04/28/2026, claim 1 has been amended, claim 63 has been newly added. Accordingly, claims 1, 3-4, 6, 13-14, 16, 19, 30, 47-48, 53-56 and 63 are pending and under current examination.
Priority
The instant application is a national stage entry of PCT application PCT/US2021/029387, filed 04/27/2021 under 35 USC 371. Acknowledgement is made of the applicant’s claim for benefit to prior-filed U.S. provisional patent applications 63/015,730 (filed 04/27/2020).
Status of Prior Rejections/Response to Arguments
The rejection to claims 1, 3-4, 6, 13-14, 16, 19 and 56 under 35 U.S.C. 103 over Marsh et al. is maintained:
The rejection to claims 1, 3-4, 6, 13-14, 16, 19, 30, 47, 48 and 53-56 under 35 U.S.C. 103 over Marsh et al. in view of Fukuda et al. is maintained:
Applicant has traversed the rejection, asserting that the claimed subject matter realizes unexpected results. Specifically, dosing of alemtuzumab based on body surface area (BSA, mg/m2), more particularly a dose of about 8 mg/m2 - about 12 mg/m2, helps to increase the number of patients that reach the ideal therapeutic range of alemtuzumab concentration on day 0 (transplant day) significantly, and, therefore, reduces the risk of potentially suffering from acute GVHD or from mixed chimerism and delayed early post-HCT immune recovery (Remarks, p6).
Applicant’s argument is fully considered but not found persuasive. Applicant is reminded that in submitting evidence asserted to establish unobvious results, there is a burden on Applicant to indicate how the examples asserted to represent the claimed invention are considered to relate to the examples intended to represent the prior art and, particularly, to indicate how those latter examples do represent the closest prior art. The evidence relied upon should also be reasonably commensurate in scope with the subject matter claimed and illustrate the claimed subject matter relative to the prior art subject matter. See MPEP § 2145. It should also be established that the differences in the results are in fact unexpected and unobvious and of both statistical and practical significance. MPEP § 716.02(b). In the instant case, Applicant has failed to indicate how the alleged unexpected results differ from the closest prior art. Specifically, the dose based on body surface area (BSA) of about 8 mg/m2 - about 12 mg/m2 can be converted to the dose by weight, which is known in the art (i.e., see reference Nair et al. (J Basic Clin Pharma 2016;7:27-31), Table 1, also the modified rejection set forth below), the dose based on body surface area of 8 mg/m2 - 12 mg/m2 is the dose based on weight of 0.22 mg/kg - 0.32 mg/kg (calculated by the equation of the dose based on body surface area divided by Km =37). Marsh et al. teach the intermediate alemtuzumab schedule (day -14 to day -10, which is in the range of day -22 and day -8) last 5 days, with a dose of 0.2 mg/kg/dose for 5 doses (p505, right column). The dose of 0.2 mg/kg in Marsh et al.’s teaching is in the range of (or nearly to) the dose as recited in instant application. Moreover, instant application and Marsh et al. select the dose of alemtuzumab for the same purpose (that is, achieve the result that on day 0 the blood concentration of alemtuzumab is in the range of 0.16 to 0.56 µg/mL or 0.2 to 0.4 µg/mL, which reducing the likelihood of a blood concentration of alemtuzumab greater than 0.6 µg/mL on day 0). Under such circumstance, having same (or nearly same) dose with different units (mg/m2 v.s. mg/kg) for the same result (reducing the likelihood of a subject having a blood concentration of alemtuzumab greater than 0.6 µg/mL on day 0, i.e., having the blood concentration of alemtuzumab in the range of 0.2 to 0.4 mg/mL on day 0) is not considered unexpected comparing to the prior art.
Applicant has further traversed the rejection, asserting that neither Marsh nor Fukuda discloses or even remotely suggests using BSA-based dosing of alemtuzumab in a method of using allogenic hematopoietic cells for treating the claimed non-malignant disorders, let alone the particular dose range of about 8 mg/m2 - about 12 mg/m2. The claimed subject matter is not the result of "routine optimization" because the claims do not recite any "result effective variables", since the pharmacodynamics is inherently unpredictable (Remarks, p7-8).
To response, the examiner respectfully submits that as stated above, both the dose based on body surface area and the dose based on weight are commonly used in the art and the two doses are convertible. The dose based on BSA of 8 mg/m2 - 12 mg/m2 is the dose based on weight of 0.22 mg/kg - 0.32 mg/kg. Marsh et al. teach the intermediate alemtuzumab schedule (day -14 to day -10, which is in the range of day -22 and day -8) last 5 days, with a dose of 0.2 mg/kg/dose for 5 doses (p505, right column). Herein the dose of 0.2 mg/kg in Marsh et al.’s teaching is in the range of or nearly in the range of the dose of about 8 mg/m2 - 12 mg/m2 (about 0.22 mg/kg - 0.32 mg/kg) as recited in instant claim. Moreover, Marsh et al. teach the pharmacokinetics of alemtuzumab (i.e., see p504, left column), based on the knowledge, a PHOSITA would have been able to optimize the range of the dose accordingly (i.e., using pharmacokinetic modeling as well as animal experiments), in order to achieve the result that on day 0 the blood concentration of alemtuzumab is in the range of 0.16 to 0.56 µg/mL or 0.2 to 0.4 µg/mL, which reducing the likelihood of a blood concentration of alemtuzumab greater than 0.6 µg/mL on day 0.
Moreover, Applicant has also asserted that 2-3 day schedule of alemtuzumab administration in instant application and the 5 day schedule of alemtuzumab administration in Marsh is not equivalent since the pharmacodynamics of a drug is inherently unpredictable (see Remarks, p8). Due to the significant complexity of pharmacodynamics, there is no "equivalence" between the 2-3 day schedule of alemtuzumab administration and the 5 day schedule of alemtuzumab administration in Marsh (see Remarks, p9).
To response, the examiner respectfully submits that both Marsh et al. and instant application have the same endpoint of the method: achieving the result that on day 0 the blood concentration of alemtuzumab is in the range of 0.16 to 0.56 µg/mL or 0.2 to 0.4 µg/mL, which reducing the likelihood of a subject having a blood concentration of alemtuzumab greater than 0.6 µg/mL on day 0. Since Marsh et al. teach the terminal half-life of alemtuzumab in bone marrow transplant patients has been reported to be 15 to 21 days, as well as the pharmacokinetics of alemtuzumab (see Marsh et al. p509, right column, as well as p504, left column), PHOSITA would have designed and optimized the schedule (as well as the dose) of alemtuzumab administration accordingly based on such knowledge (i.e., using pharmacokinetic modeling as well as animal experiments), as long as on day 0 the blood concentration of alemtuzumab is in the range of 0.16 to 0.56 µg/mL or 0.2 to 0.4 µg/mL (which reducing the likelihood of a subject having a blood concentration of alemtuzumab greater than 0.6 µg/mL). The rejection is maintained in modified form to address amended limitations.
New/Modified Rejections
New Claim Rejections - 35 USC § 112(a)
Claims 1, 3-4, 6, 13-14, 16, 19, 30, 47-48, 53-56 and 63 are newly rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
In the submission, Applicant amends claim 1, adding the limitation “reducing the likelihood of a subject having a blood concentration of alemtuzumab greater than 0.6 µg/mL on day 0”. However, there is no support in the specification regarding this limitation. The specification discloses the method aim to achieve a target concentration of about 0.15-0.6 µg/mL of alemtuzumab in a subject at day 0 (i.e., see parag 0006), but do not teach or suggest “reducing the likelihood of a subject having a blood concentration of alemtuzumab greater than 0.6 µg/mL on day 0”.
This is a new matter rejection, necessitated by Applicant’s amendment. Claims 3-4, 6, 13-14, 16, 19, 30, 47-48, 53-56 and 63 depend from claim 1 directly or indirectly, and thus inherit the deficiency and are rejected on the same basis.
New Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 3-4, 6, 13-14, 16, 19, 30, 47-48, 53-56 and 63 are newly rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. The rejection is necessitated by Applicant’s amendment as well as reconsidering the claim scope.
Claim 1 recites “reducing the likelihood of a subject having a blood concentration of alemtuzumab greater than 0.6 µg/mL on day 0” renders instant claim indefinite. The phrase “reducing the likelihood” is not defined in the claim, the specification does not provide definition or clarification, therefore the metes and bounds of the reduction is not defined, the scope of the claim is not clear.
Claims 3-4, 6, 13-14, 16, 19, 30, 47-48, 53-56 and 63 depend from claim 1 directly or indirectly, and thus inherit the deficiency and are rejected on the same basis.
Claim Interpretation
As stated above, claim 1 is indefinite. In the interest of compacted prosecution, the phrase “reducing the likelihood of a subject having a blood concentration of alemtuzumab greater than 0.6 µg/mL on day 0” is interpreted as a subject having a blood concentration of alemtuzumab at any level below 0.6 on day 0.
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 and claim 63 is newly 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), as evidenced by Nair et al. (J Basic Clin Pharm. 2016 Mar;7(2):27-31) and Pai (Pharmacotherapy. 2012 Sep;32(9):856-68). The rejection is modified as 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. 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. teach the intermediate alemtuzumab schedule (day -14 to day -10, which is in the range of day -22 and day -8) last 5 days, with a dose of 1 mg/kg (0.2 mg/kg/dose for 5 doses) (p505, right column), but do not teach about 8 mg/m2 - about 12 mg/m2 alemtuzumab is administrated to the subject. However, the dose based on body surface area (BSA) and the dose based on weight are two commonly used drug dosing in the art, as evidenced by Pai (see p2, left column), and this dose based on BSA (mg/m2) can be converted to dose based on the body weight (mg/kg), which is evidenced by Nair et al.. Nair et al. teach human equivalent dose calculation based on body surface area (table 1), the dose of mg/m2 can be converted to dose of mg/kg after divided by km (Km=37), therefore about 8 mg/m2 - about 12 mg/m2 alemtuzumab is about 0.22-0.32 mg/kg. As discussed above, Marsh et al. teach the dose of 0.2 mg/kg, which is in the range of or nearly in the range of the dose of about 0.22-0.32 mg/kg.
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 Marsh et al.’s method of administering alemtuzumab, use another commonly used drug dosing in the art (a dose based on BSA), and select and optimize the alemtuzumab administration dose as needed to make sure the alemtuzumab levels achieving levels between 0.16 and 0.56 µg/mL or 0.2 and 0.4 µg/mL on day 0 (to reduce the likelihood of a subject having a blood concentration of alemtuzumab greater than 0.6 µg/mL). The dose is taught by Marsh et al. and could be adjusted as needed (i.e., based on pharmacokinetic modeling as well as animal experiments). It is not considered inventive to find optimal workable ranges by routine experimentation. Generally, differences in concentration or temperature or as herein the dose of alemtuzumab will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature or the dose 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 (not greater than 0.6 µg/ml), 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 of not greater than 0.6 µg/ml (i.e., between 0.2 and 0.4 μg/mL) on day 0, one of ordinary skill in the art would have substituted the 5 days schedule of alemtuzumab administration, and use 2-3 days schedule of alemtuzumab administration based on the known knowledge from i.e., pharmacokinetic modeling as well as animal experiments. 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 (which is 0.27 mg/kg) 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 the level of alemtuzumab not greater than 0.6 µg/ml (i.e., 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 substituted 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.
Regarding claim 63, Marsh et al. teach a day 0 the concentration of blood alemtuzumab in the range of 0.16 to 0.56 µg/mL or more preferably, 0.2 to 0.4 µg/mL (see Abstract), which is in the range of about 0.15 µg/mL – about 0.6 µg/mL as recited in instant claim.
Claims 1, 3-4, 6, 13-14, 16, 19, 30, 47, 48 and 53-56 stand rejected and 63 is newly 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), as evidenced by Nair et al. (J Basic Clin Pharm. 2016 Mar;7(2):27-31) and Pai (Pharmacotherapy. 2012 Sep;32(9):856-68), as applied to claims 1, 3-4, 6, 13-14, 16, 19, 56 and 63, and in view of Fukuda et al. (Blood, 2016, 128 (22): 2203, published in 2016, as cited in IDS). The rejection is modified as 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 interindividual 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.
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/Q.G./Examiner, Art Unit 1633
/FEREYDOUN G SAJJADI/Supervisory Patent Examiner, Art Unit 1699
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