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
Claims 1-9, 11-19, and 21-22 are rejected.
No claims are allowed.
New 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.
1. Claims 1-7 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Upadhyay et al., (WO 2019/097413 A1, May 23, 2019) (hereinafter Upadhyay) in view of USPC Official Monographs: Betadex Sulfobutyl Ether Sodium (Betadex Sulfobutyl Ether Sodium, January 03, 2017) (hereinafter USPC).
Upadhyay discloses a stable non-aqueous pharmaceutical composition comprising a hydrophobic drug or a pharmaceutically acceptable salt, wherein the composition comprises of cyclodextrin (Claim 1). The hydrophobic drug comprises of Bendamustine (Claim 2). The concentration of hydrophobic drug in the said composition would range from about 0.1 mg/ml to about 250 mg/ml (Claim 3). The cyclodextrin consists of sulfobutylether beta- cyclodextrin (Claim 4). Stable non-aqueous pharmaceutical compositions may comprise sodium chloride as a stabilizer (page 9, lines 17-18). Example 7 teaches a stable non-aqueous pharmaceutical composition comprising bendamustine hydrochloride 25 mg/ml, sulfobutylether beta- cyclodextrin sodium 100 mg/ml, and sodium chloride 5.0 mg/ml (i.e., 25mg/ml / 25mg/ml : 5.0mg/ml / 25mg/ml = a mass ratio of bendamustine to stabilizer which is 1:0.2) (Example 7, pages 13-14). The stable non-aqueous composition of Example 7 can be further diluted using 0.9% NaCl or water for injection (i.e., a diluent) prior to administration (page 14, lines 2-4).
Upadhyay differs from the instant claims insofar as not disclosing wherein the cyclodextrin is a chlorine-containing cyclodextrin, having a content of chlorine in the cyclodextrin is 0.08-5 wt%, and wherein the chlorine-containing cyclodextrin refers to a cyclodextrin containing sodium chloride.
However, USPC discloses in the official monograph for Beta cyclodextrin sulfobutyl ether sodium (i.e., sulfobutylether beta- cyclodextrin sodium) that the acceptance criteria for a solution of sulfobutyl ether sodium beta cyclodextrin requires the amount of sodium chloride to be less than 0.2% (pages 5-6, Limit of Sodium Chloride, 4-Hydroxybutane-1-Sufonic Acid, and Bis(4-sulfobutyl) Ether Disodium, Acceptance Criteria).
Accordingly, it would have been obvious to one of ordinary skill in the art that the sulfobutylether beta- cyclodextrin sodium of Upadhyay would have comprised some amount of sodium chloride and it would have been obvious to formulate it to comprise less than 0.2% of sodium chloride since this is the maximum acceptable limit of sodium chloride comprised within formulations of Beta cyclodextrin sulfobutyl ether sodium (i.e., sulfobutylether beta- cyclodextrin sodium), as taught by USPC and as noted on page 13, lines 6-9 of the instant specification, the content of chlorine in the cyclodextrin refers to the mass percentage of sodium chloride relative to the cyclodextrin.
Regarding the limitation of claim 1 reciting “wherein a mass ratio of the bendamustine or the salt to the cyclodextrin is 1 : 5 to 1 : 100,” as discussed above, Upadhyay teaches concentration of hydrophobic drug (i.e., bendamustine) in the said composition would range from about 0.1 mg/ml to about 250 mg/ml and an exemplary concentration of sulfobutylether beta-cyclodextrin is taught at 100 mg/ml. Thus, the claimed ratio would have been obvious since after selecting a concentration of bendamustine and combining it with the exemplary concentration of sulfobutylether beta-cyclodextrin disclosed by Upadhyay, one would have arrived at a ratio between bendamustine to the cyclodextrin that overlaps with the claimed ratio. In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art”, a prima facie case of obviousness exists. MPEP 2144.05 A.
2. Claims 9, 11-17, 19, and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Upadhyay et al., (WO 2019/097413 A1, May 23, 2019) (hereinafter Upadhyay) in view of USPC Official Monographs: Betadex Sulfobutyl Ether Sodium (Betadex Sulfobutyl Ether Sodium, January 03, 2017) (hereinafter USPC), and further in view of Sundaram (US 2018/0185488 A1, July 05, 2018) (hereinafter Sundaram).
As discussed above, Upadhyay and USPC make obvious the limitations of claim 1 but do not teach a method for preparing a medicament for cancer treatment, the method comprising providing a subject with an injection of bendamustine or a salt thereof.
However, Sundaram teaches a method of treating indolent B cell non-Hodgkin's lymphoma in a subject comprising parenterally administering to the subject a liquid composition comprising bendamustine, a charged cyclopolysaccharide, and a parenterally acceptable diluent; (Claim 1). Parenterally acceptable diluents include water for injection (WFI), 0.9% saline (normal saline) ([0028]). Preferred charged cyclopolysaccharides include sulfobutyl ether beta-cyclodextrin ([0037]). Sundaram teaches that Bendamustine is used in the treatment of a number of cancers including leukemias, Hodgkin's disease and multiple myelomas ([0002]).
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art to have used the bendamustine composition of Upadhyay and USPC in a method for preparing a medicament for cancer treatment, such as leukemias, Hodgkin's disease and multiple myelomas, comprising providing a subject with an injection of bendamustine or a salt thereof, since bendamustine is a known and effective agent for treating cancer, as taught by Sundaram.
3. Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Upadhyay et al., (WO 2019/097413 A1, May 23, 2019) (hereinafter Upadhyay) in view of USPC Official Monographs: Betadex Sulfobutyl Ether Sodium (Betadex Sulfobutyl Ether Sodium, January 03, 2017) (hereinafter USPC), and further in view of Nakashima et al., 2012, (Coadministration of 5% glucose solution has a decrease in bendamustine-related vascular pain grade) (cited by examiner on Form 892 dated 12/30/2024) hereinafter Nakashima.
As discussed above, Upadhyay and USPC make obvious the limitations of claims 1 and 7 but do not teach wherein the diluent is 5% glucose.
However, Nakashima discloses that coadministration of 5% glucose solution has a decrease in bendamustine-related vascular pain grade (Title). Nakashima teaches that in Japan and the United States the prescribing information of bendamustine discloses that a single-use vial contains bendamustine HCl as lyophilized powder, and should be dissolved only in sterile water with a bendamustine HCl concentration of 2.5 or 5 mg/ml. However, to decrease the administered bendamustine concentration in the patients more effectively, they proposed the method that bendamustine, which is dissolved in saline 250 mL, and 5% glucose solution 250mL are administered simultaneously to the patient. By the method, the pain was improved from grade 3 to grade 1. Similarly, by the administration of 5% glucose solution, the vascular pain was improved from grade 3 to grade 1 in other two patients (page 1 column 2).
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to have prepared the bendamustine composition as taught by Upadhyay and USPC with 5% glucose as the diluent to reduce the concentration of bendamustine in the injection and thereby reducing vascular pain associated with bendamustine injection, as taught by Nakashima.
4. Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Upadhyay et al., (WO 2019/097413 A1, May 23, 2019) (hereinafter Upadhyay) in view of USPC Official Monographs: Betadex Sulfobutyl Ether Sodium (Betadex Sulfobutyl Ether Sodium, January 03, 2017) (hereinafter USPC), Sundaram (US 2018/0185488 A1, July 05, 2018) (hereinafter Sundaram), and further in view of Nakashima et al., 2012, (Coadministration of 5% glucose solution has a decrease in bendamustine-related vascular pain grade) (cited by examiner on Form 892 dated 12/30/2024) hereinafter Nakashima.
As discussed above, Upadhyay, USPC, and Sundaram make obvious the limitations of claims 9 and 16 but do not teach wherein the diluent is 5% glucose.
However, Nakashima discloses that coadministration of 5% glucose solution has a decrease in bendamustine-related vascular pain grade (Title). Nakashima teaches that in Japan and the United States the prescribing information of bendamustine discloses that a single-use vial contains bendamustine HCl as lyophilized powder, and should be dissolved only in sterile water with a bendamustine HCl concentration of 2.5 or 5 mg/ml. However, to decrease the administered bendamustine concentration in the patients more effectively, they proposed the method that bendamustine, which is dissolved in saline 250 mL, and 5% glucose solution 250mL are administered simultaneously to the patient. By the method, the pain was improved from grade 3 to grade 1. Similarly, by the administration of 5% glucose solution, the vascular pain was improved from grade 3 to grade 1 in other two patients (page 1 column 2).
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to have prepared the bendamustine composition as taught by Upadhyay and USPC with 5% glucose as the diluent to reduce the concentration of bendamustine in the injection and thereby reducing vascular pain associated with bendamustine injection, as taught by Nakashima.
Response to Applicant’s Arguments
Applicant’s arguments have been considered but are moot because new rejections necessitated by Applicant’s amendments have been made.
With regards to the Applicant’s remarks regarding unexpected results, Applicant argues that the instantly claimed invention provides the unexpected result of further increasing the stability of bendamustine or a salt thereof through the inclusion of a cyclodextrin containing chlorine.
Applicant’s argument has been fully considered but found not to be persuasive. The results do not appear to be unexpected. Applicant’s showing in Example 8 discloses 4 compositions containing cyclodextrins with different chlorine concentrations ranging from 0 in formulation 1, to 3% in formulation 4. The table provided in Example 8 indicates that the HP1 impurity area% in formulation 1 after 6 hours was 4.82% compared to 3.49% in formulation 4 and the area percentages of API (i.e., bendamustine) were 94.78% and 96.05% after 6 hours, respectively. As noted on page 13, lines 6-9 of the instant specification, the chlorine-containing cyclodextrin refers to a cyclodextrin containing sodium chloride, wherein the content of chlorine in the cyclodextrin refers to the mass percentage of sodium chloride relative to the cyclodextrin. As discussed above, Upadhyay teaches that sodium chloride is used as a stabilizer to formulate stable non-aqueous pharmaceutical composition comprising bendamustine hydrochloride. Thus, it would have been obvious to one of ordinary skill in the art that the presence of sodium chloride stabilizes bendamustine in a formulation and it would have been reasonable to expect that increasing the amount of sodium chloride comprised within the cyclodextrin would increase the stability of the API (i.e., bendamustine) of the instant invention. Accordingly, the results of the increased stability of bendamustine in the instant invention would not have been unexpected to one of ordinary skill in the art.
Further, any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. See MPEP 716.02. Since each formulation comprises different amounts of chlorine, one of ordinary skill in the art would reasonably expect some difference in results. The Table on page 32 of the specification shows wherein API for 0% chlorine has a difference of 4.92% from 0h to 6h, API for 0.01% chlorine has a difference of 4.69% from 0h to 6h, API for 1% chlorine has a difference of 4.51% from 0h to 6h, and API for 3% chlorine has a difference of 3.71% from 0h to 6h. The evidence relied upon should establish that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance. See MPEP 716.02(b). Applicant has not explained how 4.92% (0% chlorine) vs 4.69% (1% chlorine) or 3.71% (3% chlorine) is of statistical and practical significance. 1% chlorine differs from 0% chlorine by 0.23 and 3% chlorine differs from 0% chlorine by 1.21. It is not clear how these differences show wherein 1% and 3% is of practical significance, for example, therapeutically, such that 1% or 3% chlorine is unexpected.
Conclusion
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Samantha J Knight whose telephone number is (571)270-3760. The examiner can normally be reached Monday - Friday 8:30 am to 5:00 pm ET.
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/S.J.K./Examiner, Art Unit 1614
/TRACY LIU/Primary Examiner, Art Unit 1614