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 .
Applicant’s arguments, filed 04/14/2026, have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
The examiner notes that Applicants arguments with respect to El Rashidy et al and APOKYN are moot at this time, as the references are not currently relied upon in view of Applicants’ amendments.
Claim Status
Claims 1-5, 7, 8, 11, 12, and 14-20, are pending and under examination.
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.
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 1-5, 7, 8, 11, 12, 14-16, and 18-20, are rejected under 35 U.S.C. 103 as being unpatentable over Schnait et al (US 20180280465 A1), Gupta et al (US 20020002176 A1), and Ang et al (Drug Design, Dev. And Ther., 2016, 10, pp. 3253-3265).
Schnait et al teach aqueous compositions comprising apomorphine and a carrier for subcutaneous administration (abs, ¶ 62, table 12, claim 1). The aqueous composition can be directly administered as a ready to use composition via subcutaneous injection using a prefilled injection pen (¶ 46). In embodiments, the apomorphine composition is injected (¶¶ 72, 102). In embodiments, the aqueous composition comprises about 5 mg/ml of apomorphine or a pharmaceutically acceptable salt thereof (¶ 46, table 12). In embodiments, the composition further comprises reduced glutathione (antioxidant), ascorbic acid, sodium chloride, etc., with a pH of 4 (table 12). The compositions have high stability to oxidative degradation, due to the antioxidative behavior of the combination of reduced glutathione and ascorbate (¶ 208). Ascorbic acid is disclosed as both an antioxidant and a buffer (¶ 58). In embodiments, apomorphine is used in combination with citrate, mannitol, etc. (table 9). Table 13 discloses embodiments wherein the impurities as high as 0.08 wt% and as low as 0.06 wt% (table 13). Comparative data on apomorphine assay was determined by an HPLC method (¶ 235). The composition may optionally further comprise preservatives, etc. (¶ 65).
Schnait et al do not to teach EDTA nor the antioxidants of claim 8.
Gupta et al teach pharmaceutical compositions comprising apomorphine and a pharmaceutically acceptable carrier, where it was known to include antioxidants including sodium formaldehyde sulfoxylate (abs, ¶¶ 19, 46). Further, it was known to further include chelating agents, such as ethylene diamine tetraacetic acid (¶ 47).
Similarly, Ang et al teach stable apomorphine HCl solutions comprising an antioxidant and EDTA solution (abs). The compositions comprising EDTA remained stable for at least 72 hours, which was longer than those without EDTA (conclusion). All samples changed color except for the sodium metabisulfite + ascorbic acid, the sodium metabisulfite + EDTA solutions, and the ascorbic acid + EDTA solutions (table 2).
Regarding claim 1, Schnait et al teach embodiments comprising about 5 mg/ml apomorphine, a pharmaceutically acceptable carrier (i.e., water), reduced glutathione (antioxidant), ascorbic acid, sodium chloride, etc., with a pH of 4.
Regarding EDTA, it would have been obvious to modify the composition of Schnait et al by including known chelating agents suitable for pharmaceutical compositions comprising apomorphine, such as ethylene diamine tetraacetic acid (EDTA), as taught by Gupta et al. Additional motivation for including EDTA is provided by Ang et al, where it was known to include EDTA as a stabilizer for compositions comprising apomorphine, where EDTA used in combination with an antioxidant appears to result in increased stability of the apomorphine compositions, as taught by Ang et al.
Regarding an isotonicity agent, the composition made obvious above comprises sodium chloride, thereby meeting the claimed limitation.
Regarding subcutaneous administration, where the compositions of Schnait et al are disclosed as capable of subcutaneous administration, it appears the intended use limitation is met.
Regarding the device of claims 1 and 2, where the composition as instantly claimed is made obvious above and is disclosed as suitable for administration via subcutaneous injection using a prefilled injection pen, the composition is capable of meeting the intended use limitation of being present as a unit dose in a device
Purely arguendo, if the limitation of being present in a unit dose in a device is not simply intended use and the composition is not necessarily present in a unit dose device, then it would have been obvious to include the composition as a unit dose in a device, such as a prefilled pen, as taught by Schnait et al.
Regarding claim 3, where the claim is directed to a composition comprising apomorphine, EDTA, an isotonicity agent, and a pharmaceutically acceptable carrier, it appears the limitation of the composition being present as a unit dose in an autoinjector is simply an intended use limitation. As such, where the composition of Schnait et al are disclose as suitable for injection, it appears that the composition of Schnait et al would be capable of being present as a unit dose in an autoinjector, thereby meeting the intended use limitation.
Regarding claims 4 and 5, the composition made obvious above comprises 5 mg/ml apomorphine, as taught by Schnait et al.
Regarding claim 7, the composition made obvious above comprises reduced glutathione (antioxidant), thereby meeting the claimed limitation, which is taught to result in compositions having high stability to oxidative degradation.
Regarding claim 8, where the composition made obvious above comprises apomorphine and antioxidants, it would have been obvious to use other known antioxidants suitable for pharmaceutical compositions comprising apomorphine, such as sodium formaldehyde sulfoxylate, as taught by Gupta et al.
Regarding claim 11, the composition made obvious above comprises ascorbic acid, a suitable buffer as taught by Schnait et al.
Regarding claim 12, where the composition made obvious above comprises a buffer, it would have been obvious to select from other suitable buffers, including citrate buffer, as taught by Schnait et al, in order to control the pH to a desired and optimal range.
Regarding claim 14, the composition made obvious above comprises sodium chloride, thereby meeting the claimed limitation.
Regarding claim 15, the composition made obvious above do not appear to comprise a preservative, thereby meeting the claimed limitation.
Purely arguendo, if one the components in the embodiments from table 12 of Schnait et al were to also read on a preservative, it would have been obvious to formulate the composition substantially free of a preservative, where the inclusion of a preservative is taught to be optional.
Regarding claim 16, the composition made obvious above comprises a pH of 4, falling within the claimed range.
Regarding claims 18 and 19, where the claim is directed to a composition comprising apomorphine and a pharmaceutically acceptable carrier, it appears the limitation of being packed in a blister package or aluminum pouch as instantly claimed is simply an intended use limitation of the composition. As such, while Schnait et al do not specifically disclose the packaging of claims 18 and 19, it would be reasonably expected that the composition would be capable of being packed under vacuum in a blister packaging comprising an oxygen absorber or packaged in an aluminum pouch under vacuum, as instantly claimed.
Regarding claim 20, it would have been obvious to formulate the composition made obvious above comprising apomorphine impurities of 0.08 and 0.07 wt%, as taught by Schnait et al. The skilled artisan would recognize that it would be desirable to formulate the pharmaceutical formulation with low levels of impurities. Accordingly, the limitation of comprising no more than 0.5 wt% morphine impurity is met. Further, Schnait et al discuss the comparative data for apomorphine was measured by using an HPLC method.
Response to Arguments
First, Applicants assert Schnait et al do not disclose EDTA. Applicants assert Schnait et al do not mention anything on morphine impurity specifically.
Second, Applicants assert Gupta et al and Ang et al do not disclose or teach anything to cure the deficiency of Schnait et al. Applicants assert by reading Schnait et al in view of Gupta et al and Ang et al, the skilled artisan would not be taught or motivated to use EDTA as a stabilizer to prepare stable pharmaceutical formulations as claimed.
First, respectfully, this argument is not persuasive. Schnait et al were not cited for teaching EDTA, but rather motivation for including EDTA was provided by Gupta et al and Ang et al. Regarding the argument of morphine impurity, Schnait et al appears to teach total impurities of apomorphine, which inherently includes morphine, if present. Accordingly, where the total apomorphine impurities are 0.08 and 0.07 wt%, as taught by Schnait et al, the specific impurity of morphine is necessarily 0.08 and 0.07 wt% or less, thereby meeting the claimed limitation.
Second, respectfully, this argument is not persuasive. Applicants assert Gupta et al and Ang et al do not disclose or teach anything to motivate the skilled artisan to use EDTA to prepare a stable pharmaceutical formulation, however, Gupta et al teaches EDTA was known to be included in pharmaceutical formulations comprising apomorphine, and Ang et al teaches the inclusion of EDTA to apomorphine containing compositions resulted in increased stability compared to formulations without EDTA. Therefore, as discussed above, it would have been obvious to include EDTA to the compositions of Schnait et al, with the reasonable expectation of improved stability.
Claims 3 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Schnait et al (US 20180280465 A1), Gupta et al (US 20020002176 A1), and Ang et al (Drug Design, Dev. And Ther., 2016, 10, pp. 3253-3265), as applied to claims 1-5, 7, 8, 11, 12, 14-16, and 18-20 above, and further in view of Prestrelski et al (US 20180369255 A1).
Schnait et al are discussed above and further teach the subject to be treated may be a mammal (¶ 79).
The reference are discussed above, and purely arguendo, if the autoinjector is not simply an intended use of the composition of claim 1, the following applies. The references do not appear disclose a method of administering the composition to a mammal via an autoinjector as instantly claimed.
Prestrelski et al teach injectable formulations of small molecule drugs, such as apomorphine, where it was known to include apomorphine in an autoinjector (abs, ¶¶ 14, 17, 48, 51, 64, claim 7).
Regarding claim 3, even if purely arguendo, the use of an autoinjector is not simply an intended use limitation, it would have been obvious to include the apomorphine composition in an autoinjector, where autoinjectors were known to be suitable for injectable compositions comprising apomorphine, as taught by Prestrelski et al.
Regarding claim 17, it would have been obvious to administer the apomorphine composition made obvious above to a mammal via an autoinjector, for the same reasons discussed above by Prestrelski et al, thereby meeting the intended use limitation of the composition of claim 1.
Response to Arguments
Applicants assert Prestrelski et al do not teach or provide motivation to include EDTA.
Respectfully, this argument is not persuasive. The examiner notes that Prestrelski et al were not cited for teaching EDTA, but rather Gupta et al and Ang et al, as discussed above.
Claims 18 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Schnait et al (US 20180280465 A1), Gupta et al (US 20020002176 A1), and Ang et al (Drug Design, Dev. And Ther., 2016, 10, pp. 3253-3265), as applied to claims 1-5, 7, 8, 11, 12, 14-16, and 18-20 above, and further in view of Devouassoux et al (US 20140262883 A1).
The references are discussed above, and purely arguendo, if the packaging is not simply an intended use of the composition of claim 1, the following applies.
Devouassoux et al teach pharmaceutical packaging systems which prevent oxygen degradation of oxygen-sensitive drugs, such as morphine, wherein the packaging comprises an oxygen absorber (abs). The packing may be a bag or blister packaging (¶¶ 5, 10, 12). The bag or blister packaging comprises an oxygen barrier material, such as aluminum foil (¶ 5). The packaging may undergo vacuumization (¶¶ 47, 64, 96).
Regarding claim 18, even if purely arguendo the packaging is not simply an intended use of the composition, it would have been obvious to include the composition made obvious above in a blister packaging comprising an oxygen absorber, wherein the packaging is under vacuum, as taught by Devouassoux et al, in order to prevent oxidative degradation of apomorphine.
Regarding claim 19, even if purely arguendo the packaging is not simply an intended use of the composition, it would have been obvious to include the composition made obvious above in an aluminum pouch under vacuum, as taught by Devouassoux et al, in order to prevent oxidative degradation of apomorphine.
Response to Arguments
Applicants assert Devouassoux et al do not disclose or teach anything to cure the deficiency of Schnait et al.
Respectfully, this argument is not persuasive. The examiner notes that Devouassoux et al were not cited for teaching EDTA, but rather Gupta et al and Ang et al, as discussed above.
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 JOSHUA A ATKINSON whose telephone number is (571)270-0877. The examiner can normally be reached M-F: 9:00 AM - 5:00 PM + Flex.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sahana Kaup can be reached at 571-272-6897. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JOSHUA A ATKINSON/Examiner, Art Unit 1612
/SAHANA S KAUP/Supervisory Primary Examiner, Art Unit 1612
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