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 .
Priority
This application is a 371 of PCT/IB2021/053096 (04/15/2021),
and claims foreign priority to ITALY 102020000008209 (04/17/2020).
Status
Claims 1-5, 11, 14, 16-19 are pending.
Rejections not reiterated are withdrawn.
Claim Rejections - 35 USC § 103
Claims 1-5, 11, 14, 16-19 are rejected under 35 U.S.C. 103 as being unpatentable over Leonelli et al. (Helv. Chim. Acta. 2005, 88, 154-159) in view of Campisi et al. (US20110189265).
Regarding claim 1, Leonelli teaches preparation of HA-paclitaxel conjugate as shown in Scheme 2 (p. 156):
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The experimental details of the preparation are provided on p. 158:
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Thus, Leonelli teaches the claim’s step (a) activating paclitaxel in CH2Cl2 (organic solvent) with 4-bromobutanoic acid (aka 4-bromobutyric acid spacer/linker), with DMAP (catalyst) to obtain compound (6) (intermediate of the HA-paclitaxel conjugate). Leonelli teaches equivalents to claim’s step (b) with the intermediate being washed, dried, evaporated, column chromatograph (CC) and crystallized (“EtOH/hexane 1:1”) to give a “white solid”. Leonelli teaches equivalent to step d including washing with ethanol and water, dialysis against distilled water and freeze-drying.
Regarding claim 1’s amended language specifying the derivatization or esterification degree, Leonelli teaches “ca. 25%” (p. 157: “the chosen ratio of reactants should ease the substitution-degree evaluation of the bioconjugate and ensure its hydrosolubility due to the presence of a still large number of free COONa groups.”; p. 158: “White cotton-like material. A ca. 25% substitution degree for 8 was deduced”).
Regarding claim 1’s amended language specifying the starting HA is of fermentative origin, the Leonelli product used is identical (p. 158: “HA-TBA (7; Mw ~= 185 kDa, batch n.110) was obtained from Fidia (Abano Terme, PD, Italy).”).
Regarding claim 1’s amended language specifying the product is a fine and homogeneous powder with a degree of purity greater than 98% by weight dry product and containing less than 1% impurity, Leonelli teaches the solid product was pure and without impurities (p. 158: “The precipitate was purified by extensive dialysis (cut off ca. 12 kDa) against distilled H2O and finally freeze-dried: pure 8 (0.37 g). White cotton-like material.”).
Leonelli does not specifically teach the particular crystallizing step in step b, the use of DMSO in step c, and step d’s purifying steps. Leonelli teaches “ca. 25%” substitution but not specifically derivatization of 15-21% w/w.
Campisi teaches preparation of conjugates of HA with chemotherapeutic drugs, including HA-paclitaxel conjugates (Abstract). Campisi teaches synthesis of the HA-drug conjugates including combining the drug intermediate with HA TBA in DMSO ([0085]; [0093]-[0094]) followed by the addition of an NaBr solution and precipitation with ethanol, and washing with ethanol ([0086]-[0087]; [0095]; [0097]) followed by drying under vacuum at 40 C ([0087]; [0089]; [0095]).
One of ordinary skill in the art following the teaching of Leonelli would have readily considered combining the teachings with Campisi which is in the same field of endeavor of HA-drug conjugate preparations. Campisi teaches similar levels of derivatization, fermentative origin, molecular weight, solid, and purity all of which one of ordinary skill in the art would consider in optimization of the resulting product to improve therapeutic efficacy. One of ordinary skill in the would consider routine the modification of Leonelli’s preparation steps to optimize the purity and efficacy of the resulting HA-drug conjugate product, including using well-known steps of isolation/purification by crystallization as suggested by Leonelli in precipitation of solids as well as using known solvents and rearranging preparation/purification steps. One of ordinary skill in the art would have considered utilizing the solvent DMSO instead of Leonelli’s DMP in view of Campisi’s success with DMSO in the same step of preparing HA TBA salt. One of ordinary skill in the art would also have considered replacing Leonelli’s brine (NaCl) with Campisi’s NaBr in view of Campisi’s success with NaBr in the same/equivalent ion exchange/precipitation step. One of ordinary skill in the art would have also considered utilizing a similar workup as Campisi’s including filtration/washing with ethanol and drying at 40C both at atmospheric pressure and under vacuum which would be saturated initially in the process. One of ordinary skill in the art would have considered optimization of the level of derivatization in view of Leonelli’s teaching to insure hydrosolubility and therapeutic compatibility (p. 157: “the chosen ratio of reactants should ease the substitution-degree evaluation of the bioconjugate and ensure its hydrosolubility due to the presence of a still large number of free COONa groups.”).
One of ordinary skill in the art would have had a reasonable expectation of success in the modified combination due to the high level of skill in the art and the prior art being to the same type of HA-drug conjugate preparation.
Regarding claim 2, Leonelli teaches the carbodiimide is EDC.
Regarding claim 3, Leonelli teaches the catalyst is DMAP.
Regarding claim 4, Leonelli teaches use of hexane as a solvent in the equivalent step b which is a homolog of heptane (differing by one repeating -CH2- group) such that one of ordinary skill in the art would expect similar effect and utilize such as solvent in the crystallization step (see MPEP 2144.09).
Regarding claim 5, sample workup steps including drying are routine in the art and one of ordinary skill in the art would know that time and temperature are results effective variables as Leonelli and Campisi varied time and temperature in their workups, such that one of ordinary skill in the art would optimize the same variables and arrive at the claimed invention through routine experimentation.
Regarding claim 11, Campisi teaches the HA derivatization in the same range ([0071]) which one of ordinary skill in the art would optimize through routine experimentation for therapeutic efficacy and arrive at the claimed invention (MPEP 2144.05).
Regarding claim 14, Leonelli teaches the use of EDC.
Regarding claim 16, Leonelli teaches use of hexane as a solvent in the equivalent step b which is a homolog of heptane (differing by one repeating -CH2- group) such that one of ordinary skill in the art would expect similar effect and utilize such as solvent in the crystallization step (see MPEP 2144.09).
Regarding claim 17-19, sample workup steps including drying are routine in the art and one of ordinary skill in the art would know that time and temperature are results effective variables as Leonelli and Campisi varied time and temperature in their workups, such that one of ordinary skill in the art would optimize the same variables and arrive at the claimed invention through routine experimentation.
With each of the above claims, the level of skill in the art is very high such that one of ordinary skill in the art would consider routine the combination of elements from the teaching of the art in the same field of endeavor. One of ordinary skill in the art would have recognized that the results of the combination would be predictable due to the well-known nature and optimizations routinely performed in the art. Thus, one of ordinary skill in the art would have arrived at the invention as claimed with a reasonable expectation of success.
Response to Remarks - 35 USC § 103
Applicant argues “the preparation of intermediate 6 for the determination of its melting point” and “is not an additional purification step of the intermediate by crystallization in an organic solvent, as recited in step b) of the claimed invention.”
This argument is not persuasive because Leonelli specifically teaches isolating and purifying the intermediate compound 6 (including the use of hexane in the similar manner as in the instant specification’s Example 1) prior to combining it with HA-TBA in the same manner as in the instant claims. Similarly, Campichi teaches precipitation and isolation of the solid product in the same manner ([0087], [0095]). One of ordinary skill in the art would have considered routine using well known techniques to isolate intermediates and arrive at the claimed invention with a reasonable expectation of success.
Applicant argues that Leonelli corresponds to WO2004035629 which is analogous to Example 2 of the instant specification which “represents a breakthrough in the process for preparing and purifying the HA-paclitaxel conjugate” while the claimed invention is unexpectedly superior in purity due to step b’s crystallization and filtration.
Applicant’s argument is not persuasive because Leonelli includes additional purification steps which would be expected by one of ordinary skill in the art to produce an improved purity product. This improved purity appears to be what Applicant observed in comparing Example 1 vs. 2. Such a result would have been the expected result – i.e., more purification would result in a more pure product. Thus, Applicant has not met their burden in establishing an unexpected result. MPEP 716.02(b), 2145.
Applicant argues Campisi et al. '265 do not disclose or suggest any synthesis of the claimed conjugate.
This argument is not persuasive as Campisi teaches various syntheses, for example in Examples 1-4.
Applicant argues that the cited art does not teach or suggest the use of DMSO or NaBr has any advantage.
This argument is not persuasive because one of ordinary skill in the art would have considered substituting these components which were recognized as equivalents known for the same purpose and routinely used in the art as evidenced by Campisi. MPEP 2144.06.
Double Patenting
Claims 1-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 9789200. Although the claims at issue are not identical, they are not patentably distinct from each other because the patent claims are to a scope of HA-antitumoral compounds where the supporting disclosure includes antitumoral of HA-paclitaxel and as detailed in the 35 USC 103 rejection over Leonelli et al. (Helv. Chim. Acta. 2005, 88, 154-159) in view of Campisi et al. (US20110189265 – PGPUB of US9789200), and incorporated herein, renders the instant claims obvious for the same reasons.
Response to Remarks - Double Patenting
Applicant argues the claimed invention concerns a process which is not disclosed or suggested by the claims of the patent.
This argument is not persuasive because the patent claims both a product and method of using the product which requires looking to the synthesis of the product in order to construe the claims in a manner that one of ordinary skill in the art would have arrived at the claimed invention with a reasonable expectation of success. MPEP 804 II.B.1.
Conclusion
No claims allowed.
THIS ACTION IS MADE FINAL. 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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/ROBERT H HAVLIN/Primary Patent Examiner, Art Unit 1626
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