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 .
Claims 1, 4-6, 8-23 and 25 are pending.
Claims 13-23 and 25 are withdrawn.
Claim 1 is amended.
Note, rejections and objections not reiterated from previous office actions are hereby withdrawn. The following rejections or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
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.
Claims 1, 4-6 and 8-12 are rejected under 35 U.S.C. 103 as being unpatentable over SOO (WO 2017/126939 A1) in view of WU (pH-Responsive Hyaluronic Acid-Based Mixed Micelles for the Hepatoma-Targeting Delivery of Doxorubicin. International Journal of Molecular Sciences. 2016.) and WACH (Hydroxyl radical-induced crosslinking and radiation-initiated hydrogel formation in dilute aqueous solutions of carboxymethylcellulose. Carbohydrate Polymers. 2014.).
Regarding claim 1 and 11, SOO teaches a method of making crosslinked hyaluronic nanoparticles (abstract and claim 1). The method comprises a hyaluronic acid solution (claim 4 and 5) that is irradiated with an electron beam to produce crosslinked nanoparticles (claim 1 and 13).
Regarding claims 5 and 6, SOO teaches the size of the nanoparticle is changed using the irradiation dose of the electron beam (Page 6, paragraph 2). The increase in irradiation caused the nanoparticles to shrink in size (Page 12, paragraph 4).
Regarding claim 8, SOO teaches the concentration of aqueous solution for hyaluronic acid is 0.5 to 7% (Page 5, bullet 1).
Regarding claim 9, SOO teaches the solution is irradiated at 30 to 230 kGy (Page 6, paragraph 2).
Regarding claim 10, SOO teaches the nanoparticles had a size of 100 nm (Figure 10 and Page 11, section 7).
Regarding claim 12, SOO teaches the nanoparticles target tumors and can be loaded with doxorubicin (Page 13, Tumor Growth inhibitory Effect of Doxorubicin-Conjugated PEG-DNP).
SOO does not teach using an acidic aqueous solution with a pH between 1.5 and 3.5, controlling the size of the nanoparticle by adjusting the pH of the solution or using HClO4 in the hyaluronic acid-containing solution.
Regarding claim 1 and 11, WU teaches a method of making hyaluronic acid nanoparticles that are used for targeting tumors and are loaded with doxorubicin (abstract). WU teaches that a lower pH value resulted in an increase in average particle size (page 4, paragraph 1). The decrease in pH allowed for the nanoparticles to swell and resulted in an increased release of the drug, doxorubicin (page 5, paragraph 3 and figure 5).
Regarding claim 4, WACH teaches irradiating a polysaccharide solution to allow for crosslinking (abstract). WACH teaches adjusting the pH of the solution with HClO4 to a pH of 2 (page 413, paragraph 4 and 10).
Regarding claim 1 and 11, the reference does not specifically teach the pH range as claimed by the Applicant. The pH is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. It would have been customary for an artisan of the ordinary skill to determine the optimal pH in order to best achieve desired results, such as an increased size of nanoparticle, since WU teaches that decreasing the pH increases the size and also increases release of the drug. Thus, absent of some demonstration of unexpected results from the claimed parameters, this optimization of the pH range would have been obvious at the time of Applicant' s invention.
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate using HClO4 in the hyaluronic acid-containing solution. The person of ordinary skill in the art would have been motivated to make those modifications, because acids are commonly used to adjust a pH to be more acidic and can be commonly chosen by one in the art, and reasonably would have expected success because the references are in the same field of endeavor, such as irradiating polysaccharide solutions to promote crosslinking and adjusting the pH of a solution.
Response to Arguments
Applicant argues, WU discloses mixed micelles composed of a hyaluronic acid glycyrrhetinic acid conjugate and a hyaluronic acid-L-histidine conjugate (HA-GA/HA-His). WU p. 364. Applicant further notes that WU measured the effect of pH on particle size on HA-GA/HAHis micelles at a pH between 7.4-7.0; at pH 6.8; and at pH 6.4, 6.0 and 5.5. To this effect, WU further investigated the in vitro drug release behavior of the HA-GA/HA-His micelles under physiological conditions (e.g., pH 7.4), tumor acidic microenvironment (e.g., pH 6.4), and intralysosomal pH (e.g., pH 5.5). Accordingly, Applicant submits that WU was primarily directed to the influence of pH on the release of the drug, e.g., DOX. See WU p. 368; see also FIG. 5. Importantly, WU does not measure the effect of pH on particle size at a pH below 5.5. Applicant respectfully submits that SOO in combination with WU does not meet the claim limitation of a pH from 1.5 to 3.5 as recited in claim 1 as currently amended. As provided in MPEP§ 2143.03, to establish a prima facie case of obviousness, all claim limitations must be considered. Said another way, "[a]ll words in a claim must be considered in judging the patentability of that claim against the prior art." In re Wilson, 424 F.2d 1382, 1385, 165 USPQ 494,496 (CCPA 1970). Accordingly, Applicant respectfully submits that the Office has not made a prima facie case of obviousness and that claim 1 as currently amended is patentable over SOO in view of WU.
The examiner does not find the argument persuasive because although the reference does not specifically teach the pH range as claimed by the Applicant. The pH is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. It would have been customary for an artisan of the ordinary skill to determine the optimal pH in order to best achieve desired results, such as an increased size of nanoparticle, since WU teaches that decreasing the pH increases the size and also increases release of the drug. Thus, absent of some demonstration of unexpected results from the claimed parameters, this optimization of the pH range would have been obvious at the time of Applicant' s invention.
Applicant argues that WU teaches that the pH-sensitive ability observed therein "was probably due to the deformation of the hydrophobic core induced by the ionizable imidazole rings of His; these rings were protonated at acidic pH, which triggered the dissociation and increased the size of the micelles." WU p. 367; see also FIG. 4 of WU. Accordingly, one of ordinary skill in the art would not be motivated to modify SOO with the method of WU to arrive at the presently claimed method for preparing cross-linked hyaluronic acid nanoparticles
The examiner does not find the argument persuasive because as discussed above, it would have been customary for an artisan of the ordinary skill to determine the optimal pH in order to best achieve desired results, such as an increased size of nanoparticle, since WU teaches that decreasing the pH increases the size and also increases release of the drug. The specific mechanism that causes the change is not required by the claim. Instant claim 1 only requires that the size increases with a decrease in pH, which is taught by WU.
Applicant argues that WACH is directed to macroscopic hydro gels. See WACH, p. 415 (emphasis added). As such, WACH is silent with regard to the effect of pH on hyaluronic acid nanoparticles. As provided in MPEP § 2143, to rejection a claim under the rationale that there is some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention, the Office must also articulate a finding that there was reasonable expectation of success. See DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 464 F.3d 1356, 1360, 80 USPQ2d 1641, 1645 (Fed. Cir. 2006). If any of these findings cannot be made, then this rationale cannot be used to support a conclusion that the claim would have been obvious to one of ordinary skill in the art. To this end, Applicant notes that WACH is silent with respect to whether a size of the hyaluronic acid nanoparticle is controlled by adjusting a pH of the aqueous solution, and wherein the size of the hyaluronic acid nanoparticle increases with a decrease in pH of the aqueous solution. As provided herein above, SOO in combination with WU neither teaches nor suggests controlling the size of the hyaluronic acid nanoparticle is by adjusting a pH of the aqueous solution between about 1.5 to about 3.5. WACH does not cure the defect of SOO in view of WU. Accordingly, one of ordinary skill in the art would not have a reasonable expectation of success in arriving at the method of claim 1 as currently amended by combining SOO and WU in view of WACH.
The examiner does not find the argument persuasive because WACH is not cited to show that nanoparticles can be controlled by adjusting the pH, but rather that HCLO4 can be used to adjust the pH of the solution. Additionally, as discussed above SOO and WU teach that the size of the hyaluronic acid nanoparticle increases with a decrease in pH of the aqueous solution.
Conclusion
No claims are allowable.
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 L. MEJIAS whose telephone number is (703)756-5666. The examiner can normally be reached M-F.
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/S.L.M./ Examiner, Art Unit 1618 /JAKE M VU/Primary Examiner, Art Unit 1618
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