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 and 4-13 are pending.
Claims 7-11 are withdrawn.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Note, rejections and objections not reiterated from previous office actions are hereby withdrawn.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.
Note, rejections and objections not reiterated from previous office actions are hereby withdrawn.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 12 are rejected under 35 U.S.C. 103 as being unpatentable over TRUJILLO (US 2014/0039322 A1) in view of FERRARIO (Pro-apoptotic and anti-inflammatory properties of the green tea constituent epigallocatechin gallate increase photodynamic therapy responsiveness. Lasers Surg Med. 2011.).
Regarding claim 1, TRUJILLO teaches a photosensitizer composition comprising methyl aminolevulinate (MAL) and EDTA with pharmaceutical acceptable carriers, such as water (page 12, paragraph 0257).
Regarding claim 4, TRUJILLO teaches using a pharmaceutical acceptable carrier, such as water (page 12, paragraph 0257).
Regarding claim 5, TRUJILLO teaches the composition can be in the form of a cream (page 12, paragraph 0257).
Additional disclosures: TRUJILLO teaches that MAL is the active ingredient and upon illumination reacts and destroys tumor cells (page 5, paragraph 0187). The percent or dose of sensitizer compound, such as MAL, is readily determined based upon knowledge in the art and normally a 20% concentration (page 5, paragraph 0192). EDTA is added to enhance efficacy (page 5, paragraph 0192) and as an iron chelating agent (page 12, paragraph 0259).
TRUJILLO does not teach adding epigallocatechin galate (EGCG).
Regarding claim 1, FERRARIO teaches that EGCG can be combined with a photosensitizer in photodynamic therapy to increase the cytotoxicity and therefor increase the effect of the photodynamic therapy (page 4, paragraph 4). The EGCG improved PDT efficacy by increasing tumor apoptosis and decreasing expression of pro-survival and angiogenic molecules within the tumor microenvironment (abstract).
Regarding claims 6, 12 and 13, the claims are product claims with intended use. As the prior art teaches the product, it would be capable of the use “preparing a drug product for photodynamic therapy”, “dermocosmetic purposes”, and “useful for cellular rejuvenation”.
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate EGCG. The person of ordinary skill in the art would have been motivated to make those modifications, because it improves PDT efficacy by increasing tumor apoptosis, and reasonably would have expected success because the references are in the same field of endeavor, such as compositions comprising a photosensitizer for photodynamic therapy for tumors.
The reference does not specifically teach the amount of MAL, EDTA and EGCG as claimed by the Applicant. The amount of MAL, EDTA and EGCG 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 amount of MAL, EDTA and EGCG in order to best achieve desired results, such as the appropriate amount of MAL for the destruction of tumors cells upon illumination, the appropriate amount of EDTA for treatment efficacy, and the appropriate amount of EGCG for improved PDT efficacy by increasing tumor apoptosis. Thus, absent of some demonstration of unexpected results from the claimed parameters, this optimization of the amount of MAL, EDTA and EGCG would have been obvious at the time of Applicant’s invention.
Response to Arguments
Applicant argues, that the additional experimental data provided above shows that with 1.5%, 3.0% and 4.5% unexpected results are also obtained. These percentages of EGCG are within the range of 15-45 mg/g. The same unexpected results can be obtained with 50 mg/g (5% EGCG) or 500 mg/g (50% EGCG). The unexpected results disclosed in the present application include complete cell death (0% viability) at extremely low concentrations of EDTA and EGCG combined with MAL (Example 2), significant increase in intracellular PpIX accumulation only when EGCG and EDTA are combined with MAL (Example 3), enhanced post-irradiation ROS production despite EGCG's known antioxidant effect (Example 4), specific reversal of MAL-PDT resistance in results for 15-45 mg/g EGCG, shows unexpected results. HSC-1 carcinoma cells, and the above additional data demonstrate that the topical formulation applied to animal ( or human) skin, which requires a significantly higher concentration due to the skin barrier, also achieves an equivalent effect. With the claim narrowed to MAL, the Examiner's "result-effective variable" rationale no longer applies because the magnitude of the effect (0% viability in resistant cells) is not predictable or incremental. Contrary to the antioxidant role attributed to EGCG in the prior art, the present specification demonstrates that EGCG, when combined with MAL and EDTA, increases both intracellular PpIX accumulation (Example 3) and post-irradiation ROS generation (Example 4), resulting in markedly enhanced PDT cytotoxicity.
Examiner does not find the argument persuasive because arguments without factual support are mere allegations and are not found persuasive. Unexpected results must be set forth as originally filed in the specification or submitted in a signed declaration or affidavit. Applicant’s arguments alone cannot take the place of such evidence.
Furthermore, In order to overcome a prima facie case of obviousness, it is incumbent upon the Applicant to provide comparative test evidence that demonstrates unexpected superiority of the claimed compositions versus the closest prior art compositions, and not simply an advantage predictable from the prior art. See In re Chapman, 148 USPQ 711, 715 (CCPA, 1966). Moreover, such proffered comparisons must be commensurate in scope with the breadth of the claims. See In re Clemens, 206 USPQ 289, 296 (CCPA, 1980) and In re Coleman, 205 USPQ 1172, 1175 (CCPA 1980). In the instant case, the claims have a wide range of concentrations for MAL, 100 –200 mg/g, EDTA, 0.5–10 mg/g and EGCG 0.1–500 mg/g. The attorney’s arguments only discuss a small concentration for EGCG 15-45 mg/g, which is not commensurate with the broad range of 0.1-500 mg/g. Additionally, the concentrations of MAL and EDTA have no data provided to prove unexpected results. The only concentration mentioned for MAL is 20%, which as discussed above is a commonly used concentration in the art.
Applicant argues, Ferrario characterizes EGCG primarily as an antioxidant, which would lead one skilled in the art to expect reduced ROS and diminished PDT efficacy. However, as discussed above, the present invention showed the opposite effect when EGCG is combined with MAL and EDTA, namely, increased PpIX accumulation and increased ROS generation post-irradiation. Thus, there is no routine optimization. In fact, based on Ferrario and EGCG's antioxidant nature would discourage the skilled artisan to include EGCG directly in topical MAL compositions for PDT as PDT efficacy requires ROS generation. This, teaches away from the claimed invention.
Examiner does not find the argument persuasive because as discussed above FERRARIO teaches that EGCG can be combined with a photosensitizer in photodynamic therapy to increase the cytotoxicity and therefor increase the effect of the photodynamic therapy (page 4, paragraph 4). The EGCG improved PDT efficacy by increasing tumor apoptosis and decreasing expression of pro-survival and angiogenic molecules within the tumor microenvironment (abstract).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate EGCG. The person of ordinary skill in the art would have been motivated to make those modifications, because it improves PDT efficacy by increasing tumor apoptosis, and reasonably would have expected success because the references are in the same field of endeavor, such as compositions comprising a photosensitizer for photodynamic therapy for tumors.
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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
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618