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 .
Status of Claims
Pending claims 1, 2, 9, 11, and 42-44 have been examined on the merits.
Withdrawn Rejection
The rejection of claims 1, 2, 4, 6, 11, 29-32, 36-39 and 41 are rejected under 35 U.S.C. 103 as being unpatentable over Zawacka-Pankau et al. (J Intern Med) 2015 Feb;277(2):248-259, in view of Ramraj et al., Cancer Research, 77(13_Supplement), 3225, Ahn et al. (Sci Rep) 7, 9076 (2017), and Liu et al. (Anti-Cancer Drugs - Nature, Synthesis and Cell, InTech), 7 Dec. 2016 (Liu-3”). ("Liu-3") is withdrawn due to the Claim Amendments and Cancellation.
The rejection of claims 1, 29 and 36 rejected under 35 U.S.C. 112(b) is withdrawn due to the Claim Amendments and Cancellation.
New Grounds of Rejection due to the Applicant’s Claim Amendments
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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, 2, 9, 11, 42, and 44 are rejected under 35 U.S.C. 103 as being unpatentable over Zawacka-Pankau et al. (J Intern Med) 2015 Feb;277(2):248-259, in view of Ramraj et al., Cancer Research, 77(13_Supplement), 3225, Wen et al., Intern. J of Gyn Path 18(1):p 29-41, January 1999. Ahn et al. (Sci Rep) 7, 9076 (2017), and Liu et al. (Anti-Cancer Drugs - Nature, Synthesis and Cell, InTech), 7 Dec. 2016 (Liu-3”).
Regarding claims 1, 2, 9, 11, 42 and 44, Zawacka-Pankau (page 251, left col.; page 255, Table 1; page 256, left col.) teaches a cancer treatment targeting mutp53- and wtp53- with an effective amount of PRIMA-1 and PRIMA-1MET (alternative name APR-246), against various tumor models, including but not limited to breast cancer and ovarian carcinoma. Regarding p53 expressing ovarian cancer, Wen (page 1) in view of Zawacka-Pankau, teaches that p53 expression/overexpression and p53 mutations are well-known features of ovarian cancer. Therefore, it would have been obvious to a person of ordinary skill in the art (POSITA) to combine the teachings of Zawacka-Pankau and Wen, targeting p53 in ovarian cancer with PRIMA-1 and/or PRIMA-1MET to arrive at the claimed invention, because of the central role of p53 in ovarian cancer.
With regards to PRIMA-1 or PRIMA‐1MET in a weight-to-weight ratio, Zawacka-Pankau (page 255, right col., bridged page 2556, left col.) teaches maximal tolerated dose (MTD) of APR-246 (PRIMA‐1) is 60 mg/kg, and was administered in a clinical trial without intolerable side-effects.
The combined teachings of Zawacka-Pankau and Wen does not explicitly teach SHetA2.
However, Ramraj (page 1 and 2) teaches a method of treating cancer using an effective amount of SHetA2 with dose-responsive apoptosis in ovarian cancer cell line, as an example. This is supported by Liu-3 (page 71; page 86) teaches SHetA2 exhibited no evidence of toxicity in animal models including dogs, and SHetA2 is now in Phase-0 clinical trial for ovarian cancer chemoprevention. Liu-3 (page 86, Table 5) teaches SHetA2’s pharmacokinetic studies and explains that the studies reveal SHetA2’s oral bioavailability at 20 mg/kg and 60 mg/kg. Liu-3 (page 68) also teaches SHetA2 disrupts mortalin-p53 binding, leading to apoptosis in cancer cells. As evidence by the specification (page 2- 3) discloses that SHetA2 disrupts mortalin/p53 complexes in ovarian cancer cells. This to indicate that both PRIMA-1 and SHetA2 target p53.
Therefore, given that both SHetA2 and PRIMA‐1MET act on complementary pathways affecting p53 or p53 expressing ovarian cancer, thus, it would have been obvious to a POSITA to co-administer these agents with a reasonable expectation of enhancing anticancer activity. It is then evident that the claimed invention merely applies the known anticancer agents, each previous taught for p53-related or ovarian cancer application, at doses already shown to be effective in vivo with falls within the claimed range. Therefore, a POSITA would have been motivated to combine the teachings of Zawacka-Pankau, Wen, Ramraj and Liu-3 to administer the compounds in combination, either sequentially or simultaneously, to enhance their therapeutic efficacy and to arrive at the claimed invention.
Also, a POSITA would have been motivated to so because optimization of two compounds’ ratios would improve dose tolerance, treatment adherence, side effects, delaying drug resistance, to achieve therapeutic efficacy. Given that optimizing compounds ratios would enhance a compound efficacy, thus modifying SHetA2 and PRIMA‐1 ratios or concentration would have been an obvious approach to optimize the compound therapeutic benefits. Thus, a POSITA would have been motivated to explore various ratios to achieve optimal therapeutic effects and arrive at the claimed invention.
In addition, “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” See MPEP 2144.05.
From the teachings of the references, it is apparent that a POSITA would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
While the combined teachings of Zawacka-Pankau, Wen, and Ramraj does not explicitly teach synergistic effect, however they teach Prima-1 and SHetA2 are independently used to treat cancer, including ovarian cancer, which is comparable to the instant claims. Although, the instant claim recites their synergistic combination in cancer treatment, but the mere assertion of synergy does not render the combination nonobvious. Because a POSITA would recognize that both PRIMA-1 and SHetA2 target p53 as treatment for cancer, which would have motivated a POSITA to combine them to enhance their therapeutic efficacy. In addition, “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” See MPEP 2144.06.
Thus, it would have been prima facie obvious to a POSITA, prior to the effective filing date of the instantly claimed invention, to modify the teachings Zawacka-Pankau in view of Wen, Ramraj and Liu-3 to administer a combination of PRIMA-1 and SHetA2 either sequentially or simultaneously to enhance their therapeutic efficacy to treat cancer, and arrive at the claimed invention. Also, a POSITA would have been motivated to so because optimization of two compounds either sequentially or simultaneously would improve dose tolerance, treatment adherence, side effects, delaying drug resistance, and would achieve therapeutic efficacy. Moreover, given that APR-246 restores mutant p53 and SHetA2 interfere with mortalin binding to p53 leading to apoptosis in cancer cells, a POSITA would have reasonably expected a complementary or synergistic effect upon combining the two agents in cancer treatment. Therefore, “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” See MPEP 2144.05
Claim 43, Regarding R282W and R248W, Zawacka-Pankau (page 249, left col.) teaches mutations at R282 and R248 are very common across human cancers:
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Although Zawacka-Pankau does not explicitly mention R282W and R248W mutations, but Zawacka-Pankau teaches mutations at codons R282 and R248 as prevalent hotspots in various human cancer. Moreover, Zawacka-Pankau (page 251, left col.; page 256, left col.) teaches PRIMA-1 and PRIMA-lMET inhibit tumor growth by converting to methylene quinuclidinone (MQ), which covalently modifies cysteine residues of the core structure of both wild-type and mutant p53 proteins. Since PRIMA-1 and APR-246 are effective against both wild type and mutant p53 in various cancer models, this implies that the compounds mechanism of action, binding to and modifying cysteine residues in the core domain, is not entirely dependent on the specific mutation but rather on the general presence of modifiable cysteines. Therefore, given that PRIMA-1 and APR-246 broadly target mutant p53, it would have been obvious to a person of ordinary skill in the art (POSITA) to apply these inhibitors against R282W and R248W mutation, because regardless of the specific mutation (e.g., R248W, R282W), the compounds could still retain their binding and functional activity. Therefore, it would have been obvious to a POSITA to reasonably infer that PRIMA-1 and APR-246 to be used to treat cancers harboring these specific mutations based on the compounds established mechanism of action and the ongoing clinical evaluation, such as APR-246 in phase II clinical trial for ovarian carcinoma (Zawacka-Pankau, page 256, left col.).
Ramraj (page 1) also teaches TP53 mutations observed in high grade serous ovarian cancer (HGSOC) drive ovarian carcinogenesis. Given that Zawacka-Pankau identifies R248 and R282 as hotspot residue in p53, thus a POSITA would recognize that SHetA2’s mechanism, releasing p53 from mortalin, could extend to these mutations, including R248W and R282W. This is supported by Ahn (page 1):
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Given that HGSOC frequently harbors p53 mutations, such as such R248, and disrupt mortalin/p53 complexes in ovarian cancer, thus a POSITA would reasonably understand that other known hotspots, including R282, could also be present in ovarian cancer.
Response to Arguments
Applicant argues that the submitted data demonstrate synergism between SHetA2 and PRIMA‐1MET; however, the data disclose inconsistency. For example, in Figure 21 from Applicant Argument, the specification fails to provide the exact dose for the synergy at ED90, while both ED75 and ED50 doses cross the additive line. Therefore, the claim of synergism at a dose range of 1 mg/kg to 100 mg/kg is not justified. This is supported by Figure 37, which discloses mitochondrial disruption at concentrations that do not correspond to the doses used in the isobologram in Figure 21. Therefore, without explicitly linking Figure 21 and 37, as an example, Applicant has not shown that mitochondrial effects occur at the same concentration claimed to be synergistic at ED90. It is then evident that Applicant has not provided sufficient evidence of synergistic effect of SHetA2 and PRIMA‐1MET a dose range 1 mg/kg to 100 mg/kg each.
Conclusion
Therefore, claims 1, 2, 9, 11, and 42-44 are rejected.
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/P.P.E./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622