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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 10/31/2025 has been entered.
Information Disclosure Statement
The information disclosure statements (IDS), dated 10/31/2025, comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609. Accordingly, they have been placed in the application file and the information therein has been considered as to the merits.
Status of the application
Receipt of applicant’s claim amendments and remarks filed on 10/31/2025 are acknowledged.
However, applicants’ arguments for the previous 103 rejection are found not persuasive. Accordingly, the previous rejection is maintained and modified to address amended claims. Please see the examiners response to applicants below.
Response to Arguments
(i) Applicants argue that thiostrepton is difficult to formulate.
Formulations of thiostrepton are already known, but not with TPGS. Applicants also failed explain why it is difficult to formulate in known solvents or excipients?
The rejection explains that advantages of TPGS formulations, since it is approved by FDA. TPGS not only improved bioavailability, but also a potent excipient for overcoming multi-drug resistance in tumors and a selective anticancer agent for synergistic antitumor effects as evidenced from the teachings of Yang. Similar advantages of TPGS are shown in the teachings of Tan.
The shown data in Table 1 and filed declaration in Feb-2025, is simply routine titration of TS with various excipient. So, it is a testing solubility of TS in various excipients.
In the filed declaration in Oct-2025, applicants compared TPGS with Cremophor EL but the rejection was no based on Cremophor EL. TS in combination with TPGS is more toxic than TS alone, because TS is soluble in TPGS, more soluble more the effective, and TPGS is also toxic to tumor cells and so combination is more effective.
There are several ways to choose a suitable excipient or solvent etc. Most of the time the decision is based on their physical and chemical properties and these can be predicted based on the chemical groups present in them, such as hydrophobic or hydrophilic or acidic or basic or neutral groups or side chains etc. In addition, if an excipient shows any additional advantage(s), such as antitumor or synergism or economical or environmental reason or combination etc., then this excipient is likely to be chosen for a selected drug.
In this case, it appears that TPGS has advantages over other excipients, at least over applicants cited art. Moreover, TPGS is a vitamin E supplement, and may not expect any side effects, whereas other excipient are not supplements and so, TPGS is still a preferable excipient over other excipients.
(ii) Applicants argue that cited references do not provide a reasonable expectation of success.
Applicants show how each cited reference differ from the instant invention, but the obviousness test under 35 U.S.C. 103 is whether the invention would have been obvious in view of the prior art taken as a whole. In re Metcalf et al. 157 U.S.P.Q. 423.
Applicant is reminded that one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the instant case, all the art rejections are under 35 USC 103, which relies on the combination of the references together.
The purpose of Yang and Tan is to show the advantages of TPGS in drug formulations.
With regard to applicants remark on Tan, the art simply teaches or acknowledges that safety is an important feature of TPGS. Although the original preparation approved by the FDA is an oral formulation, i.v. injection of TPGS has not been reported to cause any side effects. We have also evaluated the safety of TPGS after i.v. injection in healthy Kunming mice at a dose of 200 mg/kg. (Yin et al., Citation2017b) The results showed that compared with saline, the TPGS group exhibited almost the same body weight changes, main organ/body index and ALT, AST, and BUN levels. H&E staining of the main organs (heart, liver, spleen, lung, and kidney) further confirmed that there were no significant differences between the two groups. Advanced study on safety and efficacy in clinical research is also needed, and conclude that taken together with its unique bio-functions, TPGS could serve as an effective drug carrier component that may greatly reduce ‘carrier material burden’ (Bamrungsap et al., Citation2012; Maksimenko et al., Citation2014). Thus, it could be utilized to develop a simple, but multi-functional DDS that could be applied clinically for cancer treatment.
So, it appears that there is no adverse effects of TPGS in the teachings of Tan.
(iii) Applicants argue that the claimed compositions are unexpectedly useful in the treatment of humans.
In the filed Oct-2025 declaration, the Fig.1 of ‘654 PCT shows treating mesothelioma with TS, but TS is already known to treat mesothelioma as explained in the rejection. Even if the composition of ‘654 PCT comprises TPGS, still it is obvious as explained in the rejection.
With regard to Fennell 2024, it simply shows intrapleural administration of TS. It does not provide any advantages of intrapleural over other modes of administrations.
It is not clear what applicants intend to provide or say based on the above data.
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 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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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, 3-4, 6-7 and 40-41 are rejected under 35 U.S.C. 103 as being unpatentable over Newick (PLOS ONE, June 2012, vol.7, issue 6, 1-4) or Cunniff (PLOS ONE, 26 May 2015, 1-27; see applicants filed IDS dated 09/22/2022) in view of Yang (Theranostics. 2018; 8(2): 464–485; see applicants filed IDS dated 09/22/2022), Tan (Drug Delivery, 2017, vol.24, No.1, 1831-1842; see applicants filed IDS dated 09/22/2022), Boutin (Cancer, 1 Nov 1994, vol.74, No.9, 2460-2467), Levin (Analytical Microbiology, 1972, vol.II, pages 347-354) and Mitchell (US 2017/0227545 A1).
For claim 1:
Newick teaches effect of thiostrepton (TS) and gentian violet (GV) on mesothelioma cells [see Figures 6 and 7].
The above is interpreted as a composition comprising TS and GV and so, it reads applicants claims.
or
Cunniff teaches effect of TS and GV on malignant mesothelioma cell proliferation [see abstract and Fig.6]. Cunniff further teaches that TS is administered intraperitoneally [see first paragraph in page 12; second paragraph in pages 16 and 21].
The above is interpreted as a composition comprising TS and GV and so, it reads applicants claims.
Differences between Newick or Cunniff are as follows:
(i) Newick or Cunniff silent on applicants Vitamin E-TPGS (aka TPGS) and its concentrations,
(ii) Newick or Cunniff silent DMSO, and
(iii) Newick or Cunniff silent intrapleural administration.
With regard to (i) of above, Yang teaches that TPGS has been approved by FDA as a safe adjuvant and widely used in drug delivery systems. The biological and physicochemical properties of TPGS provide multiple advantages for its applications in drug delivery like high biocompatibility, enhancement of drug solubility, improvement of drug permeation and selective antitumor activity. Notably, TPGS can inhibit the activity of ATP dependent P-glycoprotein and act as a potent excipient for overcoming multi-drug resistance (MDR) in tumor [See abstract]. Yang further teach that TPGS as a selective anticancer agent for synergistic antitumor effects [see page 467, left column], TPGS based formulations to improved drug oral bioavailability [see page 478, right column] and TPGS based formulations to promote drug permeation [see page 481, left column].
Tan teaches that TPGS as an FDA-approved biocompatible drug excipient, widely applied in drug delivery system (DDS), revealed that TPGS is able to act not only as a simple drug carrier but also as an assistant molecule with various bio-functions to improve anticancer efficacy. Tan further teaches that TPGS can inhibit P-glycoprotein, enhance drug absorption, induce mitochondrial-associated apoptosis or other apoptotic pathways, promote drug penetration and tumor accumulation, and even inhibit tumor metastasis. As a result, many formulations, by using original TPGS, TPGS-drug conjugates or TPGS copolymers, were prepared, and as expected, an enhanced therapeutic effect was achieved in different tumor models, especially in multidrug resistant and metastatic tumors. [See abstract].
Yang or Tan, silent on concentrations of TPGS in their disclosures. However, art established the utilities of TPGS and a skilled person in the art would determine the suitable concentration range for TPGS through a titration, which is a common practice in the art, absent evidence to the contrary.
Generally, the concentrations of components of a formulation will not support the patentability of subject matter encompassed by the prior art. Such formulations are results-effective variables which can be optimized. In in re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980), it was held that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." Further, in In re Aller, 220 F. 2d454, 456, 105 USPQ 233,235 (CCPA 1955) the courts maintained that: "Where the general condition of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." As formulating optimal compositions for medicaments is routine in the art of pharmacology, the claims are considered to be prima facie obvious.
Therefore, one would be motivated to include TPGS with suitable concentrations in the teachings of Newick or Cunniff and arrive at applicants composition with a reasonable expectation of success.
With regard to (ii) of above, both Newick or Cunniff silent on DMSO in their compositions.
However, DMSO is well known in the art for TS compositions. For example, Levin teaches that Thiostrepton has very low solubility in water but can be dissolved readily in chloroform, dioxane, dimethylacetamide, formamide, dimethylformamide, and dimethyl sulfoxide [see abstract]. Mitchell teaches that 5% DMSO is added to improve thiostrepton solubility [see Example 7.5]. Therefore, a skilled person the art would always choose established solvents in the art for the compositions of TS. In this case, art teaches that DMSO is an established solvent for TS, since it increases the solubility of TS.
With regard to (iii) of above, both Newick or Cunniff silent on intrapleural administration. Cunniff teaches that TS is administered intraperitoneally [see first paragraph in page 12; second paragraph in pages 16 and 21], which is along the lines of applicants shown data in the specification for treating mesothelioma. Specification described the utility of the claimed composition in treating mesothelioma. However, it failed to describe or show treating mesothelioma by intrapleural administration. Various modes of administrations are known in the art and a skilled person in the art would determine suitable modes of administration through a routine experimentation, and therefore, intrapleural administration is obvious, absent evidence to the contrary.
In addition to above, it appears that treating mesothelioma by administering a drug composition through intrapleural administration. For example, Boutin teaches intrapleural treatment with gamma-interferon in patients with Butch-art's Stages I and I1 epithelial or mixed malignant pleural mesothelioma and further teaches advantages of intrapleural administration in treating mesothelioma [see abstract and 2nd and 3rd paragraph in right column in page 2464]. Therefore, one would be motivated to use intrapleural administration.
For claim 4:
Cunniff teaches various concentrations, for example 5 mM of TS [see Fig.1] and 0.1-805 mM of TS [see Fig.4]. Newick also teaches various concentrations of TS, for example 1-10 mM of TS [see Fig.3].
For claim 7:
In the teachings of above art, water or solvent in the TS compositions is interpreted as pharmaceutically acceptable carrier and excipient.
For claims 40-41:
Newich teaches a concentration of 0.05 mM of GV [see Fig.7], which reads claim limitation.
Cunniff teaches 2 mg/kg of GV [see Fig.6], which reads claim limitation.
For claims 43-45:
See For claim 1 above.
Based on the above established facts from the cited prior art, it appears that all the claimed elements, i.e, individual components in the composition and their utilities etc, were known in the prior art, and one skilled person in the art could have combined the elements as claimed by known relationships, with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary skill in the art.
The strongest rationale for combining references is a recognition, expressly or impliedly in the prior art or drawn from a convincing line of reasoning based on established scientific principles or legal precedent, that some advantage or expected beneficial result would have been produced by their combination. In re Sernaker, 702 F.2d 989, 994-95, 217 USPQ 1, 5-6 (Fed. Cir. 1983). In the instant case, one would be motivated to incorporate TPGS in the compositions of TS, in light of its advantages.
The motivation to combine the art can arise from the expectation that the prior art elements will perform their expected functions to achieve their expected results when combined for their common known purpose. See MPEP 2144.07. Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention by taking the advantage of the teaching of the above cited reference and to make the instantly claimed composition with a reasonable expectation of success.
Conclusion
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SUDHAKAR KATAKAM
Primary Examiner
Art Unit 1658
/SUDHAKAR KATAKAM/Primary Examiner, Art Unit 1658