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
Claims 31-33, 38-40, and 45-47 are pending.
Priority
Instant application 17/776,276, filed 05/12/2022 claims priority as follows:
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Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
All references from IDS(s) received 05/12/2022 and 10/20/2025 have been considered unless marked with a strikethrough.
Response to Amendment
The amendment filed 10/20/2025 has been entered. Applicant has amended claims 31, 38, and 45.
Withdrawn Claim Rejections
The objection to claims 31 and 45 is withdrawn in view of the amendments filed 01/09/2024.
The rejection of claims 31-33, 38-40, and 45-47 under 35 U.S.C. 112(a), as failing to comply with the written description requirement, is withdrawn in view of the amendments filed 01/09/2024.
The rejection of claims 45-47 under 35 U.S.C. 112(b), as being indefinite, is withdrawn in view of the amendments filed 01/09/2024.
Claim Rejections - 35 USC § 103 - Maintained
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.
Claims 31-32, 38-39, and 45-46 are rejected under 35 U.S.C. 103 as being unpatentable over Twala (Doctoral Dissertation, University of the Witwatersrand, pp. 1-92, 2017; cited in IDS) in view of Li et al. (Cancer Research, vol. 67, no. 5, Mar. 2007, pp. 1988–96; cited in IDS).
Twala is a scientific dissertation which studies the RBBP6 with special focus in its p53 domain and the interaction with MDM2 (abstract). Using the same or similar computational methods as the present application, Twala arrives at the same conclusion, namely that ezetimibe tightly binds into the MDM2 p53-binding domain (hydrophobic pocket) and that, therefore, it will have significant impact in cancers with high MDM2 expression, including colorectal cancer (see Fig. 4.18 A-D and pages 47-51).
The difference between Twala and the instant claims is that Twala teaches administering ezetimibe to treat cancer in a patient in need thereof, but does not teach administering ezetimibe and curcumin.
However, Li is drawn to the finding that curcumin has anticancer, chemosensitization, and radiosensitization effects by downregulating the MDM2 oncogene (title, abstract). In particular, Li teaches that curcumin is able to inhibit the expression of MDM2, and sensitizes human cancer cells to chemotherapy and radiation through MDM2 (page 1991-1993, “Results”). Further, Li teaches that curcumin has been shown to inhibit the formation of cancers including colon, oral cavity, forestomach, esophagus, stomach, lung, liver, and skin (page 1995, left side).
Finding of prima facie obviousness
The Supreme Court in KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham. See MPEP 2143.
Examples of rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results.
Moreover, as recognized by MPEP § 2144.06(I):
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." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960) (Claims directed to a method and material for treating cast iron using a mixture comprising calcium carbide and magnesium oxide were held unpatentable over prior art disclosures that the aforementioned components individually promote the formation of a nodular structure in cast iron.); Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992) (mixture of two known herbicides held prima facie obvious); and In re Couvaras, 70 F.4th 1374, 1378-79, 2023 USPQ2d 697 (Fed. Cir. 2023) (That the two claimed types of active agents, GABA-a agonists and ARBs, were known to be useful for the same purpose—alleviating hypertension—alone can serve as a motivation to combine).
Therefore, applying KSR example rationale (A), it would have been prima facie obvious to administer a combination of ezetimibe and curcumin to treat cancer, such as colon cancer, in a patient in need of such treatment. As noted above, the motivation to combine flows logically from their having been individually taught in the prior art for treatment of the same disorder. A person having ordinary skill would have therefore reasonably predicted that the combination could also treat the same disorder.
Accordingly, claims 31-32, 38-39, and 45-46 are prima facie obvious.
Claims 33, 40, and 47 are rejected under 35 U.S.C. 103 as being unpatentable over Twala in view of Li applied to claims 31-32, 38-39 and 45-46 above, further in view of Cifter et al. (US 20100234342 A1; published 2010).
The teachings of Twala in view of Li are disclosed above and at least those teachings are incorporated herein by reference.
With respect to claims 33, 40, and 47, Li teaches that curcumin administered by p.o. (per os, i.e. by mouth) gavage (Fig. 6; page 1991, left side; and page 1994, left side). The difference between Twala and Li and the instant claims is that Twala and Li do not disclose administering ezetimibe orally.
However, oral administration of ezetimibe was known in the prior art. For example, see Cifter, which discloses ezetimibe compositions having bioavailability with improved solubility and dissolution rate (abstract). Cifter discloses that Ezetimibe is available as a table for oral administration (para. [0005]).
Applying KSR example rationale (G), it would have been prima facie obvious to orally administer ezetimibe and curcumin or pharmaceutical compositions thereof. The prior art (Li and Cifter) teaches oral administration as an effective mode of administration for both substances. A person having ordinary skill in the art would have therefore enjoyed a reasonable expectation of success in apply that mode of administration in the method of treating cancer taught by Twala and Li.
Accordingly, claims 33, 40, and 47 are prima facie obvious.
Response to Arguments
According to the Remarks filed 10/20/2025, applicant disagrees with the rejections under 35 U.S.C. 103 and alleges that the claimed combination of ezetimibe and curcumin exhibit unexpected effects for the claimed methods, as evidenced by the Declaration under 37 CFR 1.132 by Monde Ntwasa filed 10/20/2025 (“Declaration”).
Applicant relies upon the Declaration as alleged evidence that curcumin, when administered concurrently with ezetimibe, unexpectedly inhibits the conversion of ezetimibe into ezetimibe glucuronide, thereby allowing the ezetimibe to remain available in the intestine, and thus available to colon cancer cells (Declaration, page 4, para. 11).
Applicant’s arguments have been fully considered but are not found persuasive. The Declaration under 37 CFR 1.132 filed 01/16/2025 is insufficient to overcome the rejection of claims 31-33, 38-40, and 45-47 based upon 35 U.S.C. 103 as set forth in the last Office action because:
The figures presented in the Declaration (page 3, FIGS. 5A and FIG. 5B) are not decipherable. It is unclear which lines in the figure correspond to which conditions listed in the legend on the right side. The numbers labels on the x and y axes are not legible. Further, while the explanation of the figures (page 3, para. 9) states that the combination of ezetimibe and curcumin resulted in a 24% decrease in HCT116 cell index after 24 hours and 65% for both treatments after 48 hours, FIG 5A does not appear to match this description. The only sharp change in cell index of FIG. 5A appears to be the datapoint pointed to with an arrow, which shows a sharp increase in cell index:
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This sharp change is present for the untreated cells, as well as the cells treated only with curcumin. It is unclear how the above datapoint represents a significant and unexpected result for the combination when it is present under all of the conditions tested.
In other words, the data presented does not appear to be credible evidence that curcumin inhibits glucuronidation of ezetimibe.
Applicant is reminded of MPEP 716.02(b), which states:
I. BURDEN ON APPLICANT TO ESTABLISH RESULTS ARE UNEXPECTED AND SIGNIFICANT
The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992) (Mere conclusions in appellants’ brief that the claimed polymer had an unexpectedly increased impact strength "are not entitled to the weight of conclusions accompanying the evidence, either in the specification or in a declaration."); Ex parte C, 27 USPQ2d 1492 (Bd. Pat. App. & Inter. 1992) (Applicant alleged unexpected results with regard to the claimed soybean plant, however there was no basis for judging the practical significance of data with regard to maturity date, flowering date, flower color, or height of the plant.). See also In re Nolan, 553 F.2d 1261, 1267, 193 USPQ 641, 645 (CCPA 1977) and In re Eli Lilly, 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) as discussed in MPEP § 716.02(c).
II. APPLICANTS HAVE BURDEN OF EXPLAINING PROFFERED DATA
"[A]ppellants have the burden of explaining the data in any declaration they proffer as evidence of non-obviousness." Ex parte Ishizaka, 24 USPQ2d 1621, 1624 (Bd. Pat. App. & Inter. 1992).
Should it be found that the data presented in the Declaration support the assertion that curcumin, when administered with ezetimibe, inhibits the conversion of ezetimibe into ezetimibe glucuronide, this finding does not appear to be unexpected in view of the Twala reference (cited previously) as evidenced by Basu et al. (Biochemical and Biophysical Research Communications, vol. 360, no. 1, Aug. 2007.)
In the instant case, the Declaration states that:
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The above statements from the Declaration are consistent with teachings in the Twala reference. For example, Twala states (page 48, 2nd para.):
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And additionally, Twala states (pages 62-63):
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See also Appendix 6, B in Twala which shows the formation of ezetimibe-glucuronide via UGT1A1, UGT1A3, and/or UGT2B15.
Therefore, the Declaration and the Twala reference establish that gastrointestinal glucuronidation of ezetimibe was a known metabolic fate of ezetimibe prior to the filing of the instant application. Basu et al. is relied upon as evidence to show that curcumin was a known inhibitor of UGT and gastrointestinal glucuronidation, and has been previously used to improve drug efficacy in mice by inhibiting glucuronidation (title, abstract, results). Accordingly, the assertion that curcumin unexpectedly inhibits glucuronidation of ezetimibe is not persuasive in view of the evidence identified. Applicant is invited to present evidence that this finding was actually unexpected.
The results presented are not commensurate in scope with the claimed method. The claimed method does not specify the timing of administration for curcumin and ezetimibe, whereas the results of the Declaration were obtained when curcumin and ezetimibe were apparently administered simultaneously (Declaration, page 2, paras. 8-9). Moreover, the method of the independent claims is drawn to the treatment of any cancer characterized by overexpression of MDM2, whereas the results presented are obtained only with colorectal carcinoma cells, and the problem which was purportedly solved (avoiding glucuronidation of ezetimibe) is disclosed as being relevant to administration of ezetimibe to the intestine (i.e., for treating cancers of the gastrointestinal tract). Finally, the method of the independent claims encompasses any mode of administration, whereas the problem which was purportedly solved (avoiding glucuronidation of ezetimibe) appears to be relevant particularly to oral administration of ezetimibe.
At least in view of the foregoing reasons, the rejections of claims 31-33, 38-40, and 45-47 under section 103 are maintained.
Conclusion
Claims 31-33, 38-40, and 45-47 are rejected.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Kyle Nottingham whose telephone number is (571)270-0640. The examiner can normally be reached M-F from 8:30 am - 5:30 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton Brooks can be reached at (571) 270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/K.N./Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
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