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 .
Election/Restrictions
Applicant's election with traverse of Group I, claims 41-49 and 53-55, drawn to a compound having the structure of Formula VI and a pharmaceutical compositing comprising the compound; and a compound 48 having the structure of:
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as the elected compound species of Formula VI are maintained.
Claims 47, 50-52, 56-70 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention and species, there being no allowable generic or linking claim.
Expansion of Election of Species Requirement
A reasonable and comprehensive search of the elected species conducted by the Examiner determined that the prior art at the time of the present invention was such that it did not anticipate or render obvious the elected species:
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. In light of this discovery, the search is expanded to the subject matter of the subgenus of the elected species, i.e., the compound of Formula VI having the structure of:
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,
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,
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, and
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, such that it does not encompass the full scope of the claims.
Status of the Claims
Acknowledgement is made of the receipt and entry of the amendment to the claims filed on April 27, 2026, wherein claims 1-40 are canceled; claims 41 are amended; claims 42-70 are unchanged. Specifically, applicant amends the preamble of claim 41 from the recitation of “[a] compound having the structure of” to the recitation of “[a] cancer inhibiting compound having the structure of”, such that a functional language is newly added as a required feature of the claim(s).
Claims 41-70 are pending. Claims 47, 50-52 and 56-70 remain withdrawn.
Claims 41-46, 48-49 and 53-55 are under examination in accordance with the elected compound species along with the expanded compound species sets forth in the Expansion of Election of Species Requirement section above.
Priority
The instant application 18/266,936 filed on June 13, 2023 is a 371 of PCT/CN2022/074975 filed
on January 29, 2022, which claims priority to, and the benefits of U.S. Provisional Application No.
63/144,322 filed on February 1, 2021.
Action Summary
Claims 41-46, 48-49 and 53-55 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention are withdrawn in light of the claim amendments that change the limitation from “C3-C30 polycycloalkyl” to “C6-C30 polycycloalkyl”.
Claims 41-44, 48 and 53-55 rejected under 35 U.S.C. 103 as being unpatentable over Amewu et al. (US 2013/0023551 A1), in view of Patani et al. (Chem. Rev., 1996. Vol. 96, 8: 3147-3176) are maintained.
Claims 41-46, 48 and 53-55 rejected under 35 U.S.C. 103 as being unpatentable over Amewu et al. (US 2013/0023551 A1), in view of Patani et al. (Chem. Rev., 1996. Vol. 96, 8: 3147-3176) as applied to claims 41-44, 48 and 53-55 above, and further in view of Renslo et al. (US 10,662,215 B2) are maintained.
Claims 41-44, and 53-55 rejected under 35 U.S.C. 103 as being unpatentable over Amewu et al. (US 2013/0023551 A1), in view of Patani et al. (Chem. Rev., 1996. Vol. 96, 8: 3147-3176) are maintained.
Claims 41-44, 49, and 53-55 are rejected under 35 U.S.C. 103 as being unpatentable over Amewu et al. (US 2013/0023551 A1), in view of Patani et al. (Chem. Rev., 1996. Vol. 96, 8: 3147-3176) as applied to claims 41-44, and 53-55 above, and further in view of Renslo et al. (US 10,662,215 B2) are maintained.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 41-46, 48-49 and 53-55 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention (newly applied as necessitated by amendment).
Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
According to MPEP II-A-3-a-ii, “[t]he written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406”; “[a] ‘representative number of species’ means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014).”; and “’[a] patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed.’ In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004)”.
The amended claim(s) now promises a broad genus of compound(s) having the structure of:
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coupled with a new limitation that recites a broad functional characteristics: “cancer inhibiting”.
In contrast, the specification only exemplifies a limited number of compound species having the structure of Formula VI, and only tested some of the exemplified compound species against a limited number of cancer cell lines. For example, applicant only exemplify compound species having
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or
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as the core structure of:
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, but promises a broad genus of A’ (i.e., “A’ is a substituted or unsubstituted C6-C30 polycycloalkyl, or a substituted or unsubstituted C3-C30 monocycloalkyl”); and only exemplify
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as R5 and R8, but broadly claims R5 and R8 can be taken together to form a broad scope of heterocycloalkyl.
Furthermore, applicant only tested some exemplified compounds of Formula VI against a limited number of cancer cell lines, but promises a broad functional characteristic of inhibiting cancer for the full scope of Formula VI. For instance, compound 10 having the structure of:
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is the only exemplified species that contains unsubstituted alkyl at R5, and its anti-cancer activity has not been tested in the working examples. Is it further noted that the specification only test some of the exemplified compound species against a limited number of cancer cells, such as MDA-MD-231, Hela, T47D, HEK293, HepG2, Jurkat, HCT116, HL-60, Huh7, PLC, U2OS, MCF7 and HeyA8; in which applicant only test a single compound species, compound 48, against cancer cells HL-60 and Jurkat (see Example 2); and two compound species, compound 48 and 37b, against cancer cells Huh7, PLC, U2OS, MCF7 (see Example 2) and HeyA8 (see Example 3); However, applicant broadly claims the full scope of the compound of Formula VI can inhibits the full scope of cancer.
In addition, the specification discloses compound 49 and compound 51, which are both recited in instant claim 49 as a compound of formula VI, each has a IC50 value >50 μM against human colorectal HCT116 cells (see e.g., Table 8), the exact IC50 value has not been disclosed therein. These compound species of Formula VI when compared with Compound 37b, which is also a compound of Formula VI recited in claim 49, exhibits at least 83 fold difference in cancer inhibitory activity. Therefore, it is not apparent that applicant is in possession of the full scope of Formula VI for inhibiting a broad scope of cancer, because the cancer inhibiting effect vary widely among the compounds of formula VI and appears to be concentration dependent based on the disclosure.
While Applicant does not have to exemplify every possible compound species having the structure of Formula VI to satisfy the written description requirement, applicant needs to provide enough representative species from different corners of the range couple with their function(s) to represent the claimed genus fairly. In other words, applicant should give concrete examples that reflect the diversity of what they are claiming. Since the claims recite a large set of possible
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, a, Z’, X’, R5 and R8 to arrive at a compound of Formula VI along with a broad functional language (“cancer inhibiting”), applicant must provide a reasonable sampling of them so that a relevant artisan can see applicant truly envisioned the whole range, and allows one of ordinary skill in the art to correlate the full scope of Formula VI with the full scope of functional characteristic instantly claimed.
Since the disclosed species are concentrated within a limited number of structural subclasses, and only some of these compound species are tested against a limited number of cancer cells, the disclosure does not adequately represent the breadth of variation encompassed by the instant claims. In view of the foregoing, the specification does not reasonably convey to one of ordinary skill in the art that Applicant was in possession of the full scope of the compound having the structure of Formula VI coupled with the full scope of cancer inhibiting effect.
This is a written description rejection.
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 41-44, 48 and 53-55 remain rejected under 35 U.S.C. 103 as being unpatentable over Amewu et al. (US 2013/0023551 A1), in view of Patani et al. (Chem. Rev., 1996. Vol. 96, 8: 3147-3176).
Amewu et al. teaches a compound 27g, N-(2-Diethylamino-ethyl)-2-(7,8,15,16-tetraoxa-dispiro[5.2.5.2]-hexadec-3-yl)-acetamide, having the structure of:
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(see e.g., [0185]) is an exemplary compound of formula (I) useful for the treatment of malaria and/or cancer (see e.g., [0002]). Amewu et al. further teaches a pharmaceutical composition comprising a therapeutically effective amount of the compound of the invention and, preferably, a pharmaceutically acceptable vehicle (see e.g., [0079]). Amewu et al. further teaches a pharmaceutical composition for the treatment of a cancer comprising the compound and a pharmaceutically acceptable excipient (see e.g., [0056]). Amewu et al. further teaches compound having the formula (I)
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, wherein ring A represents a substituted or unsubstituted monocyclic or multicyclic ring (see e.g., [0008]). Amewu et al. further teaches when any of the foregoing substituents are designated as being optionally substituted, the substituent groups which are optionally present may be any one or more of those customarily employed in the development of pharmaceutical compounds and/or the modification of such compounds to influence their structure/activity, stability, bioavailability or other property; specific examples of such substituents include, inter alia, alkyl (see e.g., [0069]).
Amewu et al. does not teach the compound having the structure of Formula VI.
Patani et al. teaches bioisosterism represents one approach used by the medicinal chemist for
the rational modification of lead compounds into safer and more clinically effective agents (see e.g.,
“introduction” section on p. 3147). Patani et al. further teaches a group of bioisosteres elicit similar
biological activity, and have been classified as either classical or nonclassical, wherein the classical
bioisosteres are a series of replacements defined by Grimm’s Hydride Displacement Law and
Erlenmeyer’s definition of isosteres (see e.g., p. 3148-3149). Patani et al. further teaches classical bioisosteres includes divalent isosteres that can be classified into two subgroups, including those divalent isosteres where substitution of a different atom results in the alternation of two single bonds such as in the series: C-C-C, C-NH-C, C-O-C, and C-S-C (see e.g., p. 3155, left column, “B. Divalent Isosteres” section, 1st paragraph). Patani et al. further teaches the divalent replacements involving two singles bonds shown below:
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, and teaches that the use of an oxygen atom as a bioisotereic linker, which has a marginally smaller bond angle and much greater electronegativity, results in an analogue with increased potency (see e.g., p. 3156, right column, 1st paragraph; Figure 24; Table 20).
In the instant case, the difference between the compound 27g of Amewu et al. and the claimed compound of Formula VI is that the prior art compound contains methylene group (-CH2-) proceeding the amide group rather than an oxygen atom shown below (see shaded):
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.
It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to select the compound 27g of Amewu et al., and then modify said compound by replacing the -CH2- in between the cyclohexyl ring and the amide group with an oxygen atom based on the classical bioisosteres taught by Patani et al. to arrive at the claimed invention. One would have been motivated to do so, because Patani et al. teaches -CH2- and -O- are divalent isosteres that can be interchanged in medicinal chemistry to arrive compound with similar properties. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the compound 27g of Amewu et al. modified in accordance with the divalent isosteres taught by Patani et al. would have successfully demonstrate similar activity against cancer or malaria; and therefore, said modified compound at a therapeutically effective amount can successfully be incorporated with a pharmaceutically acceptable excipient to arrive at a pharmaceutical composition without any appreciable loss of activity. Please note the modified compound 27g of Amewu et al. in view of Patani et al. sets forth above is a compound having the structure of Formula VI
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, wherein A’ is
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; a is 1; Z’ is hydrogen; X’ is O; R5 is hydrogen; R8 is
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(substituted alkyl, wherein the substituents are independently an amino; and
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, wherein i is 2; R18 is hydrogen; R19 and R20 are independently a unsubstituted alkyl); and a compound having the structure of Formula VIII
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, wherein a is 1; a’ is 1; Z’ is hydrogen; X’ is O; R5 is hydrogen; R8 is
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(substituted alkyl, wherein the substituents are independently an amino); e is 0.
Regarding the limitation of “further comprising a second active agent” in claim 54, and the limitation of “wherein the second active agent is an anticancer agent” in claim 55, it would have been prima facie obvious to a person of ordinary skill in the art at the time the application was filed to combine the pharmaceutical composition of Amewu et al. and Patani et al. sets forth above with the compound 27g taught by Amewu et al. to arrive at the claimed invention. One would have been motivated to do so, because compound 27g of Amewu et al. is taught to be useful for the same purpose (the treatment of cancer or malaria). One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that by combining compounds that are useful separately for the same purpose (the treatment of cancer or malaria) would expected to be similarly useful when used together. See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
Therefore, the claimed invention is prima facie obvious to one of ordinary skill in the art at the time the application was filed, absent factual evidence to the contrary.
Claims 41-46, 48 and 53-55 remain rejected under 35 U.S.C. 103 as being unpatentable over Amewu et al. (US 2013/0023551 A1), in view of Patani et al. (Chem. Rev., 1996. Vol. 96, 8: 3147-3176) as applied to claims 41-44, 48 and 53-55 above, and further in view of Renslo et al. (US 10,662,215 B2).
The teachings of Amewu et al. and Patani et al. are sets forth above and applied as before.
Amewu et al. and Patani et al. does not teach the limitations of R10 as claimed in claims 45-46.
Renslo et al. teaches exemplary compound of formula (Ia) includes compound of Example 23 having the structure of:
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(see e.g., Table 1, Example 23).
Renslo et al. further teaches compounds of formula (Ia):
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are compounds of formula (I) useful for treating a disease, including cancer and malaria (see e.g., Col. 106, line 11-49; Col. 111, line 10-13, 18-19 and 24-25), wherein Ring A is a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene (see e.g., Col 64, line 14-35). Renslo et al. further teaches in some embodiments, L1 is a bond (see e.g., Col. 65, line 60-61). Renslo et al. further teaches in some embodiments, R1 is unsubstituted C1-C4 alkyl (see e.g., Col. 72, line 51-52). Renslo et al. further teaches the term “alkyl” means a straight or branched non-cyclic carbon chain, or combination thereof; and examples of saturated hydrocarbon radicals include groups, such as t-butyl (see e.g., Col. 5, line 9-18).
Regarding the limitations recited in claims 45-46, the difference between the modified compound 27g of Amewu et al. in view of Patani et al. sets forth above and the claimed compound is that the ring A (cyclohexane) of said modified compound is unsubstituted. It would have been prima facie to one of ordinary skill in the art at the time the application was filed to further modify the modified compound 27g of Amewu et al. in view of Patani et al. by substituting the ring A (cyclohexane) with t-butyl as the unsubstituted C1-C4 alkyl. One would have been motivated to do so, because Amewu et al. teaches the ring A of formula (I) can be substituted with a list of substituents, including alkyl; and Renslo et al. teaches the compounds of formula (Ia) with close structural similarities, and further teaches the ring A of formula (Ia) can be substituted with an unsubstituted C1-C4 alkyl, such as t-butyl to arrive at a compound useful for the same purpose of treating cancer or malaria. One of ordinary skill in the art would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the ring A (cyclohexane) of the modified compound 27g of Amewu et al. in view of Patani et al. substituted with a t-butyl as the alkyl would have successfully arrive at a compound that is similarly useful for the treatment of cancer or malaria.
Claims 41-44, and 53-55 remain rejected under 35 U.S.C. 103 as being unpatentable over Amewu et al. (US 2013/0023551 A1), in view of Patani et al. (Chem. Rev., 1996. Vol. 96, 8: 3147-3176).
Amewu et al. teaches a compound 27h, 1-Morpholin-4-yl-2-(7,8,15,16-tetraoxa-dispiro[5.2.
5.2]hexadec-3-yl)-ethanone, having the structure of:
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(see e.g., [0395]) and compound 29l having the structure of
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(see e.g., [0221]) are exemplary compounds of formula (I) useful for the treatment of malaria and/or cancer (see e.g., [0002]). Amewu et al. further teaches a pharmaceutical composition comprising a therapeutically effective amount of the compound of the invention and, preferably, a pharmaceutically acceptable vehicle (see e.g., [0079]). Amewu et al. further teaches a pharmaceutical composition for the treatment of a cancer comprising the compound and a pharmaceutically acceptable excipient (see e.g., [0056]). Amewu et al. further teaches compound having the formula (I)
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, wherein ring A represents a substituted or unsubstituted monocyclic or multicyclic ring; wherein Y is, inter alia, -C(O)NR1R2, where R1 and R2 are linked so as to form part of a substituted or unsubstituted heterocyclic ring (see e.g., [0008]-[0009]). Amewu et al. further teaches when any of the foregoing substituents are designated as being optionally substituted, the substituent groups which are optionally present may be any one or more of those customarily employed in the development of pharmaceutical compounds and/or the modification of such compounds to influence their structure/activity, stability, bioavailability or other property; specific examples of such substituents include, inter alia, alkyl (see e.g., [0069]).
Amewu et al. does not teach the compound having the structure of Formula VI.
Patani et al. teaches bioisosterism represents one approach used by the medicinal chemist for
the rational modification of lead compounds into safer and more clinically effective agents (see e.g.,
“introduction” section on p. 3147). Patani et al. further teaches a group of bioisosteres elicit similar
biological activity, and have been classified as either classical or nonclassical, wherein the classical
bioisosteres are a series of replacements defined by Grimm’s Hydride Displacement Law and
Erlenmeyer’s definition of isosteres (see e.g., p. 3148-3149). Patani et al. further teaches classical bioisosteres includes divalent isosteres that can be classified into two subgroups, including those divalent isosteres where substitution of a different atom results in the alternation of two single bonds such as in the series: C-C-C, C-NH-C, C-O-C, and C-S-C (see e.g., p. 3155, left column, “B. Divalent Isosteres” section, 1st paragraph). Patani et al. further teaches the divalent replacements involving two singles bonds shown below:
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, and teaches that the use of an oxygen atom as a bioisotereic linker, which has a marginally smaller bond angle and much greater electronegativity, results in an analogue with increased potency (see e.g., p. 3156, right column, 1st paragraph; Figure 24; Table 20).
In the instant case, the difference between the compound 27h of Amewu et al. and the claimed compound of Formula VI is that the prior art compound contains methylene group (-CH2-) proceeding the amide group rather than an oxygen atom shown below (see shaded):
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. It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to select the compound 27h of Amewu et al., and then modify said compound by replacing the -CH2- in between the cyclohexyl ring and the amide group with an oxygen atom based on the classical bioisosteres taught by Patani et al. to arrive at the claimed invention. One would have been motivated to do so, because Patani et al. teaches -CH2- and -O- are divalent isosteres that can be interchanged in medicinal chemistry to arrive compound with similar properties. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the compound 27h of Amewu et al. modified in accordance with the divalent isosteres taught by Patani et al. would have successfully demonstrate similar activity against cancer or malaria; and therefore, said modified compound at a therapeutically effective amount can successfully be incorporated with a pharmaceutically acceptable excipient to arrive at a pharmaceutical composition without any appreciable loss of activity. Please note the modified compound 27h of Amewu et al. in view of Patani et al. sets forth above is a compound having the structure of Formula VI
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, wherein A’ is
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; a is 1; Z’ is hydrogen; X’ is O; R5 and R8 are taken together with the nitrogen to form
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; and a compound having the structure of Formula VIII
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, wherein a is 1; a’ is 1; Z’ is hydrogen; X’ is O; R5 and R8 are taken together with the nitrogen to form
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; e is 0.
Regarding the limitation of “further comprising a second active agent” in claim 54, and the limitation of “wherein the second active agent is an anticancer agent” in claim 55, it would have been prima facie obvious to a person of ordinary skill in the art at the time the application was filed to combine the pharmaceutical composition of Amewu et al. and Patani et al. sets forth above with the compound 27h taught by Amewu et al. to arrive at the claimed invention. One would have been motivated to do so, because compound 27h of Amewu et al. is taught to be useful for the same purpose (the treatment of cancer or malaria). One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that by combining compounds that are useful separately for the same purpose (the treatment of cancer or malaria) would expected to be similarly useful when used together. See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
Therefore, the claimed invention is prima facie obvious to one of ordinary skill in the art at the time the application was filed, absent factual evidence to the contrary.
Claims 41-44, 49, and 53-55 remain rejected under 35 U.S.C. 103 as being unpatentable over Amewu et al. (US 2013/0023551 A1), in view of Patani et al. (Chem. Rev., 1996. Vol. 96, 8: 3147-3176) as applied to claims 41-44, and 53-55 above, and further in view of Renslo et al. (US 10,662,215 B2).
The teachings of Amewu et al. and Patani et al. are sets forth above and applied as before.
Amewu et al. and Patani et al. does not teach the compound as recited in claim 49.
Renslo et al. teaches exemplary compound of formula (Ia) includes compound of Example 23 having the structure of:
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(see e.g., Table 1, Example 23).
Renslo et al. further teaches compounds of formula (Ia):
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are compounds of formula (I) useful for treating a disease, including cancer and malaria (see e.g., Col. 106, line 11-49; Col. 111, line 10-13, 18-19 and 24-25), wherein Ring A is a substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene (see e.g., Col 64, line 14-35). Renslo et al. further teaches in some embodiments, L1 is a bond (see e.g., Col. 65, line 60-61). Renslo et al. further teaches in some embodiments, R1 is unsubstituted C1-C4 alkyl (see e.g., Col. 72, line 51-52). Renslo et al. further teaches the term “alkyl” means a straight or branched non-cyclic carbon chain, or combination thereof; and examples of saturated hydrocarbon radicals include groups, such as t-butyl (see e.g., Col. 5, line 9-18).
Regarding the limitation recited in claim 49, the difference between the modified compound 27 of Amewu et al. in view of Patani et al. sets forth above and the expanded compound species instantly claimed is that the ring A (cyclohexane) of said modified compound is unsubstituted, and said modified compound contains the morpholine ring rather than a piperazine ring shown below (see shaded):
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. It would have been prima facie to one of ordinary skill in the art at the time the application was filed to further modify the modified compound 27h of Amewu et al. in view of Patani et al. sets forth above by substituting the ring A (cyclohexane) with t-butyl as the unsubstituted C1-C4 alkyl; and then substituting the morpholine ring with a piperazine ring at the Y moiety of Formula I taught by Amewu et al. One would have been motivated to do so, because Amewu et al. teaches the ring A of formula (I) can be substituted with a list of substituents, including alkyl, and further teaches R1 and R2 together can form a heterocyclic ring that is substituted or unsubstituted by exemplifying compounds having the structure of:
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and
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; and Renslo et al. teaches the compounds of formula (Ia) with close structural similarities, and further teaches the ring A of formula (Ia) can be substituted with an unsubstituted C1-C4 alkyl, such as t-butyl to arrive at a compound useful for the same purpose of treating cancer or malaria. One of ordinary skill in the art would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the modified compound 27h of Amewu et al. in view of Patani et al. substituted with a t-butyl as the alkyl at the Ring A (cyclohexane), and then replacing the morpholine ring with a piperazine as the unsubstituted heterocyclic ring would have successfully arrive at a compound that is similarly useful for the treatment of cancer or malaria.
Therefore, the claimed invention is prima facie obvious to one of ordinary skill in the art at the time the application was filed, absent factual evidence to the contrary.
Response to Arguments
Applicant's arguments filed on April 27, 2026 have been fully considered.
Applicant's arguments filed on April 27, 2026 with respect to the rejection of claims 41-44, 48 and 53-55 under 35 U.S.C. 103 as being unpatentable over Amewu et al. (US 2013/0023551 A1), in view of Patani et al. (Chem. Rev., 1996. Vol. 96, 8: 3147-3176); the rejection of claims 41-46, 48 and 53-55 under 35 U.S.C. 103 as being unpatentable over Amewu et al. (US 2013/0023551 A1), in view of Patani et al. (Chem. Rev., 1996. Vol. 96, 8: 3147-3176) as applied to claims 41-44, 48 and 53-55 above, and further in view of Renslo et al. (US 10,662,215 B2) have been fully considered but they are not persuasive for the reasons set forth below.
Applicant's arguments filed on April 27, 2026 with respect to the rejection of claims 41-44, and 53-55 under 35 U.S.C. 103 as being unpatentable over Amewu et al. (US 2013/0023551 A1), in view of Patani et al. (Chem. Rev., 1996. Vol. 96, 8: 3147-3176); and the rejection of claims 41-44, 49, and 53-55 under 35 U.S.C. 103 as being unpatentable over Amewu et al. (US 2013/0023551 A1), in view of Patani et al. (Chem. Rev., 1996. Vol. 96, 8: 3147-3176) as applied to claims 41-44, and 53-55 above, and further in view of Renslo et al. (US 10,662,215 B2) have been fully considered but they are not persuasive for the reasons set forth below.
Applicant amends claim 41 from the recitation of “[a] compound having the structure of” to the recitation of “[a] cancer inhibiting compound having the structure of”.
In Summary, applicant argues interchanging one group for another in a molecules based upon the teachings of Patani et al. does not guarantee the replacement of any specific pair of isosteres (e.g., -CH2 with -O-) in the molecule would preserve the same function or activity; and argues only one example is cited. Applicant further argues even though Amewu et al. mentions the use of compounds for treating malaria and/or cancer, Amewu et al. only tested the antimalarial activity and presents no evidence that those compounds could treat cancer; thus, the teachings of Amewu et al. lacks any reasonable expectation of success. Applicant further argues the claimed invention demonstrate unexpected inhibitory activity against various cancer cells and cancer stem cells, and selectively inhibit cancer cells and cancer stem cells relative to non-cancerous cells. Applicant further argues the compound 27h of Amewu et al. does not renders obvious the R5 having the structure of:
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set forth in claim 48, because it has to be quaternary ammonium group.
In response to applicant’s argument that the bioisosteric replacement techniques taught by Patani et al. does not guarantee the compound would successfully yield equivalent effects (function or activity), this appears to be mere argument without objective evidence. According to MPEP 2143.02, I, “[c]onclusive proof of efficacy is not required to show a reasonable expectation of success. OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019) ("To be clear, we do not hold today that efficacy data is always required for a reasonable expectation of success. Nor are we requiring ‘absolute predictability of success.’"); Acorda Therapeutics, Inc. v. Roxane Lab., Inc., 903 F.3d 1310, 1333, 128 USPQ2d 1001, 1018 (Fed. Cir. 2018) ("This court has long rejected a requirement of ‘[c]onclusive proof of efficacy’ for obviousness." (citing to Hoffmann-La Roche Inc. v. Apotex Inc., 748 F.3d 1326, 1331 (Fed. Cir. 2014); PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1364 (Fed. Cir. 2007); Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364, 1367–68 (Fed. Cir. 2007) (reasoning that "the expectation of success need only be reasonable, not absolute"))”. In other words, an obviousness-type rejection does not require absolute predictability of success; thus, the fact that Patani et al. teaches -CH2- and -O- are divalent isosteres defined by Grimm’s Hydride Displacement Law that can be interchanged in medicinal chemistry to arrive compound with similar properties (see e.g., p. 3155, left column, “B. Divalent Isosteres” section, 1st paragraph) and exemplified said replacement in one of the examples (see e.g., p. 3156, right column, 1st paragraph; Figure 24; Table 20), one of ordinary skill in the art would have reasonably expected that the compound 27g or 27h of Amewu et al. modified in accordance with the isosteres taught by Patani et al. would have successfully demonstrate similar activity against cancer and/or malaria (see rejection above). If applicant asserts interchanging the methylene group (-CH2-) proceeding the amide group with an oxygen atom changes the activity of the compound as a whole, said objective evidence is respectfully requested.
Second, it may well be true that Amewu et al. does not exemplify the administration of the compound having the formula (I) for the treatment of cancer; However, according to MPEP 2123, II, “[d]isclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971)”. In other words, the mere fact that Amewu et al. does not exemplify the compound(s) having the formula (I) against cancer, it does not constitute a teaching away from using said compound(s) in the treatment of cancer because said prior art clearly teaches the compound(s) having the formula (I) are contemplate for use in the treatment of malaria and/or cancer (see e.g., [0002]; [0056]-[0058]). In addition, a compound and all its properties are inseparable. If applicant asserts the compound(s) taught by Amewu et al. demonstrate no anticancer activity, said objective evidence is respectfully requested.
Third, in response to applicant’s argument that the claimed invention demonstrates unexpected results (“the inhibitory activity of the inventive compounds against various cancer cells and cancer stem cells, and proves that the inventive compounds can selectively inhibit cancer cells and cancer stem cells relative to non-cancerous cells”; see page 14, last paragraph of the reply), said unexpected results are not commensurate in scope with the claimed invention.
According to MPEP 716.02(d), “whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the ‘objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.’ In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980)”.
It is respectfully noted that Applicant does not specifically points out which example(s) or result(s) demonstrates said unexpected results. To the extent that the unexpected results upon which applicant relies are demonstrated in Examples 2-3 of the specification, then the argument is not found persuasive for the reasons addressed below:
According to Example 2, some of the exemplary compounds were tested against several cancer cell lines, including human cervix Hela cells, mammary breast cancer MDA-MB-231 cells, human hepatocellular HepG2 cells, human colorectal HCT116 cells, and mammary ductal T47D cells (see e.g., p. 103, line 5-9). In contrast, claim 41 broadly recites “[a] cancer inhibiting compound having the structure of
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”, which promises a broad genus of compounds of Formula VI with inhibiting effect against the full scope of cancer.
As noted above, Applicant only exemplifies cancer inhibitory effect against a few cell lines in vitro in Example 2, and that does not provide adequate basis for concluding that similar cancer inhibitory effect would be obtained in any other species of cancer as broadly encompassed by the claim(s). In addition, applicant only exemplifies a few compound species against some of the cancer cell lines, for example, applicant only exemplified a single compound species against leukemia HL-60 cells (see e.g., p. 103, line 13), which is compound 48 having the structure of:
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with an IC50 of 1.2 μM (see e.g., Table 10); and that not provide adequate basis for concluding that similar HL-60 inhibitory results would be obtained for other compound species as broadly encompassed by instant claim(s).
Furthermore, Compound 37b having the structure of:
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(see e.g., claim 49) has an IC50 of 0.38 μM against mammary breast cancer MDA-MB-231 cells, whereas Compound 37D having the structure of
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(see e.g., p. 78, line 1) has an IC50 of 31.7 μM against the same cancer cells (see e.g., Table 1); and there is roughly a 83 fold difference between these two exemplary compounds. Since one compound is significantly more potent (83 fold) that allows much smaller concentration to achieve half-maximal inhibition, the inhibitory effect against mammary breast cancer MDA-MB-231 cells appears to be dose-dependent effect. In view of this results, it is not apparent that the full scope of compound having the structure of Formula VI at any amount can exhibits the same inhibitory profile against mammary breast cancer MDA-MB-231 cells.
In addition, the additional unexpected results upon which applicant relies (“can selectively inhibit cancer cells and cancer stem cells relative to non-cancerous cells”) is also not commensurate in scope with the claimed invention. For example, the results of Example 2 demonstrates Compound 37a having the structure of:
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(see e.g., claim 49) has an IC50 of 1.7 μM against NIH3T3 cells (see e.g., Table 7), which is non-cancerous cells (see p. 103, line 8); and said compound 37a has an IC50 of 3.9 μM against Hela cells (see e.g., Table 2). In other words, Compound 37a has higher potency against non-cancerous NIH3T3 cells when compared to Hela cells; and that appears to be conflicting with applicant’s assertion that the full scope of compound(s) having the structure of Formula VI selectively inhibit cancer cells relative to non-cancerous cells as this does not appear to be the case for compound 37a instantly claimed. It is respectfully noted that this selective inhibitory effects appears to be compound dependent and cell dependent, for examples, compound 37i has an IC50 > 100 μM against non-cancerous NIH3T3 cells whereas Compound 37a has an IC50 of 1.7 μM against the same cells (see e.g., Table 7); and that does not provide adequate basis for concluding that other compound species of Formula VI is also has the same selectively as compound 37i. Another examples is that compound 37d has an IC50 of 30.3 μM against non-cancerous NIH3T3 cells, and has an IC50 >100 against non-cancerous MDCK cells (see e.g., Tables 7 and 9), and that does not provide adequate basis for concluding that said compound is more selective towards the full scope of cancer cells relative to the full scope of non-cancerous cells.
According to Example 3, the cytotoxicity of compound 48 and 37b on cancer stem cell (CSC) model of HEY AS CSCs and mouse xenograft ovarian tumors was examined (see e.g., p. 110, line 14-15 of the specification). Specifically, the mice were injected s.c. with HEYA8 CSC cells and randomly allocate to receive one of the treatment groups, including, inter alia, (iii) compound 37b, 5 mg/kg, (iv) compound 37b, 10 mg/kg, (v) compound 48, 5mg/kg, and (vi) compound 48, 10 mg/kg (see e.g., p. 110, line 16-19 of the specification). Applicant only exemplified the results using a single species of cancer stem cell, and that is ovarian HEYA8 CSC cells (see e.g., p. 103, line 12), and that does not provide adequate basis for concluding that similar results would be obtained in any other species of cancer stem cell as broadly encompassed by the claim(s).
In view of the foregoing, the unexpected results upon which applicant relies is not commensurate in scope of the claimed invention, thus, applicant’s argument is not found persuasive.
Lastly, applicant’s argument with respect to R5 sets forth in claim 48 has to be quaternary ammonium group is not found persuasive. It is respectfully noted that claim 48 specifically recites “R5 is hydrogen” rather than “
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”. To the extent that applicant’s argument is with respect to R8 of Formula VI, it is also not found persuasive, because claim 48 itself expressly defined R15-R20 as independently hydrogen, substituted or unsubstituted alkyl, etc. Accordingly, under the broadest reasonable interpretation, the recited N+ moiety of R8 encompasses embodiment in which one or more of R15-R20 is hydrogen. Thus, claim 48 is broad enough to encompass the tertiary amino moiety present in compound 27g of Amewu et al. Any alleged inconsistency between the depicted positive charge and the expressly recited definition of R15-R20 pertains to the claim definiteness rather than patentability and does not warrant a narrower interpretation excluding the prior art species.
Therefore, given these reasons addressed above, the rejection on the record has been maintained for the same reasons of the record and for the reasons set forth herein.
Conclusion
No claims are allowed.
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 Chihyi Lee whose telephone number is (571)270-0663. The examiner can normally be reached Monday - Friday 8:30 am - 5:00 pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amy L. Clark can be reached at (571) 272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CHIHYI LEE/Examiner, Art Unit 1628 /JEAN P CORNET/Primary Examiner, Art Unit 1628
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