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 .
Current Status
This action is responsive to the amended claims of 03/27/2023. Claims 18-36 are pending. Claims 18-36 are new. Claims 22-26 and 35-36 are withdrawn. Claims 18-21 and 27-34 have been examined on the merits.
Election/Restrictions
Applicant’s election without traverse of Group I (claims 18-34) and species S-Gboxin
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, liver metastatic pancreatic cancer, and tumor with low or no expression of NNMT gene in the reply filed on 03/04/2026 is acknowledged.
Claims 22-26 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 03/04/2026.
Claims 35-36 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 03/04/2026.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
The effective filing date is 09/27/2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 03/27/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claims 20-21 and 28-33 are objected to because of the following informalities. Appropriate correction is required.
Claims 20-21 and 30-33 recite lists of 2 or more options (including chemical names, moieties, and full structures) and a majority of these lists lack a conjunction before the final option, e.g., “or”. Please add the appropriate conjunction. In the lists of only 2 options (e.g., claim 30 Z2 and Z3 are chosen from only two moieties), please replace the comma separating the 2 options with an “or”.
Claim 28 recites (Pg. 8) “metastatic renal carcinoma, and combination n thereof;” please delete the space in the word “combination”. Dependent claim 29 is similarly objected since it does not resolve the issue.
Claims 30-33 recite structures which are of poor resolution: claim 30 formula I and claim 33 the 5th-7th compound. Please provide higher resolution images to improve readability. The dependent claims 31-32 are similarly rejected since they do not resolve the issue.
Claim 30 recites
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. While it is clear these are alternatives for the double/single bond dependent on the status of R5; please add the word “when” before each instance of “R5 is none” and “R5 is not none” to reinforce these limitations as alternatives. Dependent claims 31-32 are similarly rejected since they do not resolve the issue.
Claim 33 recites “wherein he mitochondrial”, please replace “he” with “the”.
Claim Rejections - 35 USC § 112(a)
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 18-21 and 27-34 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treatment of tumors, does not reasonably provide enablement for prevention of tumors. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. This is a scope of enablement rejection.
The Wands Factors used in a scope of enablement rejection include (per MPEP 2164.01(a)):
The breadth of the claims and nature of the invention:
The claims 18-21 and 27-34 are drawn to a method of treating or preventing a tumor by administering a mitochondrial oxidative phosphorylation pathway (OXPHOS) inhibitor. Claims 18-21 are broadly drawn to any cancer and claims 27-29 recite species thereof, but claim 27 still recites a relatively broad range of cancers. Claims 18-21 and 27-29 are drawn broadly to any OXPHOS inhibitor, while claims 30-32 recite relatively broad genera of Formulas I-III. Claim 33 narrows the OXPHOS inhibitor to 4 distinct chemical structures and a few optical isomers/salts thereof.
The state of the prior art & predictability of the art:
Examiner cites XU (Xu, Y. et al., Journal of Medicinal Chemistry, 2020, 63, 14276-14307) and KUNNUMAKKARA (Kunnumakkara et al., Experimental Biology and Medicine, 2019, 244, 663-689) as representative of the state of the prior art and predictability thereof.
XU discloses certain subtypes of cancer cells require OXPHOS to survive; increased OXPHOS dependency is a frequent hallmark of cancer stem cells and cells resistant to certain therapies; suppressing OXPHOS can influence the tumor microenvironment by alleviating hypoxia and improving the antitumor immune response – thus, OXPHOS inhibitors have been in development for clinical application (Pg. 14276 Abstract). Notably, XU does not disclose any ability of OXPHOS inhibition to prevent cancer/tumors. At most, XU discloses OXPHOS inhibitors can stop metastatic spread (Pg. 14282 Right ¶2), progression (Pg. 14287 Left final ¶), or resistance to other chemotherapies (Pg. 14291-2 bridge ¶) in certain cancers.
KUNNUMAKKARA teaches cancer is a group of more than 200 neoplastic diseases caused by diverse deregulated cell signaling cascades (Pg. 633 Left ¶1); cancer occurs as a result of the dysregulation of as many as 500 different genes which may happen over a very long duration of time (20–30 years) till the symptoms become apparent (Pg. 633 Right last ¶). Therefore, the art is unpredictable regarding how and when the development of cancers is triggered.
In view of the relevant prior art, the artisan would be enabled to use an OXPHOS inhibitor to treat tumors/cancers. However, since there is a lack of predictability surrounding the development of cancers and no examples of OXPHOS-targeted prevention, the art does not provide enablement for prevention of tumors by administration of an OXPHOS inhibitor.
The level of one of ordinary skill:
The relative skill of those in the art is high, generally that of an M.D. or Ph.D. The artisan using Applicant's invention would generally be a physician with a M.D. degree and several years of experience. This factor is outweighed, however, by the unpredictable nature of the art (established above). It is well established that "the scope of enablement varies with the degree of unpredictability of the factors involved" and physiological activity is considered to be an unpredictable factor. See In re Fisher, 166 USPQ 18, at 24 (In cases involving unpredictable factors, such as most chemical reactions and physiological activity, the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved).
The art cited above provides support for the artisan to engage in treatment of tumors (see XU above). However, the skill of the artisan, especially in view of the relevant prior art, does not overcome the undue burdensome level of experimentation required to provide enablement for preventing tumors by administration of an OXPHOS inhibitor.
The amount of direction provided by the inventor and the existence of working examples:
Inventors have provided direction as to treating cancers by administration of 4 known OXPHOS inhibitors (see Pg. 56-77 Examples 1-22; Pg. 61-62 Table 3; and Pg. 64-65 Table 4 of the Specification).
The results of these working examples are summarized in Tables 3-4 and explained in Examples 1-22 of the instant Specification. Treatment of various cancer/tumor cell lines (both cultured and in vivo) with S-Gboxin, Gboxin, Oligomycin A, or IACS-010759 resulted in lowered oxygen consumption (i.e., inhibition of the OXPHOS pathway) and inhibition of tumor growth (e.g., see Fig. 25-26). Notably, Inventors have not provided any working examples wherein prevention of tumor development is shown.
Thus, Applicants have guidance/enablement in their Specification (Experimental Example 1-22) for treating tumors by administering an OXPHOS inhibitor. However, this guidance does not support preventing tumors, especially in view of the relevant prior art.
The quantity of experimentation needed to make or use the invention:
Applicants’ tumor therapy invention requires a high level/quantity of experimentation to use the invention for preventing tumors. While Applicants have provided guidance in their Specification for treating tumors, they have not provided enough evidence that OXPHOS inhibitors can be used for the scope of preventing tumors per the BRI of instant claims 18-21 and 27-34. At best, the Specification does provide enablement/guidance for treatment (not prevention) of tumors, as stated above.
Therefore, claims 18-21 and 27-34 are rejected under 35 USC 112(a) for lacking scope of enablement for preventing a tumor.
To render moot this scope of enablement rejection: Applicants should delete “prevent” and/or “prevention”/”preventing” from the claims.
Claims 18-21, 27-32, and 34 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. This is a written description rejection.
MPEP 2163(I) states “The written description requirement has several policy objectives. "[T]he ‘essential goal’ of the description of the invention requirement is to clearly convey the information that an applicant [inventor] has invented the subject matter which is claimed." In re Barker, 559 F.2d 588, 592 n.4, 194 USPQ 470, 473 n.4 (CCPA 1977). Another objective is to convey to the public what the applicant claims as the invention. See Regents of the Univ. of Cal. v. Eli Lilly, 119 F.3d 1559, 1566, 43 USPQ2d 1398, 1404 (Fed. Cir. 1997), cert. denied, 523 U.S. 1089 (1998). "The ‘written description’ requirement implements the principle that a patent must describe the technology that is sought to be patented; the requirement serves both to satisfy the inventor’s obligation to disclose the technologic knowledge upon which the patent is based, and to demonstrate that the patentee [inventor] was in possession of the invention that is claimed." Capon v. Eshhar, 418 F.3d 1349, 1357, 76 USPQ2d 1078, 1084 (Fed. Cir. 2005).”
Factors to be considered in the determination as to whether the artisan would recognize that the applicant was in possession of the claimed invention as a whole at the time of filing include: (a) Actual reduction to practice; (b) Disclosure of drawings or structural chemical formulas; (c) Sufficient relevant identifying characteristics such as: (i) Complete structure, (ii) Partial structure, (iii) Physical and/or chemical properties or (iv) Functional characteristics when coupled with a known or disclosed correlation between function and structure; (d) Method of making the claimed invention; (e) Level of skill and knowledge in the art and (f) Predictability in the art.
The Instant Disclosure:
At their broadest, the claims are very broadly drawn to methods of treatment administering mitochondrial oxidative phosphorylation pathway (OXPHOS) inhibitors (claim 18). Dependent claims 30-32 define three relatively broad genera of chemical compounds Formulas I-III, each of which encompass at least hundreds of different species. Dependent claim 33 defines 7 chemical species of Formulas I-III combined; however, these are not 7 truly distinct species.
Formula I encompasses:
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; however, structures 3 and 4 are just isomeric salts of structures 1 and 2 and do not have any truly distinct structural features (i.e., they are obvious variants of the species 1 and 2, respectively). Structures 3-4 do not add any further support for the breadth of the Formula I than structures 1-2. Formula II is represented by only 1 structure/species in claim 33 – the final structure; no other species are disclosed. Formula III is represented by 2 structures:
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; based on Examiner’s best guess of the second structure (see 112b below), the second structure is an optical isomer of the first structure. Thus, similar to Formula I, the second structure does not add any further support for the breadth of the full Formula III than the first structure. Therefore, only 4 base chemical structures are provided – these correspond to S-Gboxin, Gboxin, Oligomycin A, and IACS-010759.
The claims and specification provide no other guidance as to compounds which are OXPHOS inhibitors. Further, the specification does not provide any guidance as to the synthesis of the compounds of Formula I-III; there are no synthetic schemes for the compounds of claims 30-33 or the thousands of other compounds that are encompassed by the combined scope of Formulas I-III. Further, the specification only provides data for S-Gboxin, Gboxin, Oligomycin A, and IACS-010759 as OXPHOS inhibitors (see Pg. 56-77 Examples 1-22; Pg. 61-62 Table 3; and Pg. 64-65 Table 4 of the Specification). The compounds disclosed in the claims and specification, with the necessary activity for the claimed method, do not cover the full scope of the compounds embraced by independent claim 18 nor the Formulas I-III (claims 30-32).
It does not appear that Applicants have invented compounds of the Formulas I-III, but rather have screened existing compounds for potential therapeutic efficacy against a variety of cancer cell types (e.g., see Pg. 61-65 Tables 3-4) and then defined genus formulas much broader than the 4 compounds tested. Regarding MPEP 2163(I), the full disclosure does not “demonstrate that the patentee [inventor] was in possession of the invention that is claimed,” at least for the entire scope of the OXPHOS inhibitor and Formulas I-III as defined in claims 18-21, 27-32, and 34.
Level of Skill and Knowledge in the Art:
The relative skill of those in the art is high, generally that of an M.D. or Ph.D. The factor is outweighed by the unpredictable nature of the pharmaceutical art. It is noted that each embodiment of the invention is required to be individually assessed for physiological activity by in vitro or in vivo screening to determine which compounds exhibit the desired pharmacological activity (e.g., inhibit OXPHOS). Examiner cites XU (Xu, Y. et al., Journal of Medicinal Chemistry, 2020, 63, 14276-14307) as evidentiary reference.
XU discloses development of OXPHOS inhibitors and therapeutic strategies in clinical applications (Pg. 14276 Abstract). XU states managing toxicity is a challenging issue in such development – pharmacokinetic properties must be carefully tailored to avoid expected and unexpected adverse events (Pg. 14296 Left ¶3). Further, mitochondrial inhibition is generally considered to cause hepatotoxicity and neurotoxicity (Pg. 14296 Right ¶3). While many of the reported OXPHOS inhibitors show selective cytotoxicity to cancer cells vs. normal cells, prediction of such selectivity or toxicity is necessary for development of OXPHOS inhibitors (Pg. 14296 Right ¶3). In the instant case, since the claims are so broadly drawn it is unknown/unpredicted if the full scope of possible compounds having OXPHOS inhibitory activity would be safe for the claimed treatment method.
XU further discloses a variety of OXPHOS inhibitors (see Fig. 7-9 & Table 4); however, of these species: 1) Gboxin/S-Gboxin are the only species of Formula I, 2) only one other species of Formula II is disclosed (i.e., a total of 2 between XU and the instant), and 3) no other species of Formula III are disclosed.
Conclusions:
With only a small handful of structures disclosed and tested in the claims and specification, Factors (a) “reduction to practice” and (b) “disclosure of structural chemical formulas” have not been met. While the claims do provide functional characteristics of the compound (i.e., OXPHOS inhibitor), there is not sufficient relevant identifying characteristics for chemical structure: Factor (c) is not met. Further, since there are no methods of making the claimed inhibitors, Factor (d) is not met.
In view of the known challenges in the art (see XU above), the artisan would not be able to immediately envisage the full scope of compounds embraced by the instant claims (Factors (e) & (f)) and would be uncertain if the Applicants were in possession of the full scope of the compounds recited in the claimed methods (See MPEP 2163(I)). Furthermore, defining the administered compound by purely functional means (OXPHOS inhibitor – claims 18-21, 27-29, & 34) leaves the scope open to compounds which either a) have not yet been discovered or b) compounds which are not yet known to inhibit OXPHOS. Thus, Applicant has not clearly conveyed to the artisan that the Applicant has invented the full scope of the subject matter claimed.
Thus, claims 18-21, 27-32, and 34 are rejected as lacking written description for the full scope of mitochondrial OXPHOS inhibitor which may be a compound of Formula I, II, or III. To overcome this rejection, Applicants are also encouraged to limit the scope of inhibitor to the scope of the compounds disclosed in claim 33.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 20-21 and 28-34 are 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.
In claims 20 and 30-32, the phrases "preferably," “more preferably,” and “e.g.,” render the claims indefinite because it is unclear if the limitations following the phrase are merely exemplary embodiments or if they required by the claim. See MPEP § 2173.05(d). Further, in claims 30-32 these phrases are enclosed by parentheses, e.g., “(preferably 1, 2, 3, or 4)” recited on Pg. 9 of the claims, making it unclear if the enclosed limitation is required or merely exemplary. Therefore, the metes and bounds of the claim are undefined rendering the claim indefinite.
To overcome: please strike all instances of the above phrases and any accompanying parentheses.
Claim 28 recites “the brain tumor is selected from the group consisting of glioblastoma, neuroglioma, and combination thereof; the brain tumor comprises medulloblastoma”. By Examiner’s understanding glioblastoma and neurogliomas are types of glioma; medulloblastoma is not a glioma. Thus, it is unclear whether the brain tumor is a glioma or not. By “the brain tumor comprises medulloblastoma,” it appears as if the brain tumor must be a medulloblastoma; however, the scope of this limitation does not overlap with the scope of gliomas. Thus, it is unclear what type of brain tumor the claim is drawn to. Therefore, the metes and bounds of the claim are undefined rendering the claim indefinite. Dependent claim 29 is similarly rejected since it does not rectify the issue.
To overcome: Applicant could amend to recite the brain tumor is selected from the group consisting of glioblastoma, neuroglioma, medulloblastoma, and combinations thereof.
Claim 29 recites “the renal carcinoma cell”. Parent claim 28 recites renal carcinoma which is clear cell renal carcinoma, metastatic renal carcinoma, and combinations thereof, but does not recite “renal carcinoma cell”. While these species are each understood to comprise renal carcinoma cells, it is unclear which species claim 29 is attempting to further limit: e.g., does claim 29 further limit only the clear cell renal carcinoma or does it limit both species? Therefore, the metes and bounds of the claim are undefined rendering the claim indefinite.
Claim 30 recites “the N atom connected with R5 is N+” on Pg. 9. Formula I does not recite an R5, only an R5. There is insufficient antecedent basis for this limitation (R5) in the claim. Thus, the metes and bounds of the claim are undefined rendering the claim indefinite. Dependent claims 31-32 are similarly rejected since they don’t rectify the underlying issue.
In Claim 33, the 4th compound structure is of very low resolution so that many of the substituents are difficult to read, especially the subscripts. Since the 4th compound structure is unclear, the metes and bounds of the claim are undefined rendering the claim indefinite.
Claim 34 recites the limitation "the composition" in line 1, “the pharmaceutical composition” in line 3, and “the dosage form of the composition or preparation” in line 5. There is insufficient antecedent basis for this limitation in the claim. The parent claim 18 does not recite a composition, pharmaceutical composition, dosage form, or preparation. Further, claim 34 recites three embodiments separated by semicolons and the phrase “and/or”. Thus, these embodiments are understood, at their broadest, as alternatives each depending from claim 18. Since claim 18 does not recite any of these compositions/forms, it is unclear what claim 34 is referencing. Thus, the metes and bounds of the claim are undefined rendering the claim indefinite.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 31-32 and 34 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claims 31-32 recite further limitations for formulas I, II, and III; the phrase “and/or” is used to separate the limitations for the different formulas. Parent claim 30 recites a method of treatment comprising administering Formula I, II, or III not Formula I, II, and III. Thus, the recitation of Formula I, II, and III by claims 31-32 falls outside of the scope of parent claim 30 and the claims do not properly further limit said claim.
Claim 34 recites "the composition" in line 1, “the pharmaceutical composition” in line 3, and “the dosage form of the composition or preparation” in line 5. Parent claim 18 does not recite a composition, pharmaceutical composition, dosage form, or preparation. As stated above, claim 34 recites multiple embodiments which are outside of the scope of parent claim 18. Thus, claim 34 does not properly further limit claim 18.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 18-19 and 27-34 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by DE BRANANDER (WO 2017/100525) as evidenced by STAMENKOVIC (Stamenkovic, I. et al., Cancer Res., 2012, 72, 1137, 1-5).
Regarding claim 18, 27, 30-33, DE BRANANDER teaches a compound
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(Pg. 240 claim 93) and a method of treating a cancer in a patient by administering a pharmaceutically effective amount of the above compound or composition thereof, wherein the cancer is of the brain (Pg. 249 claim 98-99 & 101). DE BRANANDER further teaches a method of inhibiting the oxidative phosphorylation pathway (i.e., mitochondrial OXPHOS) in a cancer cell comprising administering the same compound/composition (Pg. 250 claims 108-109). The art also teaches the salt of the above compound
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(i.e., S-Gboxin) was administered to a mouse glioblastoma model Mut6 (Pg. 193 ¶439 & Pg. 199 Table) and caused tumor growth retardation compared to control (Pg. 216 ¶450).
The two compounds above are species of instant claim 33 and read on claims 30-32 Formula I: R1-R4 are H, R5 is C1 alkyl (methyl), R6 is C6 aryl substituted by one C1 haloalkyl (i.e., claim 32: R13 is trifluoromethyl and R10-R12 & R14 are H), R7-R8 are H, Z1 is -C(O)-O-, and R9 is C6 cycloalkyl substituted with one C1 alkyl and one C3 alkyl (i.e., claim 32: R15 or R16 is isopropyl, R21 or R22 is methyl, and all others of R15-R24 are H).
Examiner understands DE BRANANDER’s methods of treatment and inhibiting OXPHOS as targeting tumors with upregulated mitochondrial OXPHOS – inhibiting OXPHOS implies overactive OXPHOS. Further, as evidenced by STAMENKOVIC, the protein Imp2 is present in glioblastoma multiforme (GBM) whereas it is absent in normal brain – depletion of Imp2 in GBM impairs OXPHOS mitochondrial pathway suggesting OXPHOS is the main energy pathway for GBM (Pg. 1 Abstract). Since Imp2 is upregulated in GBM and depletion thereof lowers OXPHOS, the OXPHOS pathway must also be upregulated in GBM. Therefore, GBM is understood as a tumor which comprises up-regulation of the mitochondrial OXPHOS pathway.
Regarding claim 19, the art teaches wherein the compound inhibits one or more proteins of the OXPHOS pathway (Pg. 250 claim 110), i.e., the expression of the OXPHOS pathway in the cancer/tumor comprises protein expression; and the subject is human (Pg. 50 ¶104), i.e., a human cancer/tumor.
Regarding claim 28-29, the mouse Mut6 model replicates human glioblastoma multiforme (Pg. 210 ¶440). Thus, the tumor treated is brain tumor - glioblastoma multiforme.
Regarding claim 34, the composition administered in the treatment (Pg. 249 claim 98) is a pharmaceutical composition comprising the compounds above and a pharmaceutically acceptable carrier (Pg. 248 claim 95) formulated as a unit dosage form (Pg. 249 claim 97) for oral, intravenous, or topical administration (Pg. 248 claim 96). The oral, intravenous, or topical forms encompass solid, liquid, or semi-solid preparations as these are states of matter which such compositions are found in.
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 18 and 20-21 are rejected under 35 U.S.C. 103 as being unpatentable over DE BRANANDER (WO 2017/100525) as applied to claim 18 above, and further in view of STAMENKOVIC (Stamenkovic, I. et al., Cancer Res., 2012, 72, 1137, 1-5).
Claims 20-21, not included in the 102 above, are drawn to a certain ratio of upregulation of the mitochondrial OXPHOS pathway in the tumor cell vs. another tumor cell or a normal cell. It would be obvious to target such tumors.
Determining the Scope and Contents of the Prior Art:
DE BRANANDER teaches the method of claim 18 as explained in ¶32 above.
STAMENKOVIC teaches the protein Imp2 is present in glioblastoma multiforme (GBM) whereas it is absent in low grade gliomas and normal brain – depletion of Imp2 in GBM impairs OXPHOS mitochondrial pathway suggesting OXPHOS is the main energy pathway for GBM (Pg. 1 Abstract).
Ascertaining the Differences Between the Prior Art and the Claims at Issue:
DE BRANANDER does not teach the ratio of upregulation of mitochondrial OXPHOS vs. a normal cell or another tumor cell is >1.
STAMENKOVIC does not teach a method of administering S-Gboxin and is silent as to the activity ratio of OXPHOS compared to other/normal cells.
Resolving the Level of Ordinary Skill in the Pertinent Art:
The level of ordinary skill in the art is represented by an artisan who has sufficient background in the development of a method useful for inhibition of upregulation OXPHOS and possesses the technical knowledge necessary to make adjustments to the method to optimize/enhance the outcomes. Said artisan has also reviewed the problems in the art regarding OXPHOS upregulation in glioblastoma and understands the solutions that are widely-known in the art.
Considering Objective Evidence Present in the Application Indicating Obviousness or Nonobviousness:
The instant claims are prima facie obvious in light of the combination of references DE BRANANDER in view of STAMENKOVIC.
The artisan would find it obvious to treat a glioblastoma multiforme (GBM) tumor by administering S-Gboxin, wherein the tumor has upregulation of mitochondrial OXPHOS activity that is >1.0 when compared to OXPHOS activity in another glioma cell or a normal brain cell, in view of the combined art.
Since Imp2 is upregulated in GBM and depletion thereof lowers OXPHOS, as recognized by STAMENKOVIC (Pg. 1 Abstract), the OXPHOS pathway must also be upregulated in GBM. Further, the artisan would recognize the GBM cells as having a higher OXPHOS expression level compared to a normal brain cell or another glioma tumor cell since STAMENKOVIC teaches these cells do not have expression of the Imp2 (Pg. 1 Abstract).
While STAMENKOVIC is silent as to the ratio of OXPHOS upregulation in the GBM cells vs. normal/low-grade glioma cells, the artisan would be motivated to optimize for this value to extract the highest treatment efficacy possible and treat the patient populations most in need of OXPHOS inhibition.
MPEP 2144.05(II)(A) provides guidance about the routine optimization of prior art conditions: "Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.").” Furthermore, MPEP 2144.05(I) provides guidance about overlapping ranges: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists…Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close.”
Here, STAMENKOVIC teaches the activity level of OXPHOS is lower in normal brain and low-grade glioma cells compared to GBM cells (Pg. 1 Abstract). While no exact activity levels are given, the artisan would be able to measure such level in a subject’s tumor cells vs. a control, as demonstrated by STAMENKOVIC measuring change in OXPHOS (Pg. 1 Abstract). Further, since DE BRANANDER teaches inhibition of OXPHOS in cancer cells by S-Gboxin (Pg. 249-50 claims 98-99, 101, & 108-109), the artisan would recognize the level of activity of the OXPHOS pathway as a results-effective variable, i.e., a variable that achieves a recognized result. In this case, the recognized result would be severity of the brain cancer (see STAMENKOVIC only the high-grade GBM has the upregulated pathway (Pg. 1 Abstract)) and the suitability of inhibiting OXPHOS for such patient (higher upregulation = higher suitability). Thus, the activity ratio of OXPHOS in tumor vs. normal/other tumor cell is equivalent to the “concentration” recited in the MPEP. Absent any evidence demonstrating the contrary, the determination of the optimum or workable activity ratio would have been well within the practice of the artisan. Further, since DE BRANANDER teaches inhibition of OXPHOS in cancer cells administering S-Gboxin (Pg. 249-50 claims 98-99, 101, & 108-109), the artisan would expect the method to work in cancers with OXPHOS activity greater than 1 compared to other normal cells (instant claim 20) or other tumor cells of the same type (instant claims 20-21), i.e., glioma cells.
Claims 18-21 and 27-34 are rejected under 35 U.S.C. 103 as being unpatentable over DE BRANANDER (WO 2017/100525) as applied to claims 18-19 and 27-34 above (¶32), and further in view of JUNG (Jung, J. et al., JCI Insight, 2017, 2(10), 1-24).
The instant limitations not rejected by the above 102 are drawn to a method of treating tumor with low or no expression of NNMT gene (claim 18-19) wherein the expression is of a certain ratio compared to another tumor cell or a normal cell (claim 20-21). It would be obvious to target such tumors.
Determining the Scope and Contents of the Prior Art:
The teachings of DE BRANANDER are above, ¶32.
JUNG teaches NNMT expression in GBM vs non-tumor brain (NT) is typically upregulated; however, for ~25% of GBM samples the NNMT expression about the same or lower than that of the NT brain (Pg. 3 Fig. 1C). In Fig. 1C, the baseline NNMT expression in NT brain is set at 0 fold-change while the lower quartile of the GBM brain ranges from about 0 fold-change to about -3 fold-change. Thus, the NNMT expression in GBM samples can be ~0.3 that of a normal cell or of another GBM cell. The data originates from The Cancer Genome Atlas GBM patient database (Pg. 2 ¶3); thus, the patients are human and the NNMT is human (instant claim 19). JUNG teaches high expression of NNMT is correlated with poor patient survival (Pg. 13 last ¶) – NNMT is a negative prognostic factor for human glioma patients (Pg. 14 last 2 lines).
Ascertaining the Differences Between the Prior Art and the Claims at Issue:
DE BRANANDER does not teach the GBM has low/no expression of NNMT.
JUNG does not teach the treatment of GBM with S-Gboxin.
Resolving the Level of Ordinary Skill in the Pertinent Art:
The level of ordinary skill in the art is represented by an artisan who has sufficient background in the development of a method useful for treating GBM and possesses the technical knowledge necessary to make adjustments to the patient population to optimize/enhance the expectation of treatment success. Said artisan has also reviewed the problems in the art regarding NNMT expression in GBM and understands the solutions that are widely-known in the art.
Considering Objective Evidence Present in the Application Indicating Obviousness or Nonobviousness:
The instant claims are prima facie obvious in light of the combination of references DE BRANANDER in view of JUNG.
Regarding claims 18-21, the artisan would be motivated to treat human patients with low/no expression of human NNMT gene in glioblastoma multiforme by the methods of DE BRANANDER, in order to optimize the expectation of success in treatment efficacy since NNMT overexpression is associated with poor prognosis in GBM, as recognized by JUNG (Pg. 13 last ¶). Since DE BRANANDER teaches S-Gboxin can be used to treat GBM (Pg. 216 ¶450) and JUNG teaches NNMT is a negative prognostic factor for GBM (Pg. 14 last 2 lines), the artisan would have an expectation of success that DE BRANANDER’s method of treatment would work in GBM patients with low/no expression of human NNMT gene (instant claims 18-19). Based on JUNG’s teachings (Pg. 3 Fig. 1C) the artisan would expect the low NNMT expression to be about ≤0.3 of the expression in normal cells or the same type of tumor cell with normal expression of NNMT (instant claims 20-21).
Regarding claims 27-34, DE BRANANDER teaches the limitations of these claims as described in ¶32, above. Since the method of claim 18 is obvious, above, the dependent claims 27-34 are similarly obvious.
Claims 18-21, 27, and 30-34 are rejected under 35 U.S.C. 103 as being unpatentable over DE BRANANDER (WO 2017/100525) as applied to claims 18-19, 27, and 30-34 above (¶32), and further in view of YU (Yu, T. et al., Cell Physiol Biochem, 2015, 35, 710-721) and in view of VIALE (Viale, A. et al., Nature, 2014, 514, 1-23).
The instant claims are drawn to a method of treating tumor with low/no expression of human NNMT or upregulation of mitochondrial OXPHOS (claims 18-19) with a certain ratio of NNMT & OXPHOS expression compared to normal/other tumor (claims 20-21); the cancer is pancreatic cancer (claim 27); the administered drug is S-Gboxin (claims 30-33) or composition thereof (claim 34). It would be obvious to target such tumors.
Determining the Scope and Contents of the Prior Art:
The teachings of DE BRANANDER are above, ¶32. DE BRANANDER also teaches wherein the cancer treated is pancreatic cancer (Pg. 249 claim 101).
YU teaches aberrant expression of NNMT has been reported in pancreatic cancer – NNMT silencing markedly reduced cell proliferation whereas overexpression promoted cell growth (Pg. 710 Abstract).
VIALE teaches a subpopulation of pancreatic cancer cells surviving oncogene ablation and responsible for tumor relapse rely on oxidative phosphorylation for survival – these cells have prominent expression of genes governing mitochondrial function and high sensitivity to OXPHOS inhibitors (Pg. 1 Abstract).
Ascertaining the Differences Between the Prior Art and the Claims at Issue:
DE BRANANDER does not teach the pancreatic cancer has low/no expression of NNMT.
YU and VIALE do not teach the treatment of pancreatic cancer with S-Gboxin.
Resolving the Level of Ordinary Skill in the Pertinent Art:
The level of ordinary skill in the art is represented by an artisan who has sufficient background in the development of a method useful for treating pancreatic cancer and possesses the technical knowledge necessary to make adjustments to the patient population to optimize/enhance the expectation of treatment success. Said artisan has also reviewed the problems in the art regarding NNMT & OXPHOS expression in such cancer and understands the solutions widely-known in the art.
Considering Objective Evidence Present in the Application Indicating Obviousness or Nonobviousness:
The instant claims are prima facie obvious in light of the combination of references DE BRANANDER in view of YU and in view of VIALE.
Regarding claims 18-19, the artisan would be motivated to treat human patients with low/no expression of human NNMT gene in pancreatic cancer by the methods of DE BRANANDER, in order to optimize the expectation of success in treatment efficacy since NNMT overexpression is associated with cancer cell growth, as recognized by YU (Pg. 710 Abstract). Since DE BRANANDER teaches S-Gboxin can be used to treat pancreatic cancer (Pg. 249 claim 101) in humans (Pg. 50 ¶104), in view of YU, the artisan would have an expectation of success that DE BRANANDER’s method of treatment would work in pancreatic cancer patients with low/no expression of human NNMT gene (instant claims 18-19). Similarly, in view of VIALE teachings (Pg. 1 Abstract), the artisan would expect resistant pancreatic tumor cells to have overexpression of OXPHOS and be sensitive to inhibition of such. Thus, the artisan would have an expectation of success in applying DE BRANANDER’s method to such patient population.
Regarding claims 20-21, the artisan would be motivated to optimize the treatment for patients with optimal low/no expression of NNMT or overexpression of OXPHOS in view of YU and VIALE’s teachings of the role of such gene/pathway in pancreatic cancer. See the MPEP 2144.05 quotation ¶37, above.
Here, the art is silent as to the numeric level of expression of the gene/pathway in pancreatic cancer cells; however, since the art does measure expression of NNMT in transfected cells (YU Pg. 714 Fig. 1) and expression of mitochondrial function (VIALE Pg. 1 Abstract), the artisan would be able to measure such expression of NNMT and OXPHOS in patient’s cancer cells. Since both YU (Pg. 710 Abstract) and VIALE (Pg. 1 Abstract) teach NNMT and OXPHOS, respectively, have an effect on cancer progression, the artisan would recognize expression levels thereof as a results-effective variable. In this case, the recognized result would be severity of the pancreatic cancer progression and the suitability of inhibiting OXPHOS for such patient. Thus, the expression ratio of NNMT or OXPHOS in tumor vs. normal/other tumor cell is equivalent to the “concentration” recited in the MPEP. Absent any evidence demonstrating the contrary, the determination of the optimum or workable expression ratio would have been well within the practice of the artisan.
Further, since DE BRANANDER teaches inhibition of OXPHOS in cancer cells administering S-Gboxin (Pg. 249-50 claims 98-99, 101, & 108-109), the artisan would expect the method to work in cancers with OXPHOS activity greater than 1 compared to other normal cells (instant claim 20) or other tumor cells of the same type (instant claims 20-21), i.e., glioma cells. To be upregulated the ratio of tumor cell/other cell must be greater than 1.
Regarding claims 27-34, DE BRANANDER teaches the limitations of these claims as described in ¶32, above. Since the method of claim 18 is obvious, above, the dependent claims 27-34 are similarly obvious.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 18-21 and 27-29 are provisionally rejected on the ground of anticipatory nonstatutory double patenting as being unpatentable over claims 16-26 and 28-30 of copending Application No. 17/909,422 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The reference claims are drawn to a method of inhibiting the mitochondrial oxidative phosphorylation (OXPHOS) pathway of mitochondria, preventing/treating diseases associated with such, and preventing/treating cancers by administering a compound of Formula I
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160
208
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Greyscale
to a subject in need (ref claim 16) wherein the cancer has upregulation of the OXPHOS pathway (ref claim 24). Species of Formula I are defined in reference claims 17-18, 26, and 28 – these are understood as species of mitochondrial OXPHOS inhibitors since the method inhibits such pathway. Thus, the reference claims anticipate the instant claim 18.
The reference claims are further drawn to wherein the disease is cancer (ref claim 19) which is selected from many species recited in reference claims 20-23 and 29-30. The species recited read on the species of instant claims 27-29 and the genus cancer of the other instant claims. Reference claims 20-21 recites species which align directly with those recited in the instant claims, while reference claims 22-23 and 30 recite further narrower species thereof. Reference claim 29 recites species of the broad genus of cancer and states the cancer is human cancer (i.e., instant claim 19).
Reference claim 25 recites wherein the OXPHOS regulation means that the ratio (E1/E0) of the cancer cell to the same expression in the same type of cell is ≥1.2, ≥1.5, ≥2, ≥3, or ≥5. The artisan would immediately envisage the “same type of cell” to encompass both other tumor cells of the same type of cancer and normal cells of the same tissue. Thus, the reference claim anticipates instant claims 20-21.
Conclusion
Claims 18-21 and 27-34 are rejected.
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/S.E.B./Examiner, Art Unit 1625
/JOHN S KENYON/Primary Patent Examiner, Art Unit 1625
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