DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Application
Claims 1-30 are pending as of the response filed on 01/22/2026. Applicant’s original election of group I claims 1-16 and species of alkyl-triphenylphosphonium (“TPP”) as dodecyl-TPP (d-TPP) and a species of the second inhibitor as doxycycline (i.e., an OXPHOS inhibitor of amended instant claims) is maintained. Claims 4-5, 7-8, 11, 13-15 and 17-30 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention or nonelected species, there being no allowable generic or linking claim. Claims 1-3, 6, 9-10, 12 and 16 are examined herein.
The claim amendments do not overcome the 35 U.S.C. § 103 rejections of record. In view of the pending claims, the 35 U.S.C. § 103 rejections of record are maintained and updated to reflect any claim amendments.
Applicant’s arguments have been fully considered and are addressed below.
Claim Rejections - 35 USC § 103 - Maintained
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-3, 6, 9-10, 12 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Schultz et al. (US 2018/0214402 A1, publication date 02 August 2018, hereinafter Schultz) in view of De Francesco et al. (Vitamin C and Doxycycline: A synthetic lethal combination therapy targeting metabolic flexibility in cancer stem cells (CSCs), published 09 June 2017, hereinafter De Francesco).
Regarding instant claims 1-2, 6, 9, 12 and 16 Schultz teaches a combination of phenyl butyric acid (PBA) or a pharmaceutically acceptable salt thereof; and one or more anti-cancer compositions for the therapeutic treatment of a hyperproliferative disorder (Para. [0005]; Para. [0027]). Schultz teaches the hyperproliferative disorder is cancer (Para. [0006]). Schultz teaches embodiments in which the anti-cancer composition comprises a derivative of triphenylphosphonium (TPP), or a pharmaceutically acceptable salt thereof (Para. [0014]; Para. [0056]). Schultz teaches an exemplary embodiment in which the TPP agent is 12-TPP (i.e., d-TPP, the instantly elected species of alkyl-triphenylphosphonium, wherein x is 11 of instant claim 1) (Para. [0058]; FIG. 1). Schultz teaches triphenylphosphonium (TPP) compounds with linear aliphatic side chains preferentially accumulate in cancer cell mitochondria due to the hyperpolarized mitochondrial membrane potential, disturbing the cellular metabolism leading to ROS (reactive oxygen species; e.g. superoxide/hydrogen peroxide) imbalance (Para. [0103]). Schultz teaches combination treatment with 12-TPP leads to a decrease in viability of melanoma cells (Para. [0040]; Paras. [0103]-[0104]; FIGS. 5A-5B). Schultz teaches the composition may be formulated as a pharmaceutical composition (Para. [0084]; Para. [0095]). Schultz teaches the amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained (Para. [0085]). Schultz teaches combination therapy as a solution to overcome drug resistance mechanisms (Para. [0004]; [0048]).
Schultz do not teach the cancer therapy composition/pharmaceutical composition comprising an OXPHOS inhibitor compound.
De Francesco teaches cancer stem cells (CSCs) to be the “root cause” of tumor recurrence, distant metastasis and therapy-resistance, driving poor clinical outcome in advanced cancer patients (Pg. 67269, first column, first paragraph). De Francesco teaches a strategy for optimizing the eradication of CSCs (Abstract). De Francesco teaches chronic treatment with the FDA-approved antibiotic doxycycline effectively reduces cellular respiration, by targeting mitochondrial protein translation and induces metabolic inflexibility in CSCs, by chronically inhibiting mitochondrial biogenesis (Abstract; Pg. 67270, second column, first full paragraph). De Francesco teaches doxycycline inhibits mitochondrial biogenesis and OXPHOS, by acting via mitochondrial ribosomal proteins (MRPs) (Pg. 67281, Figure 12). De Francesco emphasizes the importance of overcoming doxycycline resistance by using a multi-targeted approach and indicates CSCs as the main promoter of tumor recurrence and patient relapse (Pg. 67278, Figure 8). De Francesco teaches doxycycline induced metabolic inflexibility may be a practical solution to avoiding treatment failure, in a variety of cancer types (Pg. 67270, second column, first full paragraph).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, in view of the teachings of Schultz and De Francesco to have addressed the root cause of therapy resistance by incorporating an OXPHOS inhibitor compound, say doxycycline, as taught by De Francesco, into the composition of Schultz to arrive at the composition of the instant claims with a reasonable expectation of success. Schultz teaches a combination of phenyl butyric acid (PBA) or a pharmaceutically acceptable salt thereof; and one or more anti-cancer compositions for the therapeutic treatment of a hyperproliferative disorder, wherein the hyperproliferative disorder is cancer. Schultz teaches anti-cancer compositions comprising a derivative of triphenylphosphonium (TPP), or a pharmaceutically acceptable salt thereof for the therapeutic treatment of cancer. Schultz teaches an exemplary embodiment in which the TPP agent is 12-TPP (i.e., dodecyl-TPP). Schultz teaches triphenylphosphonium (TPP) compounds with linear aliphatic side chains preferentially accumulate in cancer cell mitochondria due to the hyperpolarized mitochondrial membrane potential, disturbing the cellular metabolism leading to ROS imbalance. Schultz teaches the combination therapy as a solution to overcome drug resistance mechanisms. De Francesco teaches cancer stem cells (CSCs) to be the “root cause” of tumor recurrence, distant metastasis and therapy-resistance, driving poor clinical outcome in advanced cancer patients. De Francesco teaches the use of doxycycline as a strategy for the eradication of cancer stem cells. De Francesco teaches chronic treatment with the FDA-approved antibiotic doxycycline effectively reduces cellular respiration, by targeting mitochondrial protein translation and induces metabolic inflexibility in CSCs, by chronically inhibiting mitochondrial biogenesis. De Francesco teaches doxycycline inhibits mitochondrial biogenesis and OXPHOS, by acting via mitochondrial ribosomal proteins (MRPs). De Francesco emphasizes the importance of overcoming doxycycline resistance by using a multi-targeted approach and indicates CSCs as the main promoter of tumor recurrence and patient relapse.
According to MPEP 2144.06 (I), "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). In the instant case, the composition of Schultz and the composition of De Francesco, are both taught to be anti-cancer therapeutics designed to overcome drug resistance in cancer therapy. Both of them target the mitochondria/mitochondrial function and can therefore be combined to form a third composition that comprises a combination of phenyl butyric acid (PBA), dodecyl-TPP and doxycycline to arrive at the composition of the instant claims (the presence of the open-ended transitional phrase “comprising” in instant claim 1, allows for the inclusion of additional, unrecited elements).
Alternatively, one of ordinary skill in the art, would have been motivated to substitute the phenyl butyric acid (PBA) of Schultz (taught to combat drug resistance in cancer therapy) with the doxycycline, as taught by De Francesco (taught to eradicate the root cause of therapy resistance – cancer stem cells), to arrive at the composition of the instant claims.
As stated in MPEP 2144.06 (II), “An express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982)”.
Therefore, one of ordinary skill in the art would have been motivated to incorporate an OXPHOS inhibitor compound, say doxycycline, into the composition of Schultz to arrive at the composition of the instant claims with a reasonable expectation of success. The motivation being to effectively target multiple metabolic stressors, thereby addressing the root cause of developing therapy resistance (De Francesco, Pg. 67270, second column, first full paragraph). This renders the combination composition/pharmaceutical composition of instant claims 1-2, 6, 9, 12 and 16, prima facie obvious.
Regarding instant claims 3 and 10, the combined teachings of Schultz and De Francesco render the composition of instant claim 2 and pharmaceutical composition of instant claim 9, prima facie obvious.
Schultz do not teach the cancer therapy composition/pharmaceutical composition further comprising a glycolysis inhibitor compound selected from the group consisting of Vitamin C and 2-deoxy-glucose.
De Francesco teaches the use of combination strategies aimed at hitting multiple aspects of tumor progression is currently considered as a promising tool to overcome resistance (Pg. 67278, second column, continued paragraph). De Francesco teaches that when cancer stem cells (CSCs) develop resistance to doxycycline (DoxyR), they switch to a glycolytic metabolism to survive. This makes these DoxyR CSCs highly sensitive to a second "metabolic hit". De Francesco teaches the second metabolic hit could be achieved by using virtually any other “safe” metabolic inhibitors, targeting either glycolysis, OXPHOS or autophagy (Pg. 67278, Figure 8). De Francesco teaches Vitamin C inhibits glycolytic metabolism by targeting and inhibiting the enzyme GAPDH. Therefore, their use together, as a sequential drug combination, will more severely target cell metabolism and energy production, thereby preventing or blocking the propagation of CSCs (Pg. 67281, Figure 12). De Francesco teaches metabolic inhibitors successfully used for the eradication of CSCs to include 2-deoxy-glucose (2 DG) and Vitamin C (Pg. 67275, second column, second full paragraph; Pg. 67275, Figure 9). Since the concentrations of 2-deoxy-glucose and Vitamin C employed were sufficient to achieve the desired effect of eradication of CSCs, it satisfies the limitation of “a pharmaceutically effective amount of a glycolysis inhibitor” of instant claim 10, in line with the definition of “pharmaceutically effective amount” as in Para. [0034] of the instant specification.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, in view of the teachings of Schultz and De Francesco to have incorporated a further inhibitor, such as, Vitamin C or 2-deoxy-glucose, to arrive at the combination cancer therapy composition/pharmaceutical composition as in instant claims 3 and 10, with a reasonable expectation of success. The combined teachings of Schultz and De Francesco render the composition of instant claim 2 and pharmaceutical composition of instant claim 9, prima facie obvious. De Francesco teaches the use of combination strategies aimed at hitting multiple aspects of tumor progression is currently considered as a promising tool to overcome resistance. De Francesco teaches that when cancer stem cells develop resistance to doxycycline (DoxyR), they switch to a glycolytic metabolism to survive. This makes these DoxyR CSCs highly sensitive to a second "metabolic hit". De Francesco teaches the second metabolic hit could be achieved by using virtually any other “safe” metabolic inhibitors, targeting either glycolysis, OXPHOS or autophagy. De Francesco teaches pharmaceutically effective amount of metabolic inhibitors successfully used for the eradication of CSCs to include 2-deoxy-glucose (2 DG) and Vitamin C.
According to MPEP 2144.06 (I), "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). In the instant case, the composition of Schultz and the composition of De Francesco, are both taught to be anti-cancer therapeutics designed to overcome drug resistance to cancer therapy.
Therefore, one of ordinary skill in the art would have been motivated to incorporate a glycolysis inhibitor, such as Vitamin C or 2-deoxy-glucose, taught by De Francesco into the cancer therapy composition of Schultz to arrive at the combination cancer therapy composition/pharmaceutical composition of the instant claims, with a reasonable expectation of success. The motivation being to effectively starve the cancer stem cell population, thereby preventing treatment failure and minimizing metastatic dissemination (Abstract; Pg. 67281, second column, first full paragraph).
Response to Arguments
Applicants argue on pages 8-11 of the response dated 01/22/2026 that the In re Kerkhoven logic does not apply in this case. Applicants argue “This is inapplicable to the pending claims, at least because MPEP § 2144.06 relates to art-recognized equivalents for the same purpose. Schultz and De Francesco do not teach art-recognized equivalents … Increasing ROS, as with the TPP agent in Schultz, is not the same as reducing cellular respiration, as in De Francesco. There is no recognized equivalency, and the references teach different activity for each compound. As a result, the asserted motivation to combine is improper, and the rejection under § 103 should be withdrawn".
Applicants cite to MPEP § 2143.02 and argue different structures and different mechanism of action for the active agents of Schultz and De Francesco. Applicants conclude that there is no reasonable expectation of success in arriving at the instant invention by combining the teachings of the prior art references.
Applicant's arguments have been fully considered but they are not persuasive.
While the active agents of Schultz and De Francesco may act by different mechanisms, they produce the same therapeutic effect of triggering cancer cell death. The mechanism of action matters little as long as each active agent is taught to be useful for the same purpose. In the instant case, Schultz teaches an anti-cancer composition comprising a derivative of triphenylphosphonium (TPP), say 12-TPP. De Francesco teaches doxycycline, an OXPHOS inhibitor, in the eradication of drug resistant cancer stem cells. Additionally, it is well known in the field of cancer treatments to use combination therapy by combining agents with different mechanisms. Therefore, one of ordinary skill in the art would have been clearly motivated to combine the compositions of Schultz and De Francesco to arrive at the composition of the instant invention.
Furthermore, the examiner does not dispute that the alkyl-TPP of Schultz and doxycycline of De Francesco have different structures and operate via different mechanisms to achieve the same result of cancer treatment. The examiner notes that different treatment modalities are often used in the field of cancer therapeutics to improve treatment efficacy. In the instant case, as noted by Applicants, the alkyl-TPP agent of Schultz increases reactive oxygen species (ROS) levels in cancer cell mitochondria (Para. [0056]). As noted by Applicants, De Francesco teaches a “two hit” approach to overcome doxycycline resistance in cancer stem cells (Figure 8). Figure 8 of De Francesco teaches that cancer cells that have gone through a first metabolic hit would be extremely susceptible to a second metabolic hit. And the second metabolic hit can be achieved by using virtually any “safe” metabolic inhibitors, targeting either glycolysis, OXPHOS or autophagy. De Francesco teaches an instance of the second metabolic hit with Vitamin C which inhibits GAPDH (a glycolytic enzyme) and depletes the cellular pool of glutathione, resulting in high ROS production and oxidative stress (Pg. 67270, second column, continued paragraph) (it is noted that Vitamin C acts by precisely the same mechanism as the alkyl-TPP of Schultz, i.e., increasing ROS). De Francesco teaches doxycycline and Vitamin C may represent a new synthetic lethal drug combination for eradicating CSCs (i.e., agents working by different mechanisms to achieve the intended result). Therefore, a PHOSITA would have been clearly motivated to use a “two hit” strategy that targets the metabolic flexibility of cancers cells to more severely impact cell metabolism and energy production, thereby starving the cancer cells.
Hence, there is sufficient motivation to combine the teachings of Schultz, that teaches a cancer therapeutic composition comprising an alkyl-TPP agent (which induces an increase in ROS of the cancer cells - i.e., effects a first metabolic hit on the cancer cells) with the teachings of De Francesco that teaches an OXPHOS inhibitor, (which effectively reduces cellular respiration), as part of a “two hit” strategy to eradicate drug-resistant cancer cells, to arrive at the composition of the instant claims with a reasonable expectation of success.
The examiner asserts that the active agents of Schultz and De Francesco exert the same therapeutic benefit of anticancer effect, and therefore, are art recognized equivalents for the same purpose.
Regarding Applicant’s contention that there is no reasonable expectation of success, according to MPEP 2143.02(I), “The reasonable expectation of success requirement refers to "the likelihood of success" in combining or modifying prior art disclosures to meet the limitations of the claimed invention. See Elekta Ltd. v. ZAP Surgical Sys., Inc., 81 F.4th 1368, 1375, 2023 USPQ2d 1100 (Fed. Cir. 2023) and Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd., 821 F.3d 1359, 1367, 119 USPQ2d 1171, 1176 (Fed. Cir. 2016) … Conclusive 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)”. According to MPEP 2143.02 (II), “Obviousness does not require absolute predictability, but at least some degree of predictability is required”.
Thus, absolute predictability is not a necessary prerequisite to a case of obviousness. Rather, a degree of predictability that one of ordinary skill would have found to be reasonable is sufficient. In the instant case, as discussed in the 103 rejection and discussion above, a PHOSITA would have had a reasonable expectation of success in arriving at the instant composition by combining a composition that comprises alkyl-TPP and an OXPHOS inhibitor, per the teachings of Schultz and De Francesco. The motivation being to effectively target multiple metabolic stressors, thereby addressing the root cause of developing therapy resistance.
For the reasons discussed above and since Applicants have not provided any unexpected results in comparison to the closest prior art, the 35 U.S.C. § 103 rejections of record are maintained.
Conclusion
Claims 1-3, 6, 9-10, 12 and 16 are rejected.
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PADMAJA S RAO whose telephone number is (571)272-9918. The examiner can normally be reached 9:00-5:30 pm EDT.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Kortney L Klinkel can be reached on (571) 270-5239. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/PADMAJA S RAO/Examiner, Art Unit 1627
/Kortney L. Klinkel/Supervisory Patent Examiner, Art Unit 1627
Prosecution Insights