DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 03/27/2026 has been entered.
Summary
Receipt of Applicants’ Arguments, Remarks and amended claims filed on 03/27/2026 is acknowledged.
Claims 1-9, 11-17, 28-30 and 33-39 are pending.
Claims 10, 18-24, 31, 32, and 40-57 remain cancelled.
Claims 25-27, 33 and 34 are withdrawn from consideration.
Claims 1, 35 and (25 – withdrawn) have been amended.
Claims 1-9, 11-17, 28-30 and 35-39 are pending and under examination in this application.
For clarity, this is a non-final rejection with modifications.
Modified Rejections
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 1-9,11-17, 28-30 and 35-39 are rejected under 35 U.S.C. 103 as being unpatentable over Lamb (“Antibiotics that target mitochondria effectively eradicate cancer stem cells, across multiple tumor types: Treating cancer like an infectious disease”, hereinafter “Lamb”) in view of DeFrancesco (“Vitamin C and Doxycycline: A synthetic lethal combination therapy targeting metabolic flexibility in cancer stem cells (CSCs)”, hereinafter “DeFrancesco”), further in view of Zhou (“Ascorbyl palmitate-incorporated paclitaxel-loaded composite nanoparticles for synergistic anti-tumoral therapy”, hereinafter “Zhou”), and further in view of Steliou (WO 2009/038656 A1, hereinafter “Steliou”). Fanzi (CN 101125126 A) is additionally noted as background establishing the pharmaceutical formulation context of the individual active agents.
Scope and Content of the Prior Art
Lamb teaches the anti-cancer use of FDA-approved antibiotics by targeting mitochondrial biogenesis, exploiting the evolutionary similarity between mitochondrial and bacterial ribosomes. Lamb discloses that members of the erythromycin antibiotic class — including azithromycin — selectively bind to and inhibit the large subunit of the mitochondrial ribosome, thereby blocking translation of mitochondrial proteins and inhibiting mitochondrial biogenesis (Lamb, page 4570, right column, last paragraph). Lamb further discloses that members of the tetracycline antibiotic class — including doxycycline — bind with high affinity to the small subunit of the mitochondrial ribosome and independently inhibit mitochondrial biogenesis (Lamb, page 4570, right column, last two paragraphs; Figure 1A). Lamb expressly teaches both agents together across 12 cancer cell lines in 8 tumor types, and discloses doxycycline as a tetracycline derivative (page 4574, left column, 1st paragraph) and azithromycin as a derivative of erythromycin (page 4572, left column, 1st paragraph). Lamb further discloses that azithromycin and doxycycline were each tested at sub-antimicrobial concentrations (azithromycin at 250 µM, p<0.001; doxycycline across 50-500 µM range with little or no effect on cell viability, page 4580-4581, Figs. 11-12), establishing sub-antimicrobial dosing as known in this therapeutic context.
DeFrancesco teaches eradication of cancer stem cells (CSCs) by combining doxycycline with Vitamin C, wherein Vitamin C functions to block glycolysis, inhibit glycolytic enzymes, and deplete the cellular pool of glutathione, resulting in elevated reactive oxygen species (ROS) and mitochondrial oxidative stress (DeFrancesco, page 67270, left column, last paragraph to right column, 1st paragraph). DeFrancesco further discloses that oral administration of Vitamin C achieves plasma concentrations of approximately 70-220 µM (page 67280, left column, 1st paragraph). DeFrancesco further discloses that tetracyclines (doxycycline) and Vitamin C act as a synthetic lethal combination against CSCs by targeting two distinct metabolic vulnerabilities simultaneously: mitochondrial protein translation (doxycycline) and glycolytic metabolism/redox homeostasis (Vitamin C) (abstract; page 67270, left column, 3rd-4th paragraphs).
Zhou teaches a co-loaded drug delivery system encapsulating Vitamin C (as ascorbyl palmitate) and paclitaxel in composite solid lipid nanoparticles for synergistic anti-tumoral therapy, establishing that Vitamin C and ascorbyl palmitate are functionally equivalent anti-tumor agents suitable for co-encapsulation in a single delivery vehicle (abstract; page 1232, paragraph 2.3; page 1233, paragraph 3.1).
Steliou teaches antioxidant compositions comprising chiral, non-racemic, synthetic carnitinoid analog carrier molecules, wherein (1) short, medium, and long chain fatty acids including myristic acid and palmitic acid are disclosed as components of antioxidant compositions (Table 1, page 55-56, line 7); (2) acylcarnitine is disclosed as a high-energy linkage fatty acid ester of carnitine that mediates transfer of fatty acyl groups from the cytoplasm to the mitochondrial matrix for oxidation (page 15, lines 1-30); and (3) tri-phenyl-phosphonium (TPP) moiety is disclosed as a mitochondria-targeting element (page 23, lines 10-13; page 24, lines 13). Steliou’s core teaching is the utility of fatty acid conjugation for delivering biologically active molecules to the interior of mitochondria.
Fanzi (CN 101125126 A) is noted as establishing that erythromycin-class antibiotics (including azithromycin), tetracycline-class antibiotics (including minocycline), and Vitamin C are each individually recognized pharmaceutical agents in the relevant art, known to be amenable to pharmaceutical formulation and parenteral delivery (abstract; claim 9; paragraph 1 of the scope of present invention). Fanzi is not relied upon as teaching any composition combining these agents.
Differences Between the Claims and the Prior Art
Regarding claims 1 and 35 (independent), the prior art collectively teaches each structural and functional element:
Lamb teaches: (a) a first therapeutic agent that inhibits mitochondrial biogenesis and targets the large mitochondrial ribosome, specifically including azithromycin (erythromycin derivative) (page 4572, left column, 1st paragraph); (b) a second therapeutic agent that inhibits mitochondrial biogenesis and targets the small mitochondrial ribosome, specifically including doxycycline (tetracycline derivative) (page 4574, left column, 1st paragraph); and the combined use of erythromycin-family and tetracycline-family agents for cancer stem cell eradication (abstract; page 4570, right column).
DeFrancesco teaches: (c) a third therapeutic agent that induces mitochondrial oxidative stress, specifically Vitamin C, which functions to block glycolysis, deplete glutathione, and generate ROS causing mitochondrial oxidative stress (page 67270, left column, last paragraph to right column, 1st paragraph). DeFrancesco further establishes the pharmaceutical utility of combining a tetracycline-class mitochondrial biogenesis inhibitor with Vitamin C as a CSC-eradicating combination.
Zhou teaches: that Vitamin C and ascorbyl palmitate are interchangeable functional equivalents suitable for co-encapsulation and co-delivery in an anti-tumor drug delivery system (abstract; page 1232-1233). Zhou thereby teaches the third therapeutic agent recited in claims 1 and 35 as at least one of Vitamin C and ascorbyl palmitate.
Steliou teaches: fatty acid conjugation of biologically active molecules for mitochondria-targeted delivery, including myristic acid and palmitic acid as specific fatty acids (Table 1, pages 55-56); acylcarnitine-fatty acid conjugates that mediate transfer to the mitochondrial matrix (page 15); and TPP moiety as a mitochondria-targeting conjugation element (pages 23-24). Steliou thereby teaches the “conjugate with a fatty acid” and “conjugate with a TPP moiety” limitations of claims 1, 3-8, 29, 35, 38-39.
The remaining differences between the prior art and the instantly claimed composition are: (1) the specific combination of all three functional agent classes in a single composition; (2) the “consisting essentially of” claim format; and (3) fatty acid conjugation of at least one of the first or second therapeutic agents. Each of these differences would have been obvious to a person of ordinary skill in the art (PHOSITA) for the reasons set forth below.
Prima Facie Obviousness and Motivation to Combine
It would have been prima facie obvious to a PHOSITA before the effective filing date to combine an erythromycin-family large-subunit inhibitor (agent 1), a tetracycline-family small-subunit inhibitor (agent 2), and Vitamin C (agent 3) as claimed, for the following independent and mutually reinforcing reasons:
Reason 1 — Mechanistic Complementarity (from Lamb): Lamb explicitly discloses that erythromycin-class and tetracycline-class antibiotics inhibit mitochondrial biogenesis by targeting structurally and functionally distinct ribosomal subunits — the large and small subunits, respectively (page 4570, right column, last two paragraphs; Figure 1A). Lamb demonstrates this dual inhibition approach across 8 tumor types. A PHOSITA reading Lamb would immediately recognize that targeting both ribosomal subunits simultaneously — rather than sequentially — would provide more comprehensive inhibition of mitochondrial biogenesis, since each subunit performs distinct and essential functions in ribosomal assembly and protein translation. The motivation to combine agents 1 and 2 simultaneously is inherent in Lamb’s mechanistic teaching, regardless of any sequential experimental protocol described therein. See MPEP § 2123 (a reference may be relied upon for all it would have reasonably suggested to a PHOSITA, including non-preferred embodiments); Merck & Co. v. Biocraft Labs., Inc., 874 F.2d 804, 807 (Fed. Cir. 1989).
Reason 2 — Metabolic Vulnerability Complementarity (from DeFrancesco): DeFrancesco teaches that cancer stem cells acquire resistance to mitochondrial biogenesis inhibitors (such as doxycycline) by shifting metabolic dependency to glycolysis (page 67270, left column, 3rd-4th paragraphs). DeFrancesco discloses that Vitamin C overcomes this metabolic plasticity by simultaneously depleting glutathione (increasing ROS), inhibiting glycolytic enzymes, and generating mitochondrial oxidative stress, thereby preventing CSCs from escaping mitochondria-targeting therapy (abstract; page 67270). A PHOSITA would have been directly motivated by DeFrancesco to add Vitamin C as a third agent to any composition already containing a mitochondrial biogenesis inhibitor (such as those taught by Lamb) in order to foreclose the glycolytic escape pathway. The addition of Vitamin C to an erythromycin/tetracycline combination taught by Lamb follows directly from DeFrancesco’s teaching that mitochondrial inhibition plus glycolytic inhibition via Vitamin C is synergistically lethal to CSCs.
Reason 3 — Fatty Acid Conjugation for Mitochondrial Delivery (from Steliou): Steliou teaches that conjugating biologically active molecules with fatty acids mediates their transfer to the mitochondrial matrix via the acylcarnitine shuttle (page 15, lines 1-30), thereby concentrating the active agent at its site of action within the mitochondria. A PHOSITA seeking to optimize the delivery efficiency of erythromycin- or tetracycline-class agents — whose therapeutic targets are explicitly mitochondrial ribosomal subunits — would have had clear motivation to conjugate these agents with fatty acids as taught by Steliou, in order to improve mitochondrial targeting. This represents a straightforward application of known conjugation chemistry (Steliou, pages 23-24) to achieve a predictable result: improved delivery to the intended intracellular organelle target. KSR, 550 U.S. at 416 (“the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results”).
Reason 4 — Ascorbyl Palmitate as Vitamin C Equivalent (from Zhou): Zhou teaches that ascorbyl palmitate and Vitamin C are functionally interchangeable anti-tumor agents and co-encapsulates them for synergistic therapy (abstract). A PHOSITA would have recognized ascorbyl palmitate as a known lipophilic ester of Vitamin C, routinely employed as a Vitamin C surrogate in lipid-based and nanoparticle drug delivery systems. The substitution of ascorbyl palmitate for Vitamin C — or the use of both — would have been an obvious formulation choice within the ordinary skill in the art. In re Dillon, 919 F.2d 688, 692 (Fed. Cir. 1990) (en banc) (obvious to try known equivalents with reasonable expectation of success).
Regarding “Consisting Essentially of” in amended claims 1 and 35, the “consisting essentially of” transition limits the claimed composition to the three recited therapeutic agents plus components that do not materially affect the basic and novel characteristics of the composition. The basic and novel characteristic, as identified by applicant, is the simultaneous targeting of (1) the large mitochondrial ribosomal subunit, (2) the small mitochondrial ribosomal subunit, and (3) mitochondrial oxidative stress pathways. The prior art teaches all three of these functional characteristics independently and in combination. A composition differing from the prior art only in the “consisting essentially of” transition does not become patentable where all active elements are taught by the prior art, particularly where applicant has not established that any undisclosed additional component in the prior art would materially affect the basic and novel characteristics. PPG Industries v. Guardian Industries Corp., 156 F.3d 1351, 1354 (Fed. Cir. 1998). The amendment from “comprising” to “consisting essentially of” does not, by itself, overcome a prima facie case of obviousness where each recited active element was known and their combination was motivated. The examiner notes that pharmaceutically conventional excipients, carriers, and diluents — which would typically accompany such an active combination — do not materially affect the anti-cancer mitochondrial targeting mechanism and thus would not be excluded by the “consisting essentially of” limitation in any event.
A PHOSITA would have had a reasonable expectation of success in combining the three therapeutic agents as claimed, because: (a) each agent’s mechanism of action was individually well-characterized; (b) Lamb and DeFrancesco each demonstrate successful anti-CSC activity in established cell lines with these agents; (c) Steliou demonstrates that fatty acid conjugation is a routine, predictable technique for enhancing mitochondrial delivery of small molecules; and (d) no unexpected technical obstacle to the claimed combination has been identified in the prior art. In re O’Farrell, 853 F.2d 894, 903 (Fed. Cir. 1988).
Regarding claims 1 and 2, as noted above, Lamb teaches azithromycin (erythromycin derivative, large subunit) and doxycycline (tetracycline derivative, small subunit). Claims 1 and 2 are therefore unpatentable over Lamb in view of DeFrancesco.
Regarding claim 3, The composition of claim 1 wherein both agents are conjugated with fatty acids. Steliou teaches fatty acid ester/conjugate formation with biologically active molecules for mitochondrial delivery (page 15, lines 1-30; Table 1). The conjugation of both the erythromycin-family and tetracycline-family agents with fatty acids would have been obvious for the reasons stated in Reason 3 above.
Regarding claim 4, Myristic acid is expressly disclosed in Steliou (Table 1, page 55) as a suitable medium-chain fatty acid for conjugation. The selection of myristic acid from Steliou’s disclosed list is an obvious choice within the ordinary skill in the art.
Regarding claims 5 and 29, The recitation of “a conjugate with a fatty acid moiety” is directly taught by Steliou’s disclosure of acylcarnitine fatty acid ester conjugates (page 15, lines 1-30).
Regarding claims 6 and 8, The specific doxycycline-fatty acid conjugate structures are structurally represented by Steliou’s fatty acid conjugation chemistry applied to the tetracycline scaffold. The variable chain length (n=1-20) encompasses the short, medium, and long chain fatty acids expressly taught by Steliou (Table 1, pages 55-56). A PHOSITA applying Steliou’s conjugation methodology to the doxycycline scaffold would arrive at the claimed structures as predictable products of known synthetic procedures.
Regarding claim 7, Steliou expressly teaches TPP moiety as a mitochondria-targeting element (page 23, lines 10-13; page 24, lines 13). The recitation of a conjugate with a TPP moiety is therefore directly taught by Steliou.
Regarding claims 9, 36, and 37, Lamb expressly teaches azithromycin tested at 250 µM with significant anti-CSC activity (p<0.001, page 4580, Fig. 11) and doxycycline tested across the range of 50-500 µM with little or no effect on cell viability (page 4581, Fig. 12), establishing that sub-antimicrobial concentrations of each agent are operative in this anti-cancer context. Sub-antimicrobial dosing of azithromycin and doxycycline in anti-cancer applications is therefore taught by Lamb, rendering the sub-antimicrobial concentration limitation of claims 9, 36, and 37 obvious.
Regarding the additional limitation of claim 37, which further requires that the concentration of at least one of Vitamin C and an ascorbate derivative is sufficient to achieve a peak Vitamin C concentration of between 100 µM and 250 µM in at least one of blood, plasma, and serum: DeFrancesco discloses that oral administration of Vitamin C achieves plasma concentrations of approximately 70-220 µM (page 67280, left column, 1st paragraph). The claimed range of 100-250 µM overlaps substantially with DeFrancesco’s disclosed range of 70-220 µM. Where a claimed range overlaps with a range disclosed in the prior art, the claimed range is prima facie obvious. In re Peterson, 315 F.3d 1325, 1329 (Fed. Cir. 2003). The Vitamin C concentration limitation of claim 37 is therefore rendered obvious by DeFrancesco for the same reasons discussed below regarding claim 11.
Regarding claim 11, DeFrancesco discloses that oral administration of Vitamin C achieves plasma concentrations of approximately 70-220 µM (page 67280, left column, 1st paragraph). The claimed peak Vitamin C concentration range of 100-250 µM overlaps substantially with DeFrancesco’s disclosed range of 70-220 µM. Where a claimed range overlaps with a range disclosed in the prior art, the claimed range is prima facie obvious. In re Peterson, 315 F.3d 1325, 1329 (Fed. Cir. 2003). Applicant has not demonstrated that the claimed concentration range produces results that are unexpected relative to DeFrancesco’s overlapping disclosure. The Vitamin C concentration limitation of claim 11 is therefore rendered obvious by DeFrancesco.
Regarding claims 12 and 13, Lamb teaches erythromycin family members as first therapeutic agents and tetracycline family members as second therapeutic agents (page 4570, right column).
Regarding claim 14, Azithromycin is a derivative of erythromycin as expressly taught by Lamb (page 4572, left column, 1st paragraph). Claim 14 is therefore obvious over Lamb.
Regarding claim 15, The recited ascorbate ester structure corresponds to ascorbyl palmitate and related esters. Zhou teaches ascorbyl palmitate as a Vitamin C ester with anti-tumor activity (abstract; page 1232). The variable chain length (n=1-20) encompasses ascorbyl palmitate (n=14) and related homologs, the use of which as Vitamin C surrogates would have been obvious to a PHOSITA in view of Zhou and routine formulation knowledge. Zhou directly teaches ascorbyl palmitate (corresponding to n=14 in the claimed Markush series) as an anti-tumor agent, and the remaining homologs within the claimed range of n=1-20 represent obvious structural variants within a recognized homologous series. In re Hoch, 428 F.2d 1341 (CCPA 1970); In re Peterson, 315 F.3d 1325, 1329 (Fed. Cir. 2003) (overlapping or adjacent ranges prima facie obvious); KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007). Applicant has not demonstrated unexpected properties across the claimed homologous range sufficient to rebut the prima facie case.
Regarding claim 16, Lamb teaches azithromycin and doxycycline; Steliou teaches myristic acid conjugation; DeFrancesco and Zhou teach Vitamin C/ascorbyl palmitate/ascorbate derivatives. The specific combination of azithromycin-myristic acid conjugate, doxycycline-myristic acid conjugate, and Vitamin C/ascorbyl palmitate/ascorbate derivative is obvious for all reasons stated above.
Regarding claim 17, claim 17 depends from claim 16 and additionally requires that the first therapeutic agent, second therapeutic agent, and third therapeutic agent are encapsulated in a liposomal drug delivery system. Zhou teaches the co-encapsulation of a Vitamin C derivative (ascorbyl palmitate) together with a second anti-tumor agent (paclitaxel) in a single lipid-based co-delivery vehicle for synergistic anti-tumor therapy (abstract; page 1232, paragraph 2.3). While Zhou specifically employs solid lipid nanoparticles rather than liposomes, Zhou’s teaching establishes the principle and motivation for co-encapsulating a Vitamin C derivative and an anti-tumor agent in a single lipid-based delivery system. Liposomal encapsulation is a well-established, routine alternative lipid-based co-delivery platform that a PHOSITA would have recognized as an obvious formulation choice for co-delivery of the three therapeutic agents of claim 16, given the extensive literature on liposomal drug delivery systems for combination cancer therapy. The substitution of liposomes for solid lipid nanoparticles as a co-delivery vehicle represents an obvious choice among known lipid-based drug delivery platforms, each of which serves the same functional purpose of co-encapsulating and co-delivering multiple active agents to tumor cells. KSR, 550 U.S. at 416. A PHOSITA would have had a reasonable expectation of success in adapting the co-encapsulation approach taught by Zhou to a liposomal system given the routine nature of liposomal formulation in oncology drug delivery.
Regarding claims 28 and 30, these claims depend from withdrawn claim 27. Per MPEP § 821.04(a), claims dependent from a withdrawn claim are examined on their merits by incorporating the limitations of the withdrawn claim. Claim 27 recites a method wherein the third therapeutic agent is one of Vitamin C and ascorbyl palmitate, the first therapeutic agent comprises an erythromycin family member conjugated with a first fatty acid, and the second therapeutic agent comprises a tetracycline family member conjugated with a second fatty acid. These limitations are incorporated into the examination of claims 28 and 30.
Regarding claim 28, incorporating the limitations of withdrawn claim 27, the additionally recited limitation that at least one of the first fatty acid and the second fatty acid comprises myristic acid is expressly taught by Steliou, which discloses myristic acid as a suitable medium-chain fatty acid component of biologically active conjugates (Table 1, page 55). The selection of myristic acid from among the fatty acids disclosed in Steliou is an obvious choice within the ordinary skill in the art for the reasons stated in Reason 3 above.
Regarding claim 30, incorporating the limitations of withdrawn claim 27, the additionally recited limitation that the second therapeutic agent comprises a doxycycline-myristic acid conjugate and the first therapeutic agent comprises one of the specific erythromycin-family fatty acid conjugate structures depicted therein are structurally obvious extensions of Steliou’s fatty acid conjugation chemistry applied to the erythromycin and tetracycline scaffolds, as discussed above regarding claims 3, 4, 6, and 8. The variable chain length (n=1-20) in the depicted structures encompasses the fatty acids expressly taught by Steliou (Table 1, pages 55-56), and a PHOSITA applying Steliou’s conjugation methodology to the erythromycin and tetracycline scaffolds would arrive at the claimed structures as predictable products of known synthetic procedures.
Regarding claims 38 and 39, claim 38 depends from claim 35 (independent) and recites that the second therapeutic agent comprises a conjugate of doxycycline and a second fatty acid, the third therapeutic agent comprises at least one of Vitamin C, ascorbyl palmitate, and an ascorbate derivative, and the first therapeutic agent comprises one of the specific erythromycin-family fatty acid conjugate structures depicted therein. These limitations are taught by the combined references for the same reasons discussed above regarding claims 3, 6, 8, 16, and 30. Regarding claim 39, which depends from claim 38, the additionally recited limitation that at least one of the first fatty acid and the second fatty acid is one of myristic acid and palmitic acid is expressly taught by Steliou, which discloses both myristic acid and palmitic acid as suitable fatty acid components (Table 1, page 55; page 54, lines 25-27). The selection of either myristic acid or palmitic acid from Steliou’s disclosed list of fatty acids constitutes an obvious choice within the ordinary skill in the art.
Response to Remarks/Arguments
Applicant’s Remarks/Arguments filed 03/27/2026 have been considered. The rejection under 35 U.S.C. § 103 is maintained. Applicant’s arguments are addressed in turn below.
A. Regarding Applicant’s Argument that Fanzi Does Not Teach a Composition:
Applicant correctly notes that Fanzi is primarily directed to a lyophilization process and does not expressly claim or describe a composition combining erythromycin-class antibiotics, tetracycline-class antibiotics, and Vitamin C. The examiner has reconsidered the characterization of Fanzi in this rejection. Fanzi is no longer relied upon as teaching the claimed combination or any composition. Fanzi is noted solely as background establishing that azithromycin-class and tetracycline-class antibiotics and Vitamin C are each individually recognized as pharmaceutical agents in the relevant art. The basis of the § 103 rejection is restructured herein with Lamb as the primary reference for the two antibiotic agents and DeFrancesco as the primary reference for the Vitamin C agent and the motivation to combine all three. This restructuring does not constitute a new ground of rejection. The same statutory basis (35 U.S.C. § 103), the same prior art references, and the same subject matter of the claims remain at issue — only the characterization of Fanzi’s role within the combination has been clarified. A rejection does not constitute a new ground where the same statutory basis and the same prior art are applied to the same claims, even where the examiner’s reasoning is modified or refined. In re Kronig, 539 F.2d 1300, 1302 (CCPA 1976); MPEP § 706.07(a).
B. Regarding Applicant’s Argument that Lamb Teaches Only Sequential Administration:
Applicant argues that Lamb’s Figure 8 depicts a sequential two-step protocol (first overcome doxycycline resistance in DoxyR cells, then administer doxycycline) and that interpreting Lamb as teaching simultaneous administration would change Lamb’s principle of operation, citing In re Ratti, 270 F.2d 810 (CCPA 1959).
This argument is not persuasive. Applicant’s characterization conflates one specific experimental embodiment of Lamb — the DoxyR resistance-overcoming protocol of Figure 8 — with Lamb’s broader and more fundamental mechanistic teaching. Lamb’s core scientific disclosure, set forth at page 4570 (right column, last two paragraphs) independent of any sequential protocol, is that erythromycin-class agents and tetracycline-class agents inhibit mitochondrial biogenesis through mechanistically distinct and complementary mechanisms: erythromycins bind the large mitochondrial ribosomal subunit and tetracyclines bind the small mitochondrial ribosomal subunit (Figure 1A). This mechanistic teaching stands entirely apart from the DoxyR sequential resistance protocol. Lamb demonstrates the anti-CSC activity of azithromycin and doxycycline across 12 cancer cell lines and 8 tumor types without limiting that activity to a sequential administration scheme (abstract). The DoxyR sequential embodiment of Figure 8 is directed specifically at overcoming acquired doxycycline resistance — a distinct clinical problem from the general CSC eradication teaching.
A PHOSITA reading Lamb’s mechanistic disclosure of complementary large- and small-subunit inhibition would immediately recognize that simultaneous administration of both classes of inhibitors would achieve more comprehensive and concurrent mitochondrial ribosomal blockade than either agent alone, without any need to reference the DoxyR embodiment. Combining agents that target distinct, non-overlapping molecular targets to achieve comprehensive pathway inhibition is a well-recognized strategy in oncology and antimicrobial pharmacology that requires no further motivation beyond Lamb’s own mechanistic framework. In re Ratti does not apply because combining agents 1 and 2 simultaneously does not change Lamb’s principle of operation — it directly implements Lamb’s core teaching that dual-subunit inhibition is mechanistically superior to single-subunit inhibition. The claimed composition does not require abandoning, reversing, or fundamentally modifying any teaching of Lamb; it is a direct and straightforward application of Lamb’s fundamental scientific disclosure.
C. Regarding Applicant’s Argument that DeFrancesco Teaches Only Sequential Administration:
Applicant argues that DeFrancesco’s [0009] protocol describes a sequential scheme (administer oxidative metabolism inhibitor → confirm glycolytic phenotype → administer glycolytic inhibitor) and therefore does not suggest the simultaneous co-administration of doxycycline and Vitamin C.
This argument is not persuasive. DeFrancesco is relied upon not for a specific co-administration protocol but for its mechanistic and pharmacological teaching: that Vitamin C functions as a glycolytic metabolism inhibitor that depletes glutathione, elevates ROS, and induces mitochondrial oxidative stress, and that this mechanism is synergistically effective when combined with doxycycline-mediated mitochondrial biogenesis inhibition (abstract; page 67270). The instant claims are drawn to a composition — not a method of sequential administration. Whether DeFrancesco administers its agents sequentially or simultaneously is irrelevant to the question of whether a PHOSITA would have been motivated to formulate a composition containing both agents. DeFrancesco expressly discloses that the combination of doxycycline (tetracycline-class) and Vitamin C is therapeutically beneficial against CSCs — this compositional teaching motivates the formulation of a co-delivery vehicle regardless of any sequential experimental validation protocol. The [0009] protocol is a confirmation methodology, not a limitation on compositional design.
Furthermore, the instant independent claims do not require simultaneous administration. Claims 1 and 35 are drawn to compositions, not methods. The administration sequence of a composition’s components is irrelevant to the composition’s patentability.
D. Regarding Applicant’s Evidence of Unexpected Results:
Applicant argues that the Office Action failed to consider evidence of unexpected results disclosed in the specification at paragraphs [0052]-[0053] and Table 1, and that this failure constitutes reversible error under In re Sullivan, 498 F.3d 1345 (Fed. Cir. 2007).
The examiner has considered Applicant’s specification data, including Table 1 and the associated description at paragraphs [0052]-[0053]. This evidence is insufficient to overcome the prima facie case of obviousness for the following reasons:
First, specification data alone does not constitute objective evidence of unexpected results comparable to a properly submitted declaration under 37 CFR 1.132. The specification is authored by the inventors and is not independent evidence. To constitute persuasive evidence of unexpected results, comparative data must compare the claimed composition against the closest prior art using appropriate controls, presented by an independent declarant or with sufficient procedural safeguards. Attorney argument and inventor-authored specification statements are insufficient to establish unexpected results without objective, independently verifiable evidence. In re Geisler, 116 F.3d 1465, 1470 (Fed. Cir. 1997); In re Baxter Travenol Labs., 952 F.2d 388, 392 (Fed. Cir. 1991); MPEP § 716.02(b). No such declaration has been submitted.
Second, and more fundamentally, the purported “unexpected” result — that simultaneous dual-subunit mitochondrial ribosomal inhibition combined with mitochondrial oxidative stress induction produces superior anti-CSC activity — is not unexpected in light of the prior art. It is mechanistically predicted by the prior art of record. Lamb expressly teaches that targeting both the large and small mitochondrial ribosomal subunits provides comprehensive inhibition of mitochondrial biogenesis across multiple tumor types. DeFrancesco expressly teaches that Vitamin C induces mitochondrial oxidative stress and that this mechanism is synergistically effective with mitochondrial biogenesis inhibitors against CSCs. A result that is the additive or synergistic combination of independently disclosed, mechanistically complementary effects is not unexpected — it is precisely what a PHOSITA would have predicted from the combined teachings of Lamb and DeFrancesco. In re Merck & Co., 800 F.2d 1091, 1099 (Fed. Cir. 1986) (unexpected results must be commensurate with the scope of the claims and truly unexpected in light of the prior art). The fact that the three-agent combination outperforms DeFrancesco’s two-agent combination is expected: adding a second mitochondrial biogenesis inhibitor targeting a distinct ribosomal subunit (per Lamb) to DeFrancesco’s doxycycline-Vitamin C combination predictably provides more complete mitochondrial biogenesis suppression, yielding greater anti-CSC activity. This is the additive result of combining known, complementary mechanisms — not an unexpected synergy.
Applicant is advised that if it wishes to pursue an unexpected results argument, a properly structured Rule 132 declaration comparing the claimed three-agent composition against each two-agent subset and against the single agents, in appropriate cancer stem cell model systems, would be required to establish that the results are both unexpected and commensurate in scope with the full breadth of the claims. MPEP § 716.02(f). The current specification data, without such comparative structure and independent declaration, does not meet this standard.
E. Regarding the “Consisting Essentially of” Amendment:
Applicant amended independent claims 1, 25, and 35 from “comprising” to “consisting essentially of.” This amendment has been considered. The “consisting essentially of” transition limits the claim to the recited elements plus those that do not materially affect the basic and novel characteristics of the invention. PPG Industries v. Guardian Industries Corp., 156 F.3d 1351, 1354 (Fed. Cir. 1998).
The basic and novel characteristic of the claimed composition, as Applicant has defined it (simultaneous targeting of the large mitochondrial ribosomal subunit, the small mitochondrial ribosomal subunit, and mitochondrial oxidative stress pathways), is taught in its entirety by the prior art of record. Each of the three functional modalities is independently taught — Lamb for dual-subunit inhibition, DeFrancesco and Zhou for oxidative stress induction via Vitamin C/ascorbyl palmitate. Accordingly, the “consisting essentially of” transition does not create patentability because the basic and novel characteristic is not novel over the prior art. The amendment does not change the § 103 analysis: regardless of whether the claimed composition “consists essentially of” or “comprises” the three active agents, all three active agents and their functional combination were taught and motivated by the prior art before the effective filing date.
Furthermore, the examiner notes that conventional pharmaceutical excipients, carriers, and diluents — which would typically and necessarily accompany any such therapeutic composition — do not materially affect the dual-subunit mitochondrial inhibition or oxidative stress induction mechanisms, and thus are not excluded by the “consisting essentially of” limitation. The prior art compositions (e.g., Zhou’s nanoparticle carrier matrix) function as delivery vehicles; the basic anti-CSC mechanism is determined entirely by the three active agents. Whether or not Steliou’s carnitinoid carrier molecules would be excluded by “consisting essentially of” does not affect the underlying obviousness of combining the three active agents — Steliou is relied upon only for the fatty acid conjugation teaching, not as a required carrier component.
Conclusion
No claims are allowed. The rejection under 35 U.S.C. § 103 is maintained as set forth above with the modifications to the role of Fanzi noted herein.
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/ANDRE MACH/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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