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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 06/30/2025 has been entered.
Receipt of Applicants’ Remarks/Arguments and Amendments filed on 06/30/2025 is acknowledged.
Examiner clarifies that that previous Office Action filed 03/28/2025 is of Final status.
Claims 1-9,11-17, 25-30 and 33-39 are pending.
Claims 25-27, 33 and 34 are presently withdrawn from consideration based on applicant’s amendment filed on 09/11/2024 and 06/30/2025.
Claims 10, 18-24, 31, 32 and 40-57 are cancelled.
Claims 1, 2, 9, 35 and 36 are amended.
Claims 1-9,11-17, 28-30 and 35-39 are pending and are under examination in this application.
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 Fanzi (CN 101125126 A) in view of “Antibiotics that target mitochondria effectively eradicate cancer stem cells, across multiple tumor types: Treating cancer like an infectious disease” hereinafter the article is referred as Lamb, “Vitamin C and Doxycycline: A synthetic lethal combination therapy targeting metabolic flexibility in cancer stem cells (CSCs)” hereinafter referred as DeFrancesco, “Ascorbyl palmitate-incorporated paclitaxel-loaded composite nanoparticles for synergistic anti-tumoral therapy”, hereinafter the article is referred as Zhou, and further in view of Steliou (WO 2009/038656 A1).
Fanzi teaches medical frozen powder (injection) preparations (abstract) comprising erythromycin (azithromycin), tetracycline (minocycline) and vitamin C) (entire paragraph – 1. The scope of the present invention Example, and Claim 9). Notably, Fanzi discloses that the invention is applicable to any desired freeze-dried, freeze-drying and medical lyophilized powder process (top 3 lines of ¶ 1).
Regarding claims 1-3, 9, 11-13 and 16, as noted above, Fanzi teaches a composition comprising (a) erythromycin, (b) tetracycline and (b) Vitamin C. A
Lamb teaches treating cancer like an infectious disease, by repurposing FDA-approved antibiotics to eradicate cancer stem cells, in 12 different cancer cell lines, across 8 different tumor types comprising azithromycin and doxycycline (abstract). More specifically, the erythromycins selectively bind to the large subunit of the mitochondrial ribosome and inhibit mitochondrial biogenesis, by preventing the translation of mitochondrial proteins, mainly related to the mitochondrial OXPHOS complexes (Figure 1A) and similarly, the tetracyclines and glycylcyclines both bind with high affinity to the small subunit of the mitochondrial ribosome and inhibit mitochondrial biogenesis as well (Figure 1A) (page 4570, right column, last paragraph).
Regarding claims 1 and 2, Lamb teaches erythromycins selectively binds to the large subunit of mitochondrial ribosome and tetracyclines binds with high affinity to the small subunit of the mitochondrial ribosome and both (erythromycins and tetracyclines) inhibits mitochondrial biogenesis (page 4570, right column, last 2 paragraphs). Furthermore, Lamb discloses Azithromycin is a derivative of erythromycin (page 4572, left column, 1st paragraph) which corresponds to instant first therapeutic agent, and Doxycycline is a tetracycline derivative (page 4574, left column., 1st paragraph) corresponding to instant second therapeutic agent.
Regarding claims 6 and 8, as noted above, Lamb teaches derivative of tetracycline. Therefore, the limitation of the second therapeutic agent of the chemical structure of doxycycline is taught.
Regarding claims 9, Lamb teaches Doxycycline concentration and tested over the range of 50 µM to 500 µM, with little or no effects on cell viability (page 4581, Fig. 12), and Azithromycin were tested at 250 µM where p-value <0.001 (page 4580, Fig. 11). Therefore the recitation of at least one of azithromycin and doxycycline is sub-antimicrobial is taught.
Regarding claims 12 and 13, as noted above, Lamb teaches first therapeutic agent Azithromycin and second therapeutic agent Doxycycline.
Regarding claim 14, as noted above, Lamb teaches derivative of Erythromycin. Therefore, the limitation of the 1st therapeutic agent of the chemical structure of azithromycin is taught.
Regarding claim 16, as noted above, Lamb teaches azithromycin and doxycycline.
Regarding claim 35, as noted above, Lamb teaches a pharmaceutical composition for treating cancer.
Regarding claim 36, as noted above, Lamb teaches therapeutic agent Azithromycin, Doxycycline.
Regarding claim 37, as noted above, Lamb teaches Azithromycin and Doxycycline is sub-antimicrobial.
Lambs fails to specifically disclose Vitamin C and myristic acid and the combination of erythromycin and tetracycline.
DeFrancesco teaches eradication of cancers stem cells (CSCs) comprising doxycycline by targeting mitochondrial protein translation in combination with Vitamin C targeting glycolysis (abstract).
Regarding claims 1, 2 and 3, recitation of “a third therapeutic agent that induces oxidative stress”, DeFrancesco teaches doxycycline with Vitamin C, which functions to block glycolysis, inhibits glycolytic enzyme and depletes glutathione, resulting in mitochondria oxidative stress (page 67270, left column, last paragraph to right column, 1st paragraph).
Regarding claim 11, DeFrancesco teaches after oral administration, Vitamin C plasma levels reach concentration of ~70-220 µM (page 67280, left column, 1st paragraph). Therefore, overlaps the orally administration of instant Vitamin C concentration of 100 µM and 250 µM in at least blood, serum and plasma.
Regarding claim 15, as noted above, DeFrancesco teaches Vitamin C. the limitation of the 3rd therapeutic agent of the chemical structure of Vitamin C is taught.
Regarding claims 30 and 38, DeFrancesco teaches tetracycline (doxycycline) and Vitamin C (page 67270, left column, 3rd-4th paragraph).
DeFrancesco fails to teach encapsulation.
Zhou teaches a co-loaded drug delivery system based on encapsuling vitamin C (ascorbyl palmitate) and paclitaxel for synergistic cancer therapy (abstract).
Regarding claims 3 and 16, the recitation of the third therapeutic agent comprises at least one of Vitamin C and ascorbyl palmitate, Zhou teaches Vit C and ascorbyl palmitate (abstract).
Regarding claim 17, Zhou teaches Vitamin C derivative (ascorbyl palmitate) and paclitaxel dual-loaded composite solid lipid nanoparticles in a drug delivery system to improve the antitumoral effects of ascorbyl palmitate and decrease the side effects of paclitaxel (page 1232, paragraph 2.3 and page 1233, paragraph 3.1 Results & Discussion).
Steliou teaches a composition comprising (1) a class of chiral, non-racemic, synthetic carnitinoid analog earner molecules which constitute biocompatible transport compounds, (2) a subsequently formed, mitochondria targeting, coupled antioxidant-carrier complex comprising an antioxidant reversibly attached to and releasable from the synthetic carrier molecule, (3) a method for introducing a biologically active antioxidant into the interior of mitochondria of a living cell, and (4) a system for delivering a biologically active antioxidant to the interior of mitochondria of a living cell (Abstract).
Regarding claims 4, 28 and 39, Steliou teaches antioxidant compositions comprising short, medium and long chain fatty acids to include myristic acid (page 55-Table 1, and page 56-line 7).
Regarding claims 5 and 29, Steliou teaches Acylcarnitine is a high-energy linkage, fatty acid ester of carnitine that mediates the transfer of fatty acyl groups from the cytoplasm to the mitochondrial matrix for oxidation purposes (page 15, lines 1-30). Therefore, the limitation of at least one therapeutic acid conjugate with fatty acid moiety is taught.
Regarding claims 7, Steliou teaches Tri-phenyl-phosphonium (TPP) moiety (page 23, lines 10-13, and page 24 – lines 13).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the antibiotics (Azithromycin and Doxycycline) to target mitochondria to effectively eradicate cancer stem cells, across multiple tumor types, essentially treating cancer like an infectious disease as taught by Lamb, and use the antibiotics in combination as taught by Fanzi, and incorporate a third therapeutic agent Vitamin C, which functions to block glycolysis, inhibits glycolytic enzyme and depletes the cellular pool of glutathione, resulting in high Reactive Oxygen Species (ROS) and mitochondria oxidative stress as taught by DeFrancesco (page 67270, above Results paragraph), and further improving delivery of the composition comprising addition of encapsulating the composition as taught by Zhou and incorporating fatty acid moiety to mediate the transfer of fatty acyl groups from the cytoplasm to the mitochondrial matrix for oxidation purposes as taught by Steliou. One of ordinary skill in the art would have found it obvious to couple antioxidant - carnitinoid analog carrier complexes which are interchangeable surrogates of acyl CoA, and the prepared conjugated complexes can have as many as three antioxidants covalently bonded and reversibly attached to a synthetic carrier molecule to pass through both the outer and inner membranes of the mitochondria of a living cell as taught by Steliou (page 57, lines 17-25).
One would have been motivated to improve the composition for delivery to the mitochondria with the teachings of DeFrancesco, Zhou and Steliou. A person having ordinary skill in the art (PHOSITA) of chemical synthesis can prepare coupled complexes of the chosen antibiotics and antioxidants composition and each type of carnitinoid analog carrier using conventionally known synthesis methods and reaction procedures. One of ordinary skill in the art would have a reasonable expectation of success because all references are drawn to a composition and methods to improve delivery of a composition to a central nervous system, brain interstitium and and/or a spinal cord interstitium of a subject. It is obvious to combine prior art elements according to the known methods to yield predictable results. Please see MPEP 2141 (III)(A).
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Remarks/Arguments
Applicant’s Remarks/Arguments, filed 06/30/2025, with respect to the rejection(s) under 35 U.S.C. §103 are not persuasive. Therefore, the rejection under 35 U.S.C. §103 is maintained.
Applicant asserts that continued use of Fanzi (CN 101125126 A) does not teach or suggest a combination of claimed antibiotics.
Under broadest reasonable interpretation (BRI), Fanzi is relied upon for the teachings of pharmaceutical preparations comprising erythromycin (azithromycin), tetracycline (minocycline) and vitamin C). Therefore, the combination of these three components exists. Fanzi does teach and suggests the instantly claimed combination of active agents (e.g., per instant claim 2). However, as acknowledged in the rejection, there is no expressed anticipatory teachings of the three active ingredients together. The remaining non-patent references of record are relied upon by the Examiner to provide motivation to the skilled artisan to select those active ingredients of Fanzi. A person having ordinary skill in the art would be able to explore various formulations and combination comprising erythromycin (azithromycin), tetracycline (minocycline) and vitamin C) to achieve the desired outcome of the product or composition.
Applicant further asserts that Lamb in view of Zhou and further in view of Steliou does not provide any motivation or reason to combine. This is not persuasive and Examiner respectfully disagrees.
Applicant has amended claim 39 to require palmitic acid. Steliou teaches palmitic acid and their corresponding fatty acyl groups are individually and severally very desirable for use as antioxidant compositions (page 54, lines 25-27) and palmitic acid is exemplified in (Table 1, page 55).
Therefore, all elements of independent claims are taught in prior art of record. From the teachings of the combined references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Conclusion
No claims allowed.
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/ANDRE MACH/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615