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 .
Detailed Action
This application is a divisional application of US application 17/414853, now US patent 11918597, filed June 16, 2021, which is a national stage application of PCT/US2019/066553, filed December 16, 2019, which claims benefit of provisional applications 62/834794, filed April 16, 2019, 62/804411, filed February 12, 2019. And 62/780488, filed December 17, 2018. Claims 1-27 and 46-48 are pending in this application and examined on the merits herein. Applicant’s preliminary amendment submitted January 29, 2024, is acknowledged wherein claim 1 is amended and claims 28-45 and 49-51 are canceled.
Claim Objections
Claim 16 is objected to because of the following informalities: The word “ascorylb,” which is a misspelling of “ascorbyl”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 9-11 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.
Claims 9 and 10 are directed to pharmaceutical compositions containing azithromycin and doxycycline. The claims furthermore contain limitations requiring that the concentration of one or both of these compounds is sub-antimicrobial. However, since the claims are directed to a composition of matter rather than to an actual process of treating a subject, there is no clear definition of what an antimicrobial concentration of each of these compounds is. In actual use, an antibiotic is present in a dosage form in a particular amount, which is then administered to a subject. The actual concentration of the antibiotic achieved during therapy depends on the species and size of the subject, the route of administration, and the frequency of administration. Whether this concentration constitutes an antimicrobial concentration depends on the particular species of microbe is being targeted. Since all of these factors presuppose elements of a process, they cannot be discerned when the invention is a composition of matter, rendering these claims indefinite.
Claim 11 requires that the composition comprises vitamin C administered orally at a concentration sufficient to achieve a particular peak blood, serum, or plasma concentration. For similar reasons this dosage cannot be clearly determined without defining the subject to whom it is administered, particularly species and size. Therefore this claim is indefinite as well.
Claim Rejections - 35 USC § 103
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.
Claims 1, 2, 9-13, 15, 19-27, and 46 are rejected under 35 U.S.C. 103 as being unpatentable over Lamb et al. (Reference cited in PTO-1449) in view of Francesco et al. (Reference cited in PTO-1449)
Independent claim 1 claims a composition comprising an agent that targets the large mitochondrial ribosome, an agent that targets the small mitochondrial ribosome, and an agent that induces mitochondrial oxidative stress. While the composition is described as an “anti-aging composition,” this statement of intended use in the preamble does not impose any particular structural limitation on the composition that would differentiate it from any other composition containing the same active ingredients. Furthermore this intended use is very broad, and could refer to an ability of the composition to treat or prevent any condition whose incidence increases with increasing age, for example cancer. Dependent claims 2, 12, 13, 15, and independent claim 46 claim compositions wherein the three agents are azithromycin, doxycycline, and vitamin C.
Lamb et al. discloses that cancer risk is driven by a population of cancer stem cells that are dependent on mitochondrial biogenesis. (p. 4570 left column fifth and sixth paragraphs) Lamb et al. further discloses a survey of several classes of mitochondrially targeted antibiotics that can be useful for eliminating these cancer stem cells. (p. 4750 right column first paragraph) Antibiotics that were found to be effective in inhibiting cancer cell growth include azithromycin (p. 4572) and doxycycline. (pp. 4573-4574) While Lamb et al. does not specifically describe a pharmaceutical composition comprising both azithromycin and doxycycline, it would have been obvious to one of ordinary skill in the art at the time of the invention to make a pharmaceutical composition comprising both of these agents. One of ordinary skill in the art would have found this to be obvious based on a rationale of combining two agents known to be useful for treating the same subject population.
Lamb et al. additionally does not disclose compositions further comprising vitamin C. However, Francesco et al. discloses that cancer stem cells can develop resistance to doxycycline by reverting to a glycolytic phenotype, but that these cells can be more effectively treated with other metabolic inhibitors including vitamin C. (p. 67270 left column fifth paragraph – right column first paragraph, p. 67275 left column third paragraph – right column last paragraph) Francesco et al. therefore suggests administering these two agents together to produce synthetic lethality. (p. 67276 right column first and second paragraphs) Therefore it would also have been obvious to one of ordinary skill in the art at the time of the invention to add vitamin C to an azithromycin/doxycycline composition for eradicating cancer stem cells. One of ordinary skill in the art would have seen the disclosure of Lamb et al. as suggesting that this would improve the efficacy of the composition and inhibit the development of resistance to doxycycline.
Regarding claims 9-11, as discussed previously under 35 USC 112(b) the limitations recited in these claims do not define a specific dosage amount for any of the recited agents, since the resulting therapeutic concentration would be relative to the particular subject and frequency of administration. Therefore these claims do not provide meaningful further limitations that would distinguish the claimed invention from the aforementioned prior art.
Regarding claims 19-27, these claims recite various intended uses of the composition. Since the claimed invention is a composition of matter that could potentially be used as a therapeutic agent, rather than a method of treating a disease, the intended uses do not provide further structural limitations to the pharmaceutical composition, so ling as it is suitable for administration to a subject. Additionally, claims 19 and 20 relate to anti-cancer activity and claim 24 broadly describes an increase in life-span and health-span, which could be infringed by any treatment of a potentially lethal disease.
For these reasons the invention taken as a whole is prima facie obvious.
Claims 7 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Lamb et al. in view of Francesco et al. as applied to claims 1, 2, 9-13, 15, 19-27 and 46 above, and further in view of Sparey et al. (PCT international publication WO2018/193116, Reference cited in PTO-1449)
The disclosures of Lamb and Francesco are discussed above. Lamb in view of Francesco does not disclose a composition wherein one of the therapeutic agents is a conjugate with TPP. (triphenylphosphine)
Sparey et al. discloses that conjugation of azithromycin to a phosphonium ion increases its activity against cancer cells. (p. 2 paragraph 10) The specific conjugates disclosed (p. 3 paragraph 13) include phosphonium groups attached to three variables R1a-1c which are defined as unsubstituted phenyl. (p. 4 line 15) Therefore these are considered to be conjugates with TPP or a TPP derivative as recited in claim 18.
It would have been obvious to one of ordinary skill in the art at the time of the invention to use a TPP conjugate such as that described by Sparey et al. in place of azithromyxin in the compositions described by Lamb and Francesco. One of ordinary skill in the art would have found this to be obvious as Sparey suggests that this conjugation improves the anti-cancer activity of this agent, thereby suggesting a motivation of applying a known improvement to a prior art invention ready for improvement.
Therefore the invention taken as a whole is prima facie obvious.
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Lamb et al. in view of Francesco et al. in view of Sparey et al. as applied to claims 1, 2, 7, 9-13, 15, 18-27 and 46 above, and further in view of Zielonka et al. (Reference cited in PTO-1449)
The disclosures of Lamb, Francesco, and Sparey are discussed above. Lamb in view of Francesco in view of Sparey does not disclose a composition wherein both of the erythromycin and tetracycline compounds are conjugated with TPP. (triphenylphosphine)
However, Zielonka et al. discloses that there is a need for mechanisms to target therapeutic agents to mitochondria. (p. 10045 left column first paragraph) This can be accomplished by chemically conjugating an active agent to a triphenylphosphine targeting moiety. (p. 10045 section 2.1 and figure 1) Zielonka et al. discloses a number of specific TPP conjugated molecules. (p. 10046 figure 2)
It would have been obvious to one of ordinary skill in the art at the time of the invention to conjugate both the azithromycin and doxycycline in the aforementioned compositions (Lamb in view of Francesco) with TPP, in view of the disclosures of Sparey and Zielonka. One of ordinary skill in the art would have found it to be obvious to use these conjugates because the cited references indicate that they would be expected to be more effective at targeting mitochondria, which is the mechanism by which these compounds work according to Lamb.
Therefore the invention taken as a whole is prima facie obvious.
Claims 3-5 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Lamb et al. in view of Francesco et al. as applied to claims 1, 2, 9-13, 15, 19-27 and 46 above, and further in view of Bonner et al. (US pre-grant publication 2022/0001015, Reference cited in PTO-1449)
The disclosures of Lamb and Francesco are discussed above. Lamb in view of Francesco does not disclose a composition wherein one or both of the therapeutic agents is a conjugate with a fatty acid such as myristic acid.
Bonner et al. discloses that lymphatic transport of orally administered drugs avoids first-pass metabolism. (p. 1 paragraph 4) Bonner et al. further discloses conjugates of a parent drug to a lipid to promote lymphatic transport. (p. 2 paragraphs 32-34) These prodrugs are transported by the lymphatic system, and release the parent compound in systemic circulation without first-pass metabolism by the liver, resulting in improved oral bioavailability. (p. 4 paragraph 67) Fatty acids usable in these conjugates include myristic acid. (p. 68 paragraph 256) Therapeutic agents usable as the parent compound include both azithromycin and doxycycline. (p. 98 paragraph 303) It would have been obvious to one of ordinary skill in the art at the time of the invention to administer the azithromycin and doxycycline active agents described by Lewis et al. as fatty acid conjugates of the type described by Bonner et al. One of ordinary skill in the art would have found this modification to be obvious because it consists of applying a known improvement to an existing product, and would be expected to predictably improve the oral bioavailability of azithromycin and doxycycline in the method described by Lamb et al.
Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over Lamb in view of Francesco in view of Bonner as applied to claims 1-5, 9-13, 15, 16, 19-27, and 46 above, and further in view of Sawant et al. (Reference included with PTO-892)
The disclosures of Lamb, Francesco, and Bonner are discussed above. Lamb in view of Francesco in view of Bonner does not disclose a composition wherein the vitamin C is ascorbyl palmitate and the composition is a liposomal composition.
Firstly, it is noted that Bonner suggests that the compounds can be prepared for extended absorption in a liposomal delivery system. This would have suggested to one of ordinary skill in the art that the composition can be prepared as a liposome.
Additionally, Sawant et al. discloses that Palmitoyl ascorbate (ascorbyl palmitate) is a stable alternative to free ascorbate that can be incorporated into liposomes and is known to accumulate in tumors. (p. 302 left column second paragraph) It would have been obvious to one of ordinary skill in the art at the time of the invention to use ascorbyl palmitate, such as liposomal ascorbyl palmitate, as the vitamin C source in pharmaceutical compositions containing doxycycline and ascorbyl palmitate as described by Francesco et al. One of ordinary skill in the art would have seen the disclosure of Sawant et al. as suggesting that using liposomal ascorbyl palmitate as a vitamin C source for treating cancer would be superior to using free ascorbic acid, for example because of improves stability and tumor accumulation.
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 1, 2, 5, 7, 9-15, 18-27, 46, and 47 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 and 10-14 of U.S. Patent No. 11957700. (Cited in PTO-892, herein referred to as ‘700) Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of ‘700 suggest the presently claimed compositions.
Specifically, claims 1-5 of ‘700 claim a senolytic composition comprising a fatty acid conjugate of a macrolide which are the same first therapeutic agents (e.g. azithromycin) recited in present claim 1, as well as myristic acid conjugates and specific structures as recited in claims 14 and 47. Dependent claim 6 of ‘700 further specifies that the composition contains an additional senolytic agent. Claims 7 and 10 describe this additional agent as selected from a list including doxycycline, TPP conjugates, and vitamin C, which are second and third agents as recited in present claim 1 and present dependent claims 2, 7, 9-11, 15, and 18. Therefore it would have been obvious to one of ordinary skill in the art at the time of the invention to produce a combination including all of the aforementioned additional active agents (e.g. doxycycline and vitamin C) One of ordinary skill in the art would have seen a triple combination of three agents to be obvious because claim 6 of ‘700 and its dependent claims already suggest making a composition of the macrolide compound with any of the recited additional active agents, thereby suggesting that more than one of said additional agents could be added as well.
Claims 1, 2, 5, 7, 9-15, 18-27, 46, and 47 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 7, and 8 of U.S. Patent No. 12208111. (Cited in PTO-892, herein referred to as ‘111) Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of ‘111 suggest the presently claimed compositions.
Specifically, claims 1-4 of ‘111 claim a method of inducing death of senescent cells comprising administering to a subject a fatty acid conjugate of a macrolide which are the same first therapeutic agents (e.g. azithromycin) recited in present claim 1, as well as myristic acid conjugates and specific structures as recited in claims 14 and 47. Dependent claims 5, 7, and 8 of ‘111 further specifies that the composition contains an additional senolytic agent, which is selected from a list including doxycycline, TPP conjugates, and vitamin C, which are second and third agents as recited in present claim 1 and present dependent claims 2, 7, 9-11, 15, and 18. Therefore it would have been obvious to one of ordinary skill in the art at the time of the invention to produce a combination including the macrolides recited in claims 1-4 of ‘111 as well as the various additional active agents (e.g. doxycycline and vitamin C) that are recited in the dependent claims. One of ordinary skill in the art would have seen a triple combination of three agents to be obvious because the claims of ‘111 already suggest administering all of these compounds together, thereby suggesting that more than one of said additional agents could be added as well.
Claims 1-27 and 46-48 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9, 11-17, and 28-30 of copending Application No. 17/414842 (reference application, US pre-grant publication 2022/0040316, cited in PTO-892, herein referred to as ‘842). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of ‘842 anticipate the present claims. Specifically, claim 1 of ‘842 claims a composition of an erythromycin or fatty conjugate thereof, a tetracycline or fatty acid conjugate thereof, and vitamin C or ascorbyl palmitate. Dependent claim 4 further defines the fatty acid as myristic acid. These are the same active ingredients recited in the compositions of present claims 1-5, 12, 13, 15, 16, and 46. Furthermore claims 6 and 14 of ‘842 recite the same specific structures recited in present claims 6, 14, 47, and 48. Regarding present claims 7, 8, and 18, claim 7 of ‘842 specifically describes one or both of the first and second active agent (i.e. the erythromycin and tetracycline) are conjugated to TPP. Regarding present claims 9-11, claims 9 and 11 of ‘842 recited the same additional limitations. Regarding present claim 17, claim 17 of ‘842 specifies the same additional limitations. Regarding present claims 19-27, these claims merely describe an intended use of the composition and do not provide any further objective structural limitations to the claimed composition.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 2, 5, 7, 9-15, 18-27, 46, and 47 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 51-53, 55, and 56 of copending Application No. 17/987745 (reference application, US pre-grant publication 2025/0120994, cited in PTO-892, herein referred to as ‘745). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of ‘745 suggest the presently claimed compositions.
Specifically, claims 51 and 52 of ‘745 claim a pharmaceutical composition comprising a myristic acid conjugate of a macrolide which are the same first therapeutic agents (e.g. azithromycin) recited in present claims 1 and 2, as well as specific structures as recited in claims 14 and 47. Dependent claims 53, 55, and 56 claim compositions of this compound with additional active agents including doxycycline, TPP conjugates, and vitamin C, which are second and third agents as recited in present claim 1 and present dependent claims 2, 7, 9-11, 15, and 18. Therefore it would have been obvious to one of ordinary skill in the art at the time of the invention to produce a combination including all of the aforementioned additional active agents (e.g. doxycycline and vitamin C) One of ordinary skill in the art would have seen a triple combination of three agents to be obvious because the claims of ‘745 already suggest making a composition of the macrolide compound with any of the recited additional active agents, thereby suggesting that more than one of said additional agents could be added as well.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed in this action.
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/ANDREA OLSON/ Primary Examiner, Art Unit 1693 3/27/2026