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 office action is a response to applicant’s communication submitted August 31, 2026, wherein claims 1 and 16 are amended and claims 9-11 are canceled. 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 1-8, 12-27, and 46-48 are pending in this application.
Claims 1-8, 12-27, and 46-48 as amended are examined on the merits herein.
Withdrawn Rejections
Applicant’s amendment, submitted August 31, 2026, with respect to the rejection of claims 9-11 under 35 USC 112(b) for indefinitely describing a “sub-antimicrobial” dosage of an antibiotic, has been fully considered and found to be persuasive to remove the rejection as claims 9-11 have been canceled. Therefore the rejection is withdrawn.
Applicant’s amendment and arguments, submitted August 31, 2026, have been fully considered. Consideration of figures 1B, 1C, and 2A-D, for example, indicates that there appears to be a superadditive effect of combining doxorubicin and azithromycin on markers of cellular respiration. This finding is sufficient evidence of secondary considerations to overcome the rejections of claims 1, 2, 9-13, 15, 19-27, ad 46 under 35 USC 103 for being obvious over Lamb in view of De Francesco, of claims 7 and 18 under 35 USC 103 for being obvious over Lamb in view of De Francesco in view of Sparey, of claim 8 under 35 USC 103 for being obvious over Lamb in view of De Francesco in view of Sparey in view of Zielonka, of claims 3-5 and 16 under 35 USC 103 for being obvious over Lamb in view of De Francesco in view of Bonner, and of claim 17 under 35 USC 103 for being obvious over Lamb in view of De Francesco in view of Bonner in view of Sawant, are withdrawn.
The rejection of claims 1-27 and 46-48 for claiming the same invention as claims 1-9, 11-17, and 28-30 is withdrawn in view of the terminal disclaimer submitted August 31, 2026.
The following new grounds of rejection are introduced:
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, 12, 13, 15, 19-27, and 46 are rejected under 35 U.S.C. 103 as being unpatentable over Lewis et al. (US pre-grant publication 2015/0191415, cited in PTO-1449 submitted 1/29/2024) in view of Levy et al. (US pre-grant publication 2015/0141381, cited in PTO-892)
Independent claim 1 is directed to a composition comprising a compound that targets the large mitochondrial ribosome, a compound that targets the small mitochondrial ribosome, and a compound that induces oxidative stress. Dependent claims 2, 12, and 13 and independent claim 46 more specifically define these compounds as azithromycin, doxycycline, and vitamin C. While claim 1 refers to the action of the compounds in senescent cells, this is an intended use and provides no specific further structural limitation that is not infringed by the three compounds themselves.
Lewis et al. discloses a method for treating diseases associated with aging, comprising administering to a subject a combination of a macrolide and a tetracycline. (p. 1 paragraphs 4-5) Macrolides usable in this method include azithromycin. (p. 2 paragraph 26) Tetracyclines include doxycycline. (p. 2 paragraph 27) In a particular embodiment the disease is associated with inflammation. (p. 1 paragraph 7) Specific disease associated with inflammation include for example ALS, Alzheimer’s disease, multiple sclerosis, atherosclerosis, and Parkinson’s disease. (p. 3 paragraphs 36-38) Lewis et al. further discloses a pharmaceutical composition comprising both a macrolide and a tetracycline. (p. 2 paragraph 11) Lewis et al. does not describe a composition further comprising vitamin C.
Levy et al. discloses a method for treating a disease comprising administering a tetracycline compound to the subject, having a structure which encompasses doxycycline. (p. 1 paragraphs 9-10) This compound is administered to treat an inflammatory condition (p. 2 paragraphs 32-34) Specific inflammatory conditions include for example neurological disorders such as multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, and ALS, (p. 2 paragraph 37) as well as arteriosclerosis and atherosclerosis. (p. 2 paragraph 32) Therefore Levy also describes using tetracyclines for treating many of the same inflammatory conditions described by Lewis. Levy further discloses that when the disease being treated is a neurological disease, neuroprotective agents can be included in the composition, for example vitamin C. (p. 8 paragraph 92)
It would have been obvious to one of ordinary skill in the art at the time of the invention to include vitamin C along with a macrolide (azithromycin) and a tetracycline (doxycycline) in a pharmaceutical composition according to Lewis, in order to treat neurological diseases. One of ordinary skill in the art would have found it to be obvious because Levy specifically describes combining vitamin C with doxycycline and discloses many of the same therapeutic indications as Lewis.
Regarding the specific intended use or mode of action (e.g. targets the large mitochondrial ribosome in senescent cells) recited in claim 1, these intended uses do not provide a further objective structural limitation to the composition and therefore are not seen to differentiate the claimed composition from one intended for treating e.g. Alzheimer’s disease as described by Lewis and Levy. Furthermore, as described in paragraph 14 on p. 8 of the present specification, mitochondrial inhibition is a property not just of the specific antibiotics doxycycline and azithromycin, but of tetracycline and macrolide antibiotics generally. Furthermore as evidenced by Duewelhenke et al. (Reference included with PTO-892) a variety of different antibiotics, including macrolides and tetracyclines generally, have the effect of inhibiting mitochondrial function.
Furthermore the arguments submitted August 31, 2026, regarding alleged unexpected results for the combination of azithromycin and doxycycline, these unexpected results are not persuasive to overcome the above rejection. Specifically, Applicant’s disclosure indicates that there exists a more-than-additive effect on cellular respiration caused by coadministration of certain concentrations of azithromycin and doxycycline. This fact does not overcome the prima facie case of obviousness because Lewis et al. already specifically describes coadministration of a macrolide and a tetracycline. Therefore the data described above from the present disclosure do not constitute a comparison with the closest prior art.
Regarding the table at the bottom of p. 28 of the present specification, while this table describes an unexpected benefit for simultaneous administration of doxycycline and azithromycin with vitamin C, without pretreatment by any subcombination of said agents, Levy already describes coadministration of vitamin C with tetracyclines and would not suggest pre- or post- treatment. Therefore this data is not a comparison with the closest art either.
Regarding claims 19-27, these claims describe potential effects of the composition. Since the claims are directed to a composition of matter rather than to a method of treating a particular subject population, a composition comprising azithromycin, doxycycline, and vitamin C would infringe these claims whether or not it is specifically described in the art as being useful for these specific purposes. Furthermore, certain recited limitations such as “increases at least one of organismal life-span and health-span,” in claim 24, and references to memory and mental acuity in claims 25-27, would clearly be met by a method of treating or ameliorating Alzheimer’s disease, for example, as described by Lewis and Levy.
For these reasons the claimed inventio nis seen to be prima facie obvious.
Claims 3-5 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Lewis et al. in view of Levy et al. as applied to claims 1, 2, 12, 13, 15, 19-27, and 46 above, and further in view of Bonner et al. (US pre-grant publication 2022/0001015, Reference of record in previous action)
The disclosures of Lewis and Levy are discussed above. Lewis in view of Levy 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 Lewis in view of Levy in view of Bonner as applied to claims 1-5, 12, 13, 15, 16, 19-27, and 46 above, and further in view of Sawant et al. (Reference included with PTO-892)
The disclosures of Lewis, Levy, and Bonner are discussed above. Lewis in view of Levy 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 Levy 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.
The following rejections of record in the previous action are maintained:
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, 12-15, 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. (of record in previous action, 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, 12-15, 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. (of record in previous action, 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, 2, 5, 7, 12-15, 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, of record in previous action, 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.
Response to Arguments
Applicant’s arguments, submitted August 31, 2026, with respect to the above grounds of rejection, have been fully considered and not found to be persuasive to remove the rejection. Applicant argues that the cited claims of ‘700, ‘111, and ’745 all do not disclose a composition of a first agent that targets the large mitochondrial ribosome, as a second agent that targets the small mitochondrial ribosome, and a third agent that induces mitochondrial oxidative stress. However, in all three rejections, the cited patent claims are directed to a composition or process involving a fatty acid conjugate of a macrolide such as azithromycin, which is, as admitted in Applicant’s disclosure, a compound targeting the large mitochondrial ribosome, and then suggests combinations with other senolytic agents, including both doxycycline and Vitamin C, which meet the requirements of the other two agents recited in the claims. Therefore the reference claims do in fact meet the requirements of the present claims even if they do not specifically recite the same biological functions for each agent that are given in present claim 1
Conclusion
Claims 1-5, 7, 12-27, 46, and 47 are rejected. Claims 6, 8, and 48 are objected to for depending from a rejected base claim but would be allowable if rewritten in independent form incorporating all the limitations of the rejected base claim and any intervening claims.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ANDREA OLSON whose telephone number is (571)272-9051. The examiner can normally be reached M-F 6am-3:00pm.
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/ANDREA OLSON/ Primary Examiner, Art Unit 1693 10/8/2026
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