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 .
Election/Restrictions
Applicant’s election without traverse of Group (I) with the addition of compound
PNG
media_image1.png
284
748
media_image1.png
Greyscale
as the elected compound species in the reply filed on 10/28/2024 is acknowledged and maintained.
Priority
This application is a 371 of PCT/JP2020/012498, filed March 19, 2020, which claims the benefit of Japanese Patent Application No. 2019-053528, filed March 20, 2019.
Claims Status
Acknowledgement is made of the receipt and entry of the amendment to the claims filed on December 01, 2025.
Claims 11-22, 25-29, and 32-34 are pending. Claims 1-10, 23-24, and 30-31 are canceled. Claims 11-12, 25-29, and 33 are withdrawn. It is noted that formula III which represents structure III and formula IV which represents structure IV in claim 32 do not read on the elected species. Claims 13-22, 32, 34 are examined in accordance to the elected species.
Action Summary
Claims 13-16 and 32 rejected under 35 U.S.C. 103 as being unpatentable over by Yano (US2015/0191571 A1) in view of Sparey et al (WO2018/193114A1) and Zielonka et al (PNAS, January 29, 2013, vol. 110, no. 5, pages 1863–1868), are maintained, but revisited and modified to include new claim 34.
Claims 13-22 and 32 rejected under 35 U.S.C. 103 as being unpatentable over by Yano (US2015/0191571 A1) in view of Sparey et al (WO2018/193114A1) and Zielonka et al (PNAS, January 29, 2013, vol. 110, no. 5, pages 1863–1868) as applied to claims 13-16, and 32 in further view of Lind (US6,579,857 B1) and Shi et al (Cancer Res. 2011 July 1; 71(13): 4518–4526), are maintained.
Applicant’s argument requesting to correct the record that Zielonka et al (Chem Rev. 2017, 117, 10043-10120) is the correct citation is persuasive. The examiner contends that Zielonka et al (Chem Rev. 2017, 117, 10043-10120) is the correct citation as the third reference cited in the rejections set forth below. The citation of the 2013 PAS article was apparently made in error.
Affidavit
The Declaration by Dr. Hiroki Nagase under 37 CFR 1.132 filed 12/08/2025 is insufficient to overcome the rejection of claims 13-22, 32, 34. The Declarant argues that a skilled person would consider the doxycycline and other tetracycline analogs disclosed in Sparey to be small molecules. A skilled person would also consider the claimed PIP-TPP conjugates to be macromolecules, and clearly not small molecules. Furthermore, a skilled person would not consider the clinical effect of linking a TTP group to small molecules such those mentioned in Zielonka to predict the clinical effect of linking a TTP group to a macromolecule such those currently claimed.
In response, the Declarant’s argument is not persuasive. Just because doxycycline and other tetracycline analogs are not considered to be small molecules does not mean a skilled person cannot used a triphenylphosphonium ion linker for the compound taught by Yano. Specifically, Yano teaches the polyamide compound is used for promoting replication of wild-type mitochondrial DNA and as a pharmaceutical composition. (See claims 4 and 5.) Sparey teaches the compounds having a phosphonium ion linked to a tetracycline antibiotic are able to modulate cancer cell metabolism in cancer cell lines and, accordingly, prevent and/or treat cancer. (See paragraph [0004].) Zielonka teaches mitochondria are recognized as one of the most important targets for new drugs in cancer, cardiovascular, and neurological diseases and currently, the most effective way to deliver drugs specifically to mitochondria is by covalent linking a lipophilic cation such as alkyltriphenylphosphonium to a pharmacophore of interest. (See Abstract.) The compounds of Sparey and Yano are considered pharmacophore of interest as both small or large are drawn to cancer therapy. Zielonka also teaches the TPP+ cations are utilized to deliver the probes, antioxidants, and pharmacophore to mitochondria and that anatomy is as follow:
PNG
media_image2.png
448
746
media_image2.png
Greyscale
and
PNG
media_image3.png
398
222
media_image3.png
Greyscale
. (See figures 1 and 2, and Section 2.1) Zielonka teaches the increased uptake and retention of lipophilic cations provides a rationale not only for the development of new, more selective anticancer drugs, but also for the imaging agents allowing for early detection and localization of tumors using a variety of imaging modalities, including MRI, PET, and fluorescence. TPP+-linked imaging agents show the potential for imaging early tumors that are not detectable by palpation in animal models. (See fourth paragraph of the left column of page 10098.) Furthermore, Zielonka teaches the advantages of TPP+-based mitochondrial targeting over other approaches for mitochondrial delivery of small molecules including the stability of TPP+ moiety in biological systems, a combination of lipophilic and hydrophilic property, low chemical reactivity toward cellular components, and relatively safe in human. (See left column of page 10046.) A skilled person looking to enhance the delivery of the polyamide compound taught by Yano to the mitochondria for the treatment of cancer would look into the cancer art for specific linker such as the triphenylphosphonium ion linker taught by Sparey or TPP+-based mitochondrial targeting taught by Zielonka by linking said TTP ion linker to the compound 12 of Yano at the R4-R5 position. Therefore, a skilled person would reasonably consider the clinical effect of linking a TTP group to small molecules such those mentioned in Zielonka and Sparey to predict the clinical effect of linking a TTP group to a macromolecule such those taught by Yano because Yano clearly teaches R4-R5 can vary and also because the increased uptake and retention of lipophilic cations provides a rationale not only for the development of new, more selective anticancer drugs, but also for the imaging agents allowing for early detection and localization of tumors using a variety of imaging modalities, including MRI, PET, and fluorescence. TPP+-linked imaging agents show the potential for imaging early tumors that are not detectable by palpation in animal models, and lastly because both Zielonka and Yano are drawn to mitochondrial targeting therapies for the treatment of cancer.
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.
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 non-obviousness.
Claims 13-16, 32, and 34 remain rejected under 35 U.S.C. 103 as being unpatentable over by Yano (US2015/0191571 A1) in view of Sparey et al (WO2018/193114A1) and Zielonka et al (Chem Rev. 2017, 117, 10043-10120).
Yano teaches a polyamide compound binding to a target double-stranded DNA, wherein said target double-stranded DNA comprises at least one nucleotide pair, where the polyamide compound is compound 7
PNG
media_image4.png
472
910
media_image4.png
Greyscale
wherein, R' is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxyl group, an amino group, a carboxyl group, or an acyl group having 1 to 4 carbon atoms,
R2 is independently a hydrogen atom, or a hydroxyl group,
R3. R6. and R7 are independently a hydrogen atom, an amino group, or NH R is a single bond or B-alanine residue,
R5 is a hydroxyl group, or N-dimethylaminopropyl residue, and the hydrogen atom of the Im residue, Py residue. Hp residue, B residue, Y-aminobutyric acid residue, or (R)2,4-diaminobu tyric acid residue may be substituted with an alkyl group having 1 to 4 carbon atoms, an amino group, a hydroxyl. (See page 18.) The polyamide compound can be used for treating mitochondrial genetic diseases caused by mutation of the mitochondrial (mt)DNA. (See Abstract.) Additionally, Yano exemplified the following compound 12:
PNG
media_image5.png
494
1142
media_image5.png
Greyscale
. As one of the preferred polyamide compounds (See claims 1, 2, and 3, and page 65). Yano teaches the polyamide compound is used for promoting replication of wild-type mitochondrial DNA and as a pharmaceutical composition. (See claims 4 and 5). The polyamide compounds can be formulated as an injection. (See paragraph [0092].)
Yano does not teach the elected compound species.
PNG
media_image1.png
284
748
media_image1.png
Greyscale
Sparey teaches a compound of formula (I) as derivatives of tetracycline antibiotics, e.g., doxycycline, having a phosphonium cation tethered to the tetracycline tetracycle that is useful as cancer therapies. (See Abstract.) Moreover, Sparey teaches
PNG
media_image6.png
226
764
media_image6.png
Greyscale
as one of preferred compounds of the formula (I). (See paragraph [00212].) Furthermore, Sparey teaches that the compounds of the invention may reduce, disrupt, or inhibit the growth or proliferation of a cancer cell or it may induce the death of a cancer cell. As such, cancer cell metabolism, and reducing cell proliferation, is a potential target for disrupting cancer growth and ultimately a therapeutic pathway for cancer treatment. (See paragraph [0003].) The compounds having a phosphonium ion linked to a tetracycline antibiotic are able to modulate cancer cell metabolism in cancer cell lines and, accordingly, prevent and/or treat cancer. (See paragraph [0004].)
Zielonka teaches the use of mitochondria-targeted triphenylphosphonium (TPP+)-based compound for therapeutic and diagnostic application and for the treatment of cancer. (See Title and Abstract.) Moreover, Zielonka teaches the TPP+ cations are utilized to deliver the probes, antioxidants, and pharmacophore to mitochondria and that anatomy is as follow:
PNG
media_image2.png
448
746
media_image2.png
Greyscale
and
PNG
media_image3.png
398
222
media_image3.png
Greyscale
. (See figures 1 and 2, and Section 2.1) Furthermore, Zielonka teaches the advantages of TPP+-based mitochondrial targeting over other approaches for mitochondrial delivery of small molecules including the stability of TPP+ moiety in biological systems, a combination of lipophilic and hydrophilic property, low chemical reactivity toward cellular components, and relatively safe in human. (See left column of page 10046.)
It would have been prima facie obvious to one of ordinary skill in the art as well at the time the invention as made to select compound 12 and modify said compound by replacing the pyrrole-imidazole polyamide core having 12 rings with the 10 rings system of the compound 7 and replacing the acyl group (CH3C(O)-) moiety with
PNG
media_image7.png
254
338
media_image7.png
Greyscale
taught by Sparey to give Applicant’s claimed compound. One would have been motivated do so, is because not only Yano teaches pyrrole-imidazole polyamide core having 7 and 12 rings are interchangeable, but also because Sparey teaches tetracycline antibiotic derivatives having TPP+ moiety such as
PNG
media_image7.png
254
338
media_image7.png
Greyscale
reduce, disrupt, or inhibit the growth or proliferation of a cancer cell or it may induce the death of a cancer cell, and also because Zielonka teaches the advantages of TPP+-based mitochondrial targeting anatomy
PNG
media_image3.png
398
222
media_image3.png
Greyscale
over other approaches for mitochondrial delivery of small molecules include the stability of TPP+ moiety in biological systems, a combination of lipophilic and hydrophilic property, low chemical reactivity toward cellular components, and relatively safe in human for cancer therapy. As such, one would reasonably expect the modified compound to successfully delivery the mitochondria targeting moiety taught by Yano for treating cancer.
With respect to the following limitations “a pharmaceutical composition that binds to a mitochondrial disease-related mitochondrial DNA sequence” and “the pharmaceutical composition is an anticancer agent” limitations. Said limitations are not expressly taught by the prior art references in combination. However, the fact that the elected compound species are obvious over the compound taught by the combination of the prior art references, said limitations are necessarily present. Products of identical chemical composition cannot have mutually exclusive properties. In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).
Claims 13-22, 32, and 34 remain rejected under 35 U.S.C. 103 as being unpatentable over by Yano (US2015/0191571 A1) in view of Sparey et al (WO2018/193114A1) and Zielonka et al (Chem Rev. 2017, 117, 10043-10120) as applied to claims 13-16, 32, and 34 in further view of Lind (US6,579,857 B1) and Shi et al (Cancer Res. 2011 July 1; 71(13): 4518–4526).
The teachings of Yano, Sparey, and Zielonka have been discussed above.
Yano, Sparey, and Zielonka collectively do not teach a kit and a cytocidal drug in this case Navitoclax.
Lind teaches a kit that includes each therapeutic agent packaged together in dosage form adds convenience to medical practitioners. Separate packaging of the two compositions permits administration by separate routes, at separate times, and/or at separate rates. Separate packaging also permits formulating each composition uniquely, e.g., with its own carriers and preservatives, to optimize shelf life and the like. (See lines 29-38 of column 9.)
Shi teaches combination treatment with Navitoclax and a spindle specific anti-mitotic, such as a Kinesin-5 inhibitor, might be more effective than paclitaxel alone. (See Abstract.)
It would have been prima facie obvious for a person of ordinary skill in the art at the time of the invention was filed to combine the method disclosed by the combination of Yano, Sparey, and Zielonka with the method set forth by Shi along to package both method into a Kit because each is taught by the prior art to be useful for the same purpose (i.e., cancer) and also because Lind teaches a kit that includes each therapeutic agent packaged together in dosage form adds convenience to medical practitioners and separate packaging of the two compositions permits administration by separate routes, at separate times, and/or at separate rates. See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). Further, a person of ordinary skill in the art would reasonably have expected to be successful because both compositions were shown to be useful separately for the exact same purpose and thus would be expected to be similarly useful when used together. The obvious Kit is capable of being used as a research reagent and diagnosis. While none of the references teaches Navitoclax is a cytocidal drug, the teaching of the same drug necessarily implies navitoclax is a cytocidal drug absent evidence to the contrary.
Yano teaches pyrrole-imidazole polyamide core having 7 and 12 rings are interchangeable. Sparey teaches tetracycline antibiotic derivatives having TPP+ moiety such as
PNG
media_image7.png
254
338
media_image7.png
Greyscale
reduce, disrupt, or inhibit the growth or proliferation of a cancer cell or it may induce the death of a cancer cell. Zielonka teaches the advantages of TPP+-based mitochondrial targerting anatomy
PNG
media_image3.png
398
222
media_image3.png
Greyscale
over other approaches for mitochondrial delivery of small molecules include the stability of TPP+ moiety in biological systems, a combination of lipophilic and hydrophilic property, low chemical reactivity toward cellular components, and relatively safe in human for cancer therapy. As such, one would reasonably expect the selection of compound 12 and the modification of said compound by replacing the pyrrole-imidazole polyamide core having 12 rings with the 10 rings system of the compound 7 and replacing the acyl group (CH3C(O)-) moiety with
PNG
media_image7.png
254
338
media_image7.png
Greyscale
to successfully delivery the mitochondria targeting moiety taught by Yano for treating cancer.
Acknowledgement is made of the receipt and entry of Applicant’s remark filed on December 01, 2025.
Applicant’s argument (rejection based on Yano in view of Sparey)
Applicant argues that examples 1-20 on pages 55-68 describe twenty compounds of formula I wherein a doxycycline core is bound to a TPP moiety through an alkyl linker comprising one or two carbamoyl groups. In a section entitled "Inhibition of proliferation assay" starting on page on 69, Sparey discloses an experiment in which a confluence value was assigned to doxycycline at a concentration of 10 µM. The confluence value is defined as a percent that represents the fraction of a culture dish surface that is occupied by cells. See paragraph 00218 of Sparey. The confluence values of doxycycline and the twenty example compounds in Sparey are showed in the table on page 70. Exhibit A below
PNG
media_image8.png
866
656
media_image8.png
Greyscale
PNG
media_image9.png
440
644
media_image9.png
Greyscale
the signature line of this response lists the confluence values of examples 1-20 from the table in Sparey and also indicates (i) the carbamoyl group that links the TPP to the doxycycline core on the terminal phenyl ring, (ii) the position of the carbamoyl group on the terminal phenyl ring relative to the hydroxy group, and (iii) the anion of the phosphonium salt. The confluence values of only seven of the twenty example compounds listed in exhibit A are more than 50 % lower than that of doxycycline (examples 1, 5, 6, 7, 11, 19, and 20); four of the twenty example compounds showed no or little improvement in the confluence values (examples 3, 8, 10, and 12); and three of the twenty example compounds had significantly higher confluence values than doxycycline (4, 15, and 16). Moreover, there are no trends that would lead a skilled person to other advantageous doxycycline analogs, afortiori, any PIP macromolecules.
Examiner’s response
In response, Applicant’s argument is not persuasive. It may well be true that some of the doxycycline compounds containing doxycycline core bound to a TPP moiety through an alkyl linker had significantly higher confluence values than doxycycline and some show no or little improvement while others are more than 50% lower than doxycycline. However, the Examiner contends that percent confluence (the percentage of the surface area of a culture vessel covered by cells) is a measure of cell density and population, whereas mitochondrial delivery which forms the basis for the rejection refers to the efficiency of getting a therapeutic agent. Nothing in Sparey that discourages from using the alkyltriphenylphosphonium moiety for delivering doxycycline to the mitochondria or any other compounds. Testing inhibition of proliferation through percent confluence does not appear to be a test for targeting mitochondria although it could indirectly be linked to mitochondrial dysfunction as an inference. In fact, Sparey did not pair the percent confluence with the more targeted mitochondrial assays that would give a more comprehensive understanding of how the compound affect the cells. Again, the fact that Yano teaches the polyamide compound is used for promoting replication of wild-type mitochondrial DNA and as a pharmaceutical composition, the fact that Sparey teaches the compounds having a phosphonium ion linked to a tetracycline antibiotic are able to modulate cancer cell metabolism in cancer cell lines and, accordingly, prevent and/or treat cancer, and the fact that Zielonka teaches mitochondria are recognized as one of the most important targets for new drugs in cancer, cardiovascular, and neurological diseases and currently, the most effective way to deliver drugs specifically to mitochondria is by covalent linking a lipophilic cation such as alkyltriphenylphosphonium to a pharmacophore of interest, a person of ordinary skill in the art would reasonably expect linking the alkyltriphenylphosphonium taught by Sparey to the polyamide compound 12 taught by Yano to give a compound capable of delivering compound 12 to mitochondria for treating cancer successfully.
Applicant’s argument (rejection based on Yano in view of Zielonka)
Applicant argues that Zielonka does not suggest any advantages of TPP+-based mitochondrial targeting of molecules other than small molecules, such as macromolecules. Zielonka clearly distinguishes "small molecules" from "macromolecules." See page 10048, left column, section 2.4, lines 8-10 of Zielonka ("Mitochondriotropic liposomes were proposed as efficient carriers of both small molecules and macromolecules to mitochondria.") In the opinion of a present inventor and an expert in the field, a skilled person would consider the doxycycline and other tetracycline analogs disclosed in Sparey to be small molecules, as is attested to in the declaration that will be submitted shortly. As will also be attested to in the declaration, a skilled person would consider the presently claimed PIP-TPP conjugates to be macromolecules, and clearly not small molecules.
Examiner’s response
In response, Applicant’s argument is not persuasive. Clearly, Zielonka teaches preclinical studies have shown that mitochondria-targeted agents including MitoQ protect against doxorubicin-induced cardiotoxicity and cisplatin-mediated nephropathy in animal models. (See third paragraph of Section 9 of page 10097.) Zielonka teaches the increased uptake and retention of lipophilic cations provides a rationale not only for the development of new, more selective anticancer drugs, but also for the imaging agents allowing for early detection and localization of tumors using a variety of imaging modalities, including MRI, PET, and fluorescence. TPP+-linked imaging agents show the potential for imaging early tumors that are not detectable by palpation in animal models. (See fourth paragraph of the left column of page 10098.) Furthermore, Zielonka teaches the advantages of TPP+-based mitochondrial targeting over other approaches for mitochondrial delivery of small molecules including the stability of TPP+ moiety in biological systems, a combination of lipophilic and hydrophilic property, low chemical reactivity toward cellular components, and relatively safe in human. (See left column of page 10046.) Even though Zielonka exemplifies TTP+ -conjugated small molecules, Zielonka clearly teaches the increased uptake and retention of lipophilic cations provides a rationale not only for the development of new, more selective anticancer drugs. Zielonka teaches the use of mitochondria-targeted triphenylphosphonium (TPP+)-based compound for therapeutic and diagnostic application and for the treatment of cancer. (See Title and Abstract,) Therefore, a person reading Zielonka would not only limit the use of alkyltriphenylphosphonium moiety to only small molecules, but rather to include any mitochondrial targeting compound such as the ones taught by Yano.
Lastly, Applicant’s request the examiner to indicate whether new claims 33 or 34 would be separately patentable if they were amended to be independent cannot be honored because the Examiner only searched and examined the elected compound and not all conjugate of Structure V - Structure VII-TPP, Structure X, or Structure XIII - Structure XXIII.
Conclusion
Claims 13-22, 32, and 34 are not allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JEAN P CORNET whose telephone number is (571)270-7669. The examiner can normally be reached Monday-Thursday from 7.00am-5.30pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amy L Clark can be reached on 571-272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JEAN P CORNET/Primary Examiner, Art Unit 1628