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 .
Claim Status
Claims 1-22 are pending.
No claims have been amended.
No claims have been cancelled.
Thus, claims 1-22 represent all claims currently under consideration.
Priority
Domestic Priority data as claimed by Applicant:
This application is a CON of PCT/IB2024/000640 (11/12/2024)
Which is a CON of 18/388,529 (11/09/2023)
and claims benefit of 63/684,339 (08/16/2024)
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the Examiner on form PTO-892, they have not been considered.
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 5, 7-15, and 17-18 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.
Regarding claim 5, the phrase “such as” renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claims 7-14, these dependent claims do not resolve the indefiniteness of claim 5 detailed above.
Claim 13 recites “wherein the crystallization solvent is added in an amount of from about 5 to 10 volumes relative to the halide salt…” However, it is unclear how to determine the volume of the halide salt when it is in a solution, and this ambiguity renders the instant claim indefinite. The Specification appears to indicate that the crystallization solvent is added in an amount of from about 5 to 10 volumes relative to the volume of the alcoholic solution (Specification; page 3, paragraph 2, lines 9-18).
Regarding claim 15, the phrase “such as” renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claims 17-18, these dependent claims do not resolve the indefiniteness of claim 5 detailed above.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 15 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Skulachev et al. (RU2318500; published 03-10-2008; English language machine translation obtained from Espacenet on 08-28-2026).
Regarding claim 15, Skulachev discloses the preparation of SkQ1, which is 2,3-dimethyl-1,4-benzoquinone-5-decyl-triphenyl phosphonium bromide, through a three-step sequence comprising (1) oxidation of 2,3-dimethylhydroquinone (1) to the corresponding 2,3-dimethyl-1,4-benzoquinone (2); (2) addition of 11-bromoundecanoic acid (3) to the obtained 2,3-dimethyl-1,4-benzoquinone; and (3) formation of the target compound (5) as a result of the reaction with triphenylphosphine. The resulting substance is a dry yellow-brown substance with a high degree of hygroscopicity. The sample purity is not less than 98.5%, and the product purity was controlled by two methods: high-pressure high-performance liquid chromatography (HPLC) and high-resolution NMR (500 MHz). The content of SkQ1 in the obtained preparation, determined by HPLC, is 98.55% (0136-0146; English language machine translation).
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 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 1-4 and 15-22 are rejected under 35 U.S.C. 103 as being unpatentable over Skulachev et al. (RU2318500; published 03-10-2008; English language machine translation obtained from Espacenet on 08-28-2026), in view of Morissette et al. (“High-throughput crystallization: polymorphs, salts, co-crystals and solvates of pharmaceutical solids”; Adv. Drug Deliv. Rev. 2004, 56, 275-300; published 02-23-2024).
Regarding claims 19-22, claim 19 recites “The crystalline form comprising the halide salt of the compound 2,3-dimethyl-1,4-benzoquinone-5-decyl-triphenylphosphonium according to claim 1, wherein the crystalline form is produced by a method comprising: (a) providing an alcoholic solution of a halide salt of 2,3-dimethyl-1,4-benzoquinone-5-decyl-triphenylphosphonium; (b) adding a crystallization solvent to the alcoholic solution, wherein the crystallization solvent is selected from the group consisting of an ether and an ester; and (c) removing the alcohol and the crystallization solvent to obtain the crystalline form”. For the purposes of examination, the recited method steps are being interpreted as product-by-process limitations. MPEP § 2113(I) states that “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” The process limitations of claim 19 and dependent claims 20-22 are only defining the process of the product-by-process limitations and do not appear to impart any further structural features to the claimed product.
Regarding claims 1-4, 15-16, and 19-22, Skulachev teaches compounds that can be used to prepare a pharmaceutical composition for the targeted (directed) delivery of biologically active substances to the mitochondria for the treatment of diseases and conditions associated with impaired mitochondrial function (Abstract).
Skulachev further teaches the preparation of SkQ1, which is 2,3-dimethyl-1,4-benzoquinone-5-decyl-triphenyl phosphonium bromide, through a three-step sequence, and the resulting substance is a dry yellow-brown substance with a high degree of hygroscopicity. The sample purity is not less than 98.5%, and the product purity was controlled by two methods: high-pressure high-performance liquid chromatography (HPLC) and high-resolution NMR (500 MHz). The content of SkQ1 in the obtained preparation, determined by HPLC, is 98.55% (0136-0146; English language machine translation). This purity level overlaps with the range recited in instant claims 3, 15, and 21. MPEP § 2144.05(I) states that “[i]n the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists.”
Skulachev does not teach (1) a crystalline form of 2,3-dimethyl-1,4-benzoquinone-5-decyl-triphenyl phosphonium bromide in a manner consistent with instant claims 1-4 and 19-22; and (2) a purity of greater than 99% by weight, as recited in instant claims 4, 16, and 22.
Regarding point (1), although does not explicitly teach a crystalline form, Skulachev does teach that the compounds of the claimed invention further comprises its solvates, isomers or prodrug forms and a pharmacologically acceptable carrier (0053; English language machine translation).
Further regarding point (1), Morissette teaches the development and applications of high-throughput (HT) crystallization techniques for polymorphs, salts, co-crystals and solvates of pharmaceutical solids. Active pharmaceutical ingredients (APIs) are frequently delivered to the patient in the solid-state as part of an approved dosage form and provide a convenient, compact and generally stable format to store an API or a drug product. The most preferred solid form is generally the thermodynamically most stable crystalline form of the compound. HT crystallization methodologies are capable of screening hundreds or thousands of crystallization conditions in parallel using small amounts of compound for the identification and characterization of diverse forms of APIs (Title; Abstract; page 276, Col. 1, paragraphs 1-2; page 296, Col. 1, paragraph 3).
Regarding point (2), Skulachev does teach that a purity of content of SkQ1 in the obtained preparation, determined by HPLC, is 98.55%, as detailed above (0146; English language machine translation). MPEP § 2144.05(I) states that “a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close.”
Furthermore, Skulachev teaches that the sample purity is not less than 98.5%, and the product purity can be controlled by HPLC above (0144-0145; English language machine translation). Therefore, the skilled artisan could predictably arrive at the instantly claimed level of purity with a reasonable expectation of success based on the teachings of Skulachev and through means of routine experimentation that is non-inventive in nature. MPEP § 2144.05(II) states that “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.”
The teachings of Skulachev and Morissette are analogous because they both reside in the overlapping technical field of pharmaceutical compositions. As such, the skilled artisan would be sufficiently motivated to modify the method of Skulachev to incorporate the teachings of Morissette to implement high-throughput crystallization methods to the 2,3-dimethyl-1,4-benzoquinone-5-decyl-triphenylphosphonium bromide to predictably pursue a crystalline form with a reasonable expectation of success, because Morissette teaches that solid forms are a generally stable format to store an API or a drug product, and the preferred solid form is generally the thermodynamically most stable crystalline form of the compound. See MPEP § 2143(I)(A).
Therefore, 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 have modified Skulachev to incorporate the teachings of Morissette to arrive at the invention of claims 1-4, 15-16, and 19-22. The motivation to do so would permit the skilled artisan to pursue, with a reasonable expectation of success, a thermodynamically stable crystalline form of the compound convenient for its storage and used, as described above.
Regarding claims 17-18, Skulachev and Morissette do not teach wherein said halide salt of 2,3-dimethyl-1,4-benzoquinone-5-decyl-triphenylphosphonium is stable for at least two months when stored at room temperature and exposed to natural light having a natural day/night cycle, or wherein said halide salt of 2,3-dimethyl-1,4-benzoquinone-5-decyl-triphenylphosphonium remains stable after exposure to gamma radiation for sterilization of the composition, as recited in the instant claims.
However, these claim limitations are disclosed physical properties of a crystalline form of 2,3-dimethyl-1,4-benzoquinone-5-decyl-triphenylphosphonium of a purity greater than 98% by weight, this composition is rendered obvious over Skulachev and Morissette, as detailed in the rejections of claims 1 and 15 above. Therefore, the limitations of claims 17-18 are deemed inherently taught by Skulachev and Morissette. MPEP § 2112.01(II) states that “A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.”
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 1-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 and 6-20 of U.S. Patent No. 12,077,553 B2.
Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding instant claims 1-17 and 19-21, claims 1-3 and 6-20 of U.S. Patent No. 12,077,553 B2 teach every limitation of the instant claims when the compound is the crystalline form of 2,3-dimethyl-1,4-benzoquinone-5-decyl-triphenylphosphonium bromide.
Regarding instant claim 22, the range recited in claim 20 of U.S. Patent No. 12,077,553 B2 overlaps with the instantly claimed range. MPEP § 2144.05(I) states that “[i]n the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists.”
Regarding instant claim 18, U.S. Patent No. 12,077,553 B2 does not explicitly disclose this claim limitation. However, claim 15 of U.S. Patent No. 12,077,553 B2 does anticipate the composition of instant claim 15 when the composition comprises 2,3-dimethyl-1,4-benzoquinone-5-decyl-triphenylphosphonium bromide as the halide salt. Therefore, the limitation of claim 18 is deemed inherently taught by U.S. Patent No. 12,077,553 B2. MPEP § 2112.01(II) states that “A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.”
Subject Matter Free From the Prior Art
Claims 5-14 appear to be free from the prior art and could be allowable if rewritten or amended to overcome the rejections of claims 5 and 7-14 under 35 U.S.C. 112(b)/35 U.S.C. 112 (pre-AIA ), second paragraph, and the rejections of claims 5-14 on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 and 6-20 of U.S. Patent No. 12,077,553 B2 set forth in this Office Action.
The following is a statement of reasons for the indication of allowable subject matter:
The prior art of record does not teach or suggest a method for preparation of a crystalline form of a halide salt of the compound 2,3-dimethyl-1,4-benzoquinone-5-decyl-triphenylphosphonium, the method comprising: (a) providing an alcoholic solution of a halide salt of 2,3-dimethyl-1,4-benzoquinone-5-decyl-triphenylphosphonium; (b) adding a crystallization solvent to the alcoholic solution, wherein the crystallization solvent is selected from the group consisting of an ether and an ester; and (c) removing the alcohol and the crystallization solvent to obtain the crystalline form, as recited in independent claim 5.
Exemplary prior art includes:
Skulachev et al. (RU2318500; published 03-10-2008; English language machine translation obtained from Espacenet on 08-28-2026), who teaches the preparation of SkQ1, which is 2,3-dimethyl-1,4-benzoquinone-5-decyl-triphenyl phosphonium bromide, through a three-step sequence, and the resulting substance is a dry yellow-brown substance with a high degree of hygroscopicity. The sample purity is not less than 98.5%, and the product purity was controlled by two methods: high-pressure high-performance liquid chromatography (HPLC) and high-resolution NMR (500 MHz). The content of SkQ1 in the obtained preparation, determined by HPLC, is 98.55% (0136-0146; English language machine translation).
Skulachev does not teach a crystalline form of a halide salt of 2,3-dimethyl-1,4-benzoquinone-5-decyl-triphenyl phosphonium or its method of preparation, as recited in instant claim 5.
Morissette et al. (“High-throughput crystallization: polymorphs, salts, co-crystals and solvates of pharmaceutical solids”; Adv. Drug Deliv. Rev. 2004, 56, 275-300; published 02-23-2024), who teaches the development and applications of high-throughput (HT) crystallization techniques for polymorphs, salts, co-crystals and solvates of pharmaceutical solids. Active pharmaceutical ingredients (APIs) are frequently delivered to the patient in the solid-state as part of an approved dosage form and provide a convenient, compact and generally stable format to store an API or a drug product. The most preferred solid form is generally the thermodynamically most stable crystalline form of the compound. HT crystallization methodologies are capable of screening hundreds or thousands of crystallization conditions in parallel using small amounts of compound for the identification and characterization of diverse forms of APIs (Title; Abstract; page 276, Col. 1, paragraphs 1-2; page 296, Col. 1, paragraph 3).
Morissette does not teach a crystalline form of a halide salt of 2,3-dimethyl-1,4-benzoquinone-5-decyl-triphenyl phosphonium or its method of preparation, as recited in instant claim 5.
Although Skulachev in view of Morissette renders a crystalline form of 2,3-dimethyl-1,4-benzoquinone-5-decyl-triphenyl phosphonium bromide obvious, as detailed in the 103 rejections of claims 1, 15, and 19 above, neither Skulachev nor Morissette teach or suggest the method steps for the preparation of a halide salt of 2,3-dimethyl-1,4-benzoquinone-5-decyl-triphenyl phosphonium as recited in independent claim 5. The skilled artisan would not be sufficiently motivated to modify or combine the cited prior art to arrive at the preparation method according to claim 5. Therefore, the claims are free from the prior art for the reasons of record and the reasons set forth above.
Conclusion
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to Derek Rhoades whose telephone number is (703)-756-5321. The Examiner can normally be reached Monday–Thursday, 7:30 am–5:00 pm EST; Friday, 7:30 am–4:00 pm EST.
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/D.R./Examiner, Art Unit 1692
/AMY C BONAPARTE/Primary Examiner, Art Unit 1692
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