DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . Preliminary amendment filed on 10/30/2023 has been entered. Claims 1-16 are pending in this application. Claims 5 and 10-16 are withdrawn. Claims 1-4 and 6-9 are currently under examination.
Priority
This is US Application No. 18/236,260 filed on 08/21/2023.
Election/Restrictions
Applicant’s election of Group I (claims 1-9) and species (polymer in claim 3 and PEG-600-diacid in claim 4) in the reply filed on 03/11/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)). Claims 5 and 10-16 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention or species, there being no allowable generic or linking claim. Thus, claims 1-4 and 6-9 are currently under examination.
Claim Objections
Claims 1, 2, and 6-9 are objected to because of the following informalities: In claim 1, change the misspelled “Flavine” (line 1) to “Flavin”. In claim 2, insert the missing comma “,” immediately before the recitation “wherein” as seen in other dependent claim; and insert the missing conjunction “or” immediately before the recitation “GSH is” (line 3). In claim 6, change the incorrect recitation “claim 1 in a form” (lines 1 to 2) to “claim 1, wherein the composition is in a form” to become proper dependent claim format. In claim 7, insert the missing comma “,” immediately before the recitation “wherein” (line 2); and insert the missing unit “mg” immediately before the recitation “to 10 g for GSH” (line 3). In claim 8, change the incorrect recitation “claim 1 in a” (lines 1 to 2) to “claim 1, wherein the composition is in a” to become proper dependent claim format; and insert the missing phrase “the carrier is” immediately before the recitation “a pharmaceutically” (line 2) to tie to preceding recitation. In claim 9, change the incorrect recitation “claim 1 and a” (lines 1 to 2) to “claim 1, wherein the composition is a” to become proper dependent claim format. 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 3, 4, 6, and 8 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.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claims 3, 4, and 6 recite the broad recitation “a polymer… an excipient” (line 2 of claim 3), “a polymer” (line 2 of claim 4), or “oral” (line 2 of claim 6), and the claim also recites respectively “a metal salt… a liposome… a combination thereof” (lines 2 to 3 of claim 3), “preferably a PEG… more preferably PEG 600… even more preferably PEG-600-diacid… even more more preferably” (lines 3to 5 of claim 4) and “including sublingual… advantageously.. po administration: (lines 2, 3, and 5 of claim 6), which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Applicant is advised to change the recitation “an excipient, a combination thereof” (lines 2 to 3 of claim 3) to “an excipient, or a combination of distinct carriers thereof”; to replace the recitation in lines 3-5 of claim 4 with “(PEG), chitosan, collagen, starch, or hyaluronic acid, wherein the PEG is PEG 600 or PEG-600-diacid.”; to change the recitation “oral including sublingual administration (po)“ (lines 2 to 3 of claim 6) to “oral or sublingual administration”; and to delete the recitation “, advantageously iv or po administration” (line 5 of claim 6).
Claim 8 recites “a therapeutically effective amount”, which is broadly defined as “any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment… of a disease or disorder” (p. 14, lines 5-9). Since there is no specific disease or disorder in the preceding claim, it is not clear what the effective amount is. To advance the prosecution, the “a therapeutically effective amount” is interpreted as any amount.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-4 and 6-9 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon or a product of nature without significantly more. The 2019 Revised Patent Subject Matter Eligibility Guidance (issued January 7, 2019)” (https://www.govinfo.gov/content/pkg/FR-2019-01-07/pdf/2018-28282.pdf) and “October 2019 Update: Subject Matter Eligibility (issued October 17, 2019)” (https://www.uspto.gov/sites/default/files/documents/peg_oct_2019_update.pdf), are followed here. The claim is directed to a statutory category, e.g., a composition of matter (Step 1: YES). The claim is then analyzed in Step 2A (Prong one) to determine whether it is directed to any judicial exception. The claims 1-4 and 6-9 recite a composition comprising Flavin adenine dinucleotide (FAD), reduced glutathione (GSH), adenosine triphosphate (ATP), optionally myristic acid, and a carrier (a polymer or an excipient; or hyaluronic acid; or pharmaceutically acceptable carrier), which are products of nature. Accordingly, the claim is directed to at least one exception (Step 2A, prong one: YES). The claim is then analyzed in Step 2A (Prong two) and is determined that this judicial exception is not integrated into a practical application because there is no indication that mixing them or salt thereof in the recited amount (i.e., from 0,1mg to 10g for FAD or a salt thereof, a dose ranging from 0,1 to 10 g for GSH, a dose ranging from 0, 1mg to 10g for ATP or a salt thereof and a dose ranging from 0.1mg to 10g for myristic acid or a salt thereof) changes the structure, function, or other properties of the recited compounds in any marked way. Instead, each of the FAD, GSH, ATP, and myristic acid retains its naturally occurring structure and properties (e.g., metabolites in mitochondria). Thus, the claimed mixture as a whole does not display markedly different characteristics compared to the closest naturally occurring counterpart. Accordingly, the Step 2A (Prong two) is NO. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because prior to applicant’s invention and at the time of filing the application, mixing of FAD, GSH, ATP, and optionally myristic acid was well-understood, routine and conventional in the field, as evidenced by the reference under the 102 and 103 rejections below. The recitation of specific salt or amount does not affect this analysis, because it was also well-understood, routine and conventional at the time to mix specific salt or amount, e.g., to achieve commercially acceptable chemical complex for different purposes. Thus, the mixing of different salt or amount, when recited at this high level of generality, does not meaningfully limit the claim, and the claim as a whole does not amount to significantly more than each “product of nature” by itself (Step 2B: NO). The claim does not qualify as eligible subject matter.
Claim Rejections - 35 USC § 102
(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 1, 3, 4, and 6-9 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Brasile (US 2002/0012988, Jan. 31, 2002, hereinafter referred to as Brasile ‘988).
With regard to structural limitations “a composition (or a medicament) comprising Flavin adenine dinucleotide (FAD; or from 0,1mg to 10g), reduced glutathione (GSH; or from 0,1mg to 10g), adenosine triphosphate (ATP; or from 0,1mg to 10g), and a carrier (or a polymer, or an excipient, which is broadly defined as “acceptable "excipient" or carrier means any compound which facilitates the shaping of the pharmaceutical composition and does not alter the nature of the biological activity of the active ingredient(s)” on page 28 of the Specification; or polyethylene glycol; or a pharmaceutically acceptable carrier)” (claims 1, 3, 4, and 7-9):
[AltContent: rect][AltContent: rect][AltContent: rect]Brasile ‘988 disclosed Table 1 listing components of one embodiment of the perfusion solution:
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. In a preferred embodiment, chemically modified
hemoglobin, for example, polyethylene glycol-modified hemoglobin is used to maintain oxygen tension of the perfusate at a level Sufficient to Support metabolism by the organ being perfused (pages 13/29 to 15/29, [0051 and 0055].
Thus, these teachings of Brasile ‘988 anticipate Applicant’s claims 1, 3, 4, and 6-9 and would also be suitable for intravenous administration, required by claim 6.
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 6-9 are rejected under 35 U.S.C. 103 as being unpatentable over Paleni et al. (US 2022/0008451, Jan. 13, 2022, or 371 date: Apr 27, 2021, hereinafter referred to as Paleni ‘451) in view of Shin et al. (J. Biochem. Mol. Biol. Vol. 29, No. 3 pp. 253-260, 1996, hereinafter referred to as Shin ‘1996).
With regard to structural limitations “a composition (or in a form suitable for intravenous administration; or a medicament) comprising Flavin adenine dinucleotide (FAD or disodium salt; or from 0,1mg to 10g), reduced glutathione (GSH or L-glutathione; or from 0,1mg to 10g), adenosine triphosphate (ATP or disodium salt; or from 0,1mg to 10g), optionally myristic acid (or from 0,1mg to 10g), and a carrier (or a polymer, or an excipient, which is broadly defined as “acceptable "excipient" or carrier means any compound which facilitates the shaping of the pharmaceutical composition and does not alter the nature of the biological activity of the active ingredient(s)” on page 28 of the Specification; or polyethylene glycol or elected PEG-600-diacid; or a pharmaceutically acceptable carrier)” (claims 1-4 and 6-9):
Paleni ‘451 disclosed NP1: Flavine adenine dinucleotide (FAD) solution (Alpha Aesar, FAD disodium salt hydrate, 94%), at 1 mg/ml. NP2: FAD/FAD PEG solution, at a dose of 1 mg/ml of total FAD in NaCl 0.9%. NP1 (FAD alone) and NP2 (FAD-PEG) is administered in the form of two injections of 100 μl intravenous per day. NP1 or NP2 solution (1 or 5 mg/mL FAD) is injected subcutaneously in mice in a volume of 100 μl once daily (page 35/37 to 36/37, [0751, 0752, 0755, and 0775]). A composition comprises a pharmaceutically acceptable carrier and any of the foregoing compounds, preferably FAD-PEG-Diacid, more preferably FAD-PEG-600 diacid), FAD-Alginic Acid (FADALG), FAD-Poly-Lactide, FAD-Bis-Phosphonate, FAD-Gelatine, FAD-chitosan, FAD-collagen. A fatty acid combined with FAD is any one of the fatty acids selected from Oleic Acid, Myristic Acid, Nervonic Acid. FAD is at least partially encapsulated in a particle to improve its absorption, bioavailability, and/or distribution, advantageously, while limiting its destruction, particularly by pyrophosphatases and/or blood hydrolases (page 23/37, [0401 and 0402]; page 15/37, [0280]).
Paleni ‘451 did not explicitly disclose the limitations “reduced glutathione (GSH or L-glutathione; or from 0,1mg to 10g), adenosine triphosphate (ATP or disodium salt; or from 0,1mg to 10g)”, required by claims 1, 2, and 7.
Shin ‘1996 disclosed that an enzyme (FAD phosphohydrolase) that hydrolyzes flavin-adenine dinucleotide (FAD) was found to be present in rat liver lysosomal membrane. The enzyme was inhibited by reduced glutathione and other thiols, cyanide, and ascorbate. The presence of ATP, ADP, AMP, α-ß-methylene ATP, GMP, and coenzyme A (CoA) decreased the activity on FAD. The enzyme is different from ATPase, inorganic pyrophosphatase, and soluble lysosomal FAD pyrophosphatase. The FAD hydrolyzing activity was detected in Golgi, microsome, and plasma membrane, but not in mitochondria or soluble lysosomal preparations. The reduced glutathione at 10-4 M inhibited the enzyme activity by approximately 40 ~ 60%. Effect of some substances and phosphodiester compounds (50 mM) upon intact membrane FAD phosphohydrolase activity:
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(page 253, Abstract; page 256, left col., para. 2 and Table 4).
Thus, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to combine the FAD-PEG-600 diacid, and optionally myristic acid as taught by Paleni ‘451 with reduced glutathione and ATP in view of Shin ‘1996 to increase the bioavailabiity or to decrease the degradation of FAD because (a) FAD is at least partially encapsulated in a particle to improve its absorption, bioavailability, and/or distribution, while limiting its destruction, particularly by pyrophosphatases and/or blood hydrolases, and (b) a FAD phosphohydrolase that hydrolyzes flavin-adenine dinucleotide (FAD) was found to be present in several cellular membranes was inhibited by reduced glutathione and ATP, described above. Thus, one of skill in the art would have a reasonable expectation that by combining the FAD-PEG-600 diacid, and optionally myristic acid as taught by Paleni ‘451 with reduced glutathione and ATP in view of Shin ‘1996, followed by optimizing the concentrations of reduced glutathione and ATP, to increase the bioavailabiity or to decrease the degradation of FAD, one would achieve Applicant’s claims 1-4 and 6-9. “[t]he combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” Id. at ___, 82 USPQ2d at 1395. See MPEP § 2141 [R-01.2024]. "[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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP § 2144.05 [R-01.2024] [II.A].
Conclusion
No claims are allowed.
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/YIH-HORNG SHIAO/Primary Examiner, Art Unit 1691
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