DETAILED ACTION
This action is in reply to papers 05/21/2026.
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 .
Status of Claims
Claims 1-4, 7-14, 16-18, and 21-23 are pending and examined on the merits herein.
Claims 1, 9, and 17 are currently amended.
Claims 21-23 are new.
Claims 5-6 and 15-16 are cancelled.
Claims 19-20 are withdrawn from consideration as being drawn to an invention non-elected without traverse.
Withdrawn Objections/Rejections and Response to Arguments
The rejection of claim 9 under 35 U.S.C. 112(b) is withdrawn in light of the amendment to the claim.
The rejection of claim 9 on the basis of an improper Markush grouping is withdrawn in light of the amendment to the claim.
The following rejections under 35 U.S.C. 103 are withdrawn in light of the amendment to claim 1 to recite “a plurality of nano and/or microparticles suspended within the hydrogel that provide controlled release of the isolated mitochondria and one or more supportive agents encapsulated within the nano and/or microparticles into the tissue at the site of injury” at lines 2-5:
Claim(s) 1-4, 6, 9, and 16-18 over Fedorchak (US20150374633A1), in view of Westensee (Small, 2021, 17(24): e2007959) and Rotfogel (US20220168358A1);
Claim(s) 7-8 over Fedorchak (US20150374633A1), in view of Westensee (Small, 2021, 17(24): e2007959), Rotfogel (US20220168358A1), and Deplace (Journal of Controlled Release, 2019, 293: 10-20);
Claim(s) 10-11 over Fedorchak (US20150374633A1), in view of Westensee (Small, 2021, 17(24): e2007959), Rotfogel (US20220168358A1), Liang (Experimental Neurology, 2021, 337: 113536), and Yigit (Eye & Contact Lens: Science & Clinical Practice, 2013, 39(5): 335-340);
Claim(s) 12-13 over Fedorchak (US20150374633A1), in view of Westensee (Small, 2021, 17(24): e2007959), Rotfogel (US20220168358A1), Patel (Journal of Neurochemistry, 2010, 114: 291-301) and Corinne Bright (WO/2020/010164); and
Claim(s) 14 over Fedorchak (US20150374633A1), in view of Westensee (Small, 2021, 17(24): e2007959), Rotfogel (US20220168358A1), Liang (Experimental Neurology, 2021, 337: 113536), Yigit (Eye & Contact Lens: Science & Clinical Practice, 2013, 39(5): 335-340), Patel (Journal of Neurochemistry, 2010, 114: 291-301), and Corinne Bright (WO/2020/010164).
Applicant' s arguments and amendments dated 05/21/2026 have been fully considered but are moot in part and not persuasive in part due to the new grounds of rejection necessitated by applicant' s amendments. To the extent that the arguments are pertinent to the current grounds of rejection they are responded to below.
Previous claim 1 did not require controlled release of the isolated mitochondria, nor the limitation regarding controlled release into a tissue at a site of injury. The new reference, McCully (US20200123273A1), cited in the new grounds of rejection below, teaches these limitations.
Regarding Applicant’s arguments that Fedorchak does not teach a hydrogel with isolated mitochondria suspended therein, and the propriety of reliance on Westensee and Rotfogel in making up for this deficit, the new reference McCully teaches this limitation, rendering the argument moot.
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.
Claim(s) 1-4, 9, 16-17, and 21-22 are rejected under 35 U.S.C. 103 as being unpatentable over McCully (US20200123273A1), in view of Fedorchak (US20150374633A1).
Regarding claim 1: McCully teaches a method for delivering a combined mitochondrial agent to a target site of a subject (Abstract, para 10). The combined mitochondrial agent taught in McCully comprises a mitochondrion that is combined artificially with an agent, including a therapeutic agent, wherein the mitochondrion and agent are in direct and/or indirect physical contact with each other (para 46, 118, 121).
McCully teaches that the isolated mitochondria or combined mitochondrial agents can be used to treat wounds, by direct injection into tissue located around the wounds (para 200-201), and that the target site may be the eye or optic nerve of the subject (claim 23).
McCully teaches that the isolated mitochondria and combined mitochondrial agents can be mixed with a hydrogel as a pharmaceutically acceptable carrier to make a pharmaceutic composition (para 145, 327). McCully teaches that a linker, which links the mitochondria and an agent to provide a sustained release of the agent upon injection, is particularly useful (para 123).
McCully teaches that the agent may comprise one or more of the following: antibacterial agents, antifungal agents, analgesic agents, and steroids (para 128) (claim 9); vitamins, including Vitamin C, D, and E, and amino acids (para 128) (claim 21); and cetylpyridium chloride (para 128) (claim 22).
McCully does not teach 1) a thermo-gelling hydrogel or 2) a plurality of nano and/or microparticles suspended within the hydrogel.
Fedorchak teaches a method for sustained delivery of an agent to an ocular organ in a subject, comprising delivering a liquid thermoresponsive hydrogel comprising polymer microparticles loaded with a therapeutic agent, wherein the agent is sustainably released for a period of at least 5 days (Abstract; para 65). Fedorchak teaches an embodiment wherein the thermoresponsive hydrogel remains fluid below 37℃ and solidifies into a gelled composition at a temperature above 37℃ (para 59).
Fedorchak teaches that the hydrogel may be poly-N-isopropylacrylamide (PNIPAAm), polyethylene oxide/polypropylene oxide or combinations of the two, butyl methacrylate, polyethylene glycol diacrylate, polyethylene glycol (PEG), poly methacrylic acid, poly(tetramethyleneether glycol), poly(N,N′-diethylaminoethyl methacrylate), or methyl methacrylate (para 58).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the composition of McCully by using the thermoresponsive hydrogel comprising polymer microparticles loaded with a therapeutic agent, as taught in Fedorchak. One of ordinary skill in the art would have been motivated to make this modification because McCully teaches that sustained release of mitochondria and agent is desirable (para 123), and Fedorchak teaches that the use of said hydrogel allows for sustained release of the agent for a period of at least 5 days. One of ordinary skill in the art would have had a reasonable expectation of successfully making this modification because McCully teaches that a combined mitochondrial agent, comprising a mitochondrion and a pharmaceutical agent, can be encapsulated in a hydrogel.
Regarding claims 2-3: Fedorchak teaches that the hydrogel may be poly-N-isopropylacrylamide (PNIPAAm) (para 58), which is a an amorphous, homopolymer hydrogel.
Regarding claim 4: The hydrogel taught in Fedorchak is a thermoresponsive hydrogel (Abstract; para 58). Fedorchak further teaches that the hydrogel may be responsive to external stimulus including ion concentration, pH, glucose, shear stress, or a combination thereof (para 58).
Regarding claims 16-17: Fedorchak teaches that the microparticles may be biodegradable polymers, including polylactic acid (PLA) and poly (lactic-co-glycolic acid) (PLGA) (para 50).
Claim(s) 1 and 7-8 are rejected under 35 U.S.C. 103 as being unpatentable over McCully (US20200123273A1), in view of Fedorchak (US20150374633A1) and Deplace (Journal of Controlled Release, 2019, 293: 10-20).
The teachings of McCully and Fedorchak are set forth above.
McCully, in view of Fedorchak, renders obvious claim 1.
Regarding claims 7-8: McCully, in view of Fedorchak, does not teach a hydrogel comprising hyaluronic acid (HA) and methylcellulose (MC) (claim 7) or the hydrogel having about 0.1 to about 20 % by weight of the composition (claim 8).
Delplace teaches a hydrogel that is “composed of a physical blend of hyaluronan (HA) and methylcellulose (MC), that we refer to as HAMC and which is an inverse thermogelling polymer,” which thermogels at 37℃ and is used to provide sustained release of a therapeutic protein to the retina (p 11, col 1, para 4; p 12, Section 2.4; p 17, col 1, para 2) (claim 7). Delplace teaches that an “HAMC 1/4 hydrogel,” comprising 1% (w/v) of HA and 4% (w/v) of MC, is a minimally-swelling, yet stable, hydrogel with an inverse thermoregulation temperature matching body temperature (Section 2.4; Section 4, para 2) (claim 8).
Given the teachings of Fedorchak and Delplace, there was a reasonable expectation that a thermogelling HAMC hydrogel, as taught in Delplace, would equivalently as a thermogelling hydrogel, as taught in Fedorchak. Therefore, it would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention to have substituted the thermogelling hydrogel taught in Fedorchak with the HAMC hydrogel taught in Delplace with predictable results. Substitution of one element for another known in the field, wherein the result of the substitution would have been predictable, is considered to be obvious. See KSR International Co. v Teleflex Inc 82 USPQ2d 1385 (US 2007) at page 1395.
Furthermore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the composition of McCully, in view of Fedorchak, by using the thermogelling HAMC hydrogel, as taught in Delplace. One of ordinary skill in the art would have been motivated to make this modification because Delplace teaches that an HAMC 1/4 hydrogel is a minimally-swelling, yet stable, hydrogel. One of ordinary skill in the art would have had a reasonable expectation of successfully making this modification because Delplace teaches that the HAMC hydrogel can be used for sustained delivery of an agent to an ocular organ in a subject.
The combination of prior art cited above in both rejections under 35 U.S.C. 103 satisfies the factual inquiries as set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966). Once this has been accomplished the holdings in KSR can be applied (KSR International Co. v. Teleflex Inc. (KSR), 82 USPQ2d 1385 (US 2007): "Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. In the present situation, rationales B and G are applicable. The teachings of the cited prior art in the obviousness rejection above provide the requisite teachings and motivations with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR.
Claim(s) 1 and 10-11 are rejected under 35 U.S.C. 103 as being unpatentable over McCully (US20200123273A1), in view of Fedorchak (US20150374633A1), Liang (Experimental Neurology, 2021, 337: 113536), and Yigit (Eye & Contact Lens: Science & Clinical Practice, 2013, 39(5): 335-340).
The teachings of McCully and Fedorchak are set forth above.
McCully, in view of Fedorchak, renders obvious claim 1.
Regarding claim 10: McCully, in view of Fedorchak, does not teach a hydrogel comprising N-acetylcysteine amide (NACA).
Liang teaches that NACA ameliorates mitochondrial dysfunction and reduces oxidative stress in human induced-pluripotent stem cells (Abstract).
Yigit teaches that NACA can be loaded onto and released from soft contact lenses, which is a hydrogel, for treatment of ocular diseases (abstract; p 336, col 1, para 4 – col 2, para 5).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the composition of McCully, in view of Fedorchak, by adding NACA, as taught in Liang. One of ordinary skill in the art would have been motivated to make this modification to ameliorate mitochondrial dysfunction and reduce oxidative stress, as taught in Yigit. One of ordinary skill in the art would have had a reasonable expectation of successfully making this modification because Yigit teaches that NACA can be incorporated into a biocompatible hydrogel.
Regarding claim 11: Yigit teaches that the incorporation of NACA increases the final weight of the contact lens by 0.5% to 0.8, calculated as the difference of the weight of the loaded lens and weight of unloaded lens divided by the weight of unloaded lens (p 339, col 2, para 1). This reads on wherein NACA is at a weight percentage from about 0.1 to about 20% by weight of the hydrogel.
Claim(s) 1 and 12-13 are rejected under 35 U.S.C. 103 as being unpatentable over McCully (US20200123273A1), in view of Fedorchak (US20150374633A1), Patel (Journal of Neurochemistry, 2010, 114: 291-301) and Corinne Bright (WO/2020/010164).
The teachings of McCully and Fedorchak are set forth above.
McCully, in view of Fedorchak, renders obvious claim 1.
Regarding claim 12: McCully, in view of Fedorchak, does not teach a hydrogel comprising acetyl-L-carnitine (ALC).
Patel teaches that acetyl-L-carnitine (ALC) ameliorates mitochondrial dysfunction in rats following spinal cord injury, and that ALC restored mitochondrial respiration rates to normal levels when added in vitro to mitochondria isolated from rats with injured cords (Abstract).
Corinne Bright teaches a hydrogel comprising ALC to reduce and treat chemotherapy-induced peripheral neuropathy by reducing mitochondrial damage (para 335).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the composition of McCully, in view of Fedorchak, by adding ALC, as taught in Patel. One of ordinary skill in the art would have been motivated to make this modification to improve the health of mitochondria suspended in the hydrogel, as taught in Patel. One of ordinary skill in the art would have had a reasonable expectation of successfully making this modification because Corinne Bright teaches that ALC can be incorporated into a hydrogel.
Regarding claim 13: McCully, in view of Fedorchak, Patel, and Corinne Bright, does not teach a specific weight percentage of ALC in the hydrogel.
Corinne Bright teaches loading 1 to 8% by weight of another drug, capsaicin, in a hydrogel to deliver capsaicin to intact nerves to reduce painful diabetic neuropathy (para 335).
Patel teaches that 5 mM of ALC was added to mitochondria isolated from rats 24 h after either sham operation or injury (p 293, col 1, para 3). Patel further teaches that in this particular in vitro experimental setup, 5 mM of ALC was the optimal concentration after experimentation showed that dosages below 5 mM were ineffective for mitochondrial respiration, and dosages above 5 mM did not have added beneficial effects (p 293, col 1, para 3).
The method taught in Fedorchak comprises administering a therapeutically effective amount of the therapeutic agent (claim 10). Fedorchak teaches that a “therapeutically effective amount” refers to “a quantity of a specified agent sufficient to achieve a desired effect in a subject being treated with that agent. Ideally, a therapeutically effective amount of an agent is an amount sufficient to inhibit or treat the disease or condition without causing a substantial cytotoxic effect in the subject. The therapeutically effective amount of an agent will be dependent on the subject being treated, the severity of the affliction, and the manner of administration of the therapeutic composition” (para 30).
It would have been prima facie obvious for someone of ordinary skill in the art before the effective filing date of the claimed invention to have optimized the weight percentage of ALC in the hydrogel to provide a therapeutically effective amount of ALC to arrive at the claimed invention. See MPEP 2144.05(II)(A). As noted in In re Aller, 105 USPQ 233 at 235, where 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.
Claim(s) 1 and 14 are rejected under 35 U.S.C. 103 as being unpatentable over McCully (US20200123273A1), in view of Fedorchak (US20150374633A1), Liang (Experimental Neurology, 2021, 337: 113536), Yigit (Eye & Contact Lens: Science & Clinical Practice, 2013, 39(5): 335-340), Patel (Journal of Neurochemistry, 2010, 114: 291-301), and Corinne Bright (WO/2020/010164).
McCully, in view of Fedorchak, renders obvious claim 1.
As set forth above in the rejection for claim 10, McCully, in view of Fedorchak, Liang, and Yigit teaches the composition of claim 1, further comprising N-acetylcysteine amide (NACA).
As set forth above in the rejection for claim 12, McCully, in view of Fedorchak, Patel, and Corinne Bright teaches the composition of claim 1, further comprising acetyl-L-carnitine (ALC).
Liang teaches that NACA ameliorates mitochondrial dysfunction and reduces oxidative stress in human induced-pluripotent stem cells (Abstract).
Patel teaches that ALC ameliorates mitochondrial dysfunction in rats following spinal cord injury, and that ALC restored mitochondrial respiration rates to normal levels when added in vitro to mitochondria isolated from rats with injured cords (Abstract).
The teachings of Liang and Patel show that NACA and ALC are known to be useful for the same purpose, which is ameliorating mitochondrial dysfunction.
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to have combined the composition of claim 10, comprising NACA, and the composition of claim 12, comprising ALC, to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to combined these compositions because both NACA and ALC are compositions useful for ameliorating mitochondrial dysfunction. See MPEP 2144.06(I). “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
Claim(s) 1 and 18 is are rejected under 35 U.S.C. 103 as being unpatentable over McCully (US20200123273A1), in view of Fedorchak (US20150374633A1) and Westensee (Small, 2021, 17(24): e2007959).
The teachings of McCully and Fedorchak are set forth above.
McCully, in view of Fedorchak, renders obvious claim 1.
Regarding claim 18: McCully is silent regarding the percent weight of the mitochondria in the composition.
Westensee teaches mitochondria that have been isolated from HepG2 cells and subsequently encapsulated in gelatin-based hydrogel disks and artificial cells (abstract; Fig 1). Westensee teaches that GelMA disks had a final mitochondrial protein concentration of 2 mg mL-1 (p 9, col 1, para 4), which is 0.2% w/v, which is within the “about 0.1 to about 30%” range as recited in instant claim 18. Westensee further teaches that artificial cells can be used in therapeutics as support for cells and tissues with missing or lost function or to integrate non-native activity (p 1, col 1 – col 2, para 1).
It would have been prima facie obvious for someone of ordinary skill in the art before the effective filing date of the claimed invention to have optimized the weight percentage of mitochondria in the hydrogel taught by McCully, in view of Fedorchak, according to the weight percentage taught in Westensee, to arrive at the claimed invention. See MPEP 2144.05(II)(A). As noted in In re Aller, 105 USPQ 233 at 235, where 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.
Claim(s) 1 and 23 is are rejected under 35 U.S.C. 103 as being unpatentable over McCully (US20200123273A1), in view of Fedorchak (US20150374633A1) and Liu (Front. Cell Dev. Biol., 2021, 9:612554).
The teachings of McCully and Fedorchak are set forth above.
McCully, in view of Fedorchak, renders obvious claim 1.
Regarding claim 23: McCully teaches that the therapeutic agent can be any agent that has a therapeutic or prophylactic use, and may be a small molecule or an organic compound (para 118). McCully teaches that the target tissue may be the brain (para 17).
McCully does not teach fructose, NADH, or NADPH as the supportive agent.
Liu teaches that administration of exogenous NADPH protects neurons against excitotoxic injury, in both in vivo and in vitro models (Abstract; p 15, col 2 - p 16, col 2, para 2; Fig 13).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the composition of McCully, in view of Fedorchak, by using NADPH as a supportive agent, as taught in Liu. One of ordinary skill in the art would have been motivated to make this modification to protect the target brain tissue from excitotoxic injury, as taught in Liu. One of ordinary skill in the art would have had a reasonable expectation of successfully making this modification because McCully teaches that the therapeutic agent can be any agent that has a therapeutic or prophylactic use, and may be a small molecule or an organic compound, and NADPH is an organic small molecule.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 Risa Takenaka whose telephone number is (571)272-0149. The examiner can normally be reached M-F, 12-7 EST.
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/RISA TAKENAKA/Examiner, Art Unit 1632
/KARA D JOHNSON/Primary Examiner, Art Unit 1632
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