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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 12/16/2025 has been entered.
Status of Claims
Claims 1-4, 6-14, and 16-18 are pending and examined on the merits herein.
Claims 5 and 15 are cancelled.
Applicants previously elected Group I, drawn to claims 1-18, without traverse. Claims 19-20 are withdrawn.
Priority
The instant application claims benefit of provisional application 63/251,770 filed 10/04/2021.
Withdrawn Objections/Rejections
The objection to claim 6 is withdrawn in light of the amendment to claim 6, which obviates the basis of the objection regarding the abbreviation for poly(N-isopropylacrylamide).
The rejection of claims 1-4, 9, and 18 under 35 U.S.C. 102(a)(1) as being anticipated by Westensee (Small, 10 May 2021), as evidenced by Zhang (European Polymer Journal, 2023), is withdrawn in favor of a new grounds of rejection.
The rejection of claims 1-9 and 18 under 35 U.S.C. 103 over Westensee in view of Delplace (Journal of Controlled Release, 2019) and Klouda (European Journal of Pharmaceutics and Biopharmaceutics, 2008), is withdrawn in favor of a new grounds of rejection.
The rejection of claims 1-6, 9, and 15-18 under 35 U.S.C. 103 over Westensee in view of Bhattarai (Journal of Controlled Release, 2005) and Klouda, is withdrawn in favor of a new grounds of rejection.
The rejection of claims 1-4, 9-11 and 18 under 35 U.S.C. 103 over Westensee in view of Liang (Experimental Neurology, March 2021) and Yigit (Eye & Contact Lens, 2013), as evidenced by Correa (Chemical Reviews, 2021), is withdrawn in favor of a new grounds of rejection.
The rejection of claims 1-4, 9, 12-13, and 18 under 35 U.S.C. 103 over Westensee in view of Patel (Journal of Neurochemistry, 2010) and Corinne (WO/2020/010164), is withdrawn in favor of a new grounds of rejection.
The rejection of claims 1-4, 9, 12-14, and 18 are under 35 U.S.C. 103 over Westensee in view of Liang, Yigit, Patel, and Corinne, as evidenced by Correa, is withdrawn in favor of a new grounds of rejection.
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.
Claim 9 is 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. Claim 9 is drawn to “The composition of claim 1, further comprising one or more supportive agents suspended therein” (lines 1-2). It is unclear whether “one or more supportive agents” refers to “one or more supportive agents encapsulated within the nano and/or microparticles” as recited in lines 3-4 of claim 1, or whether it refers to a different supportive agent(s). The first interpretation is used for the purposes of examination.
Claim Rejections – Improper Markush Grouping Rejection
Claim 9 is rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of claim 9 regarding supportive agents suspended in the composition of claim 1 is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: First, the members do not belong to the same art-recognized class. There is no expectation from the knowledge in the art that water, vitamin C, and an anti-viral will behave in the same way in the context of the claimed invention. See MPEP 2117(A). Second, although members of a Markush grouping may still be considered to be proper where the alternatives share a substantial structural feature that is essential to a common use, the alternatives set forth in the Markush grouping in claim 9 do not share a substantial structural feature that is essential to their use as a supportive agent. See MPEP 2117(B).
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Interpretation
Claim 1 recites the preamble “A composition for protecting tissue at a site of injury” in line 1. The phrase “for protecting tissue at a site of injury” is a recitation of intended use, which does not impart a structural limitation to the composition as claimed, and therefore is not given patentable weight. See MPEP 2111.02(II).
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, 6, 9, and 16-18 are rejected under 35 U.S.C. 103 as being unpatentable over Fedorchak (US20150374633A1), in view of Westensee (Small, 2021, 17(24): e2007959) and Rotfogel (US20220168358A1).
Regarding claim 1: 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 does not teach a hydrogel with isolated mitochondria suspended therein.
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 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).
Rotfogel teaches a method for transplanting viable exogenous, isolated mitochondria to ocular tissues. Rotfogel teaches that the transplantation method may be via direct injection (Fig 1B). Rotfogel teaches that mitochondrial transplantation, a therapeutic strategy attempted for treatment of ischemic insults in the heart, liver, and nervous system, results in the internalization of the mitochondria by the distressed cells and protects them from cell death (para 6). Rotfogel teaches that a fresh reservoir of healthy mitochondria decreases ROS production within the cell, provides a new pool of intact, exogenous mtDNA and increases energy production and calcium buffering capacity, and that internalized exogenous mitochondria may also provide the cell with enough energy for mitophagy of damaged mitochondria (a form of mitochondria-specific targeted autophagy), contributing to cell survival (para 6).
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 Fedorchak to suspend isolated mitochondria, as taught in Westensee, to transplant mitochondria to replace damaged mitochondria, as taught in Rotfogel. One of ordinary skill in the art would have been motivated to make this modification because Rotfogel teaches that transplanting exogenous mitochondria has therapeutic benefits. One of ordinary skill in the art would have had a reasonable expectation of successfully making this modification because Westensee teaches that mitochondria 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 claim 6: 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).
Regarding claim 9: Fedorchak teaches that the agent for inclusion in the delivery system may be a therapeutic agent, including antibacterials, antifungals, anti-inflammatory agents, and steroids (para 41).
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).
Regarding claim 18: 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.
Claim(s) 7-8 are rejected under 35 U.S.C. 103 as being unpatentable over Fedorchak (US20150374633A1), in view of Westensee (Small, 2021, 17(24): e2007959), Rotfogel (US20220168358A1), and Deplace (Journal of Controlled Release, 2019, 293: 10-20).
The teachings of Fedorchak, Westensee, and Rotfogel are set forth above.
Fedorchak, in view of Westensee and Rotfogel, renders obvious claim 1.
Fedorchak, in view of Westensee and Rotfogel, does not teach a hydrogel comprising hyaluronic acid (HA) and methylcellulose (MC).
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 Fedorchak, in view of Westensee and Rotfogel, by substituting the thermogelling hydrogel, as taught in Fedorchak, with 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) 10-11 are rejected under 35 U.S.C. 103 as being unpatentable 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).
The teachings of Fedorchak, Westensee, and Rotfogel are set forth above.
Fedorchak, in view of Westensee and Rotfogel, renders obvious claim 1.
Regarding claim 10: Fedorchak, in view of Westensee and Rotfogel, 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 Fedorchak, in view of Westensee and Rotfogel, 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) 12-13 are rejected under 35 U.S.C. 103 as being unpatentable 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).
The teachings of Fedorchak, Westensee, and Rotfogel are set forth above.
Fedorchak, in view of Westensee and Rotfogel, renders obvious claim 1.
Regarding claim 12: Fedorchak, in view of Westensee and Rotfogel, 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 Fedorchak, in view of Westensee and Rotfogel, 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: Fedorchak, in view of Westensee, Rotfogel, 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) 14 is rejected under 35 U.S.C. 103 as being unpatentable 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).
Fedorchak, in view of Westensee and Rotfogel, renders obvious claim 1.
As set forth above in the rejection for claim 10, Fedorchak, in view of Westensee, Rotfogel, 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, Fedorchak, in view of Westensee, Rotfogel, 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).
Conclusion
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
/TITILAYO MOLOYE/Primary Examiner, Art Unit 1632