DETAILED ACTION
The present application is a national stage entry of PCT/CN2022/127372, filed 25 October 2022, which claims priority to US Provisional Application No. 63/271,411, filed 25 October 2021.
The preliminary amendment filed 25 April 2024 is acknowledged. Claims 1-8 are pending in the current application and are examined on the merits herein.
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 .
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 120 as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of the first paragraph of 35 U.S.C. 112. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994). Also, see MPEP 706.02 (section VI).
The disclosure of the prior-filed application(s), US 63/271,411, fails to provide adequate support or enablement in the manner provided by the first paragraph of 35 U.S.C. 112 for one or more claims of this application. Specifically, these applications fail to provide enablement for “wherein the isorhoifolin derivative is narirutin” (claim 2); “central nervous system or peripheral nervous system injury” (claim 3); “retinal neurons” (claim 5); “when administered nasally, can penetrate the blood-brain barrier to enter the brain” (claim 7); or the effective dosage range of claim 8. Therefore, the effective filing date of claims 2, 3 and 5-8 is seen to be the effective filing date of the claimed invention, 25 October 2022.
If applicant disagrees, applicant should present a detailed analysis as to why the claimed subject matter has clear support in the earlier priority applications. Applicant is reminded that such priority for the instant limitations requires written description and enablement under 35 U.S.C. § 112, first paragraph.
In clarifying the priority date of the instant claims, applicant should note or address whether the art rejections are prior to the priority date of the instant claims and whether said art occurred more than one year prior to said priority date. Applicant will note that the art rejections are under both 35 U.S.C. § 102(a) and 102(b) because the priority date of the instant claims is in question.
Claim Interpretation
The recitation “isorhoifolin derivative” is broadly and reasonably interpreted to include hesperidin.
Claim Rejections - 35 USC § 112(b)
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 8 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.
The recitation “wherein the effective dosage range…is from 1 nM to 864 µM” in claim 8 renders the claim herein indefinite. A concentration represents the amount of substance (e.g. in this case, nanomoles or micromoles) per liter of solution. However, it does not provide any information as to how much of the substance, i.e. dose, is administered to a subject. A dose is typically provided as a total amount (e.g. in milligrams or grams), or as an amount per body weight of the subject (e.g. mg/kg body weight).
Where applicant acts as his or her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999).
Because of the high level of uncertainty as to what the claim refers to and what is required of the invention as claimed, claim 8 is not further examined on the merits herein.
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.
Claim(s) 1 and 3-7 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Maekawa et al. (Scientific Reports, 2017, vol. 7, no. 6885, 13 pages, cited in PTO-892).
Maekawa et al. found hesperidin has a neuroprotective effect in a retinal injury mouse model (title). Intravitreal injection of hesperidin prevented a reduction in markers of the retinal ganglion cells (RGCs) and RGC death after N-methyl-D-aspartate (NMDA)-induced excitotoxicity (abstract). The concentration of hesperidin was 17% w/v in 15 µM NMDA. Hesperidin treatment also reduced calpain activation, reactive oxygen species generation and TNF-α gene expression. It also improved electrophysiological function and visual function. It suppressed multiple cytotoxic factors associated with cell death signaling, including oxidative stress, over-activation of calpain, and inflammation. Thus, Maekawa et al. teach hesperidin may be a useful therapeutic supplement in protecting the retina against excitotoxic injury that occurs in glaucoma and diabetic retinopathy.
Thus, Maekawa et al. disclose the use of hesperidin (i.e. an isorhoifolin derivative) for the treatment of neural injury, which is a central nervous system injury, that comprises retinal neurons.
The recitation “wherein the treating is neural regeneration, increase in the number of neurons, or neural repair” in claim 6 necessarily occurs upon performing the positively recited steps.
The recitation “when administered nasally, can penetrate the blood-brain barrier to enter the brain” in claim 7 is an intended use of an optional limitation.
Thus, the disclosure of Maekawa et al. anticipates claims 1 and 3-7 of the present application.
Claim(s) 1 and 3-7 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kim et al. (Anatomy & Cell Biology, 2019, vol. 52, pp. 369-377, cited in PTO-892)
Kim et al. teach hesperidin has a variety of biological properties that include antioxidant and anti-inflammatory action (abstract). These properties have been observed in models of cardiovascular disease, diabetes, and for preventing cancer (p.369). Hesperidin has also been observed to ameliorate symptoms in animal models of neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, depression, neuroimmunological multiple sclerosis, brain ischemia-reperfusion injury, and traumatic injury in central nervous system (CNS) tissues (p.369-370, bridging para). According to Table 1, studies have been performed where hesperidin was administered to mice with mild traumatic brain injury (see ref. 20). Kim et al. teach “The beneficial effects of citrus flavonoids, including hesperidin, have been reviewed in the context of their neuropharmacological properties and neuroprotective capabilities with a special focus on anti-depressive actions and protection against learning and memory deficits” (p.370). Hesperidin reduced TNF-α, in a model of neuroinflammation in the hippocampus (p.370). “Thus, it can be postulated that, similar to other antioxidant flavonoids, hesperidin activates radical scavenging activity and subsequently attenuates the inflammatory response to be ultimately protective against cell death” (p.370, last para). Hesperetin (aglycone of hesperidin) can permeate the blood brain barrier to influence neurons and neuroglial cells directly in damaged regions (p.373-374, bridging para). Kim et al. teach hesperidin protects neurons against death and promotes the survival of neuronal progenitor cells (p.374, first para).
Thus, Kim et al. disclose the use of hesperidin (i.e. an isorhoifolin derivative) for the treatment of neural injury, which is a central nervous system injury. Kim et al. also disclose the use of hesperidin for the treatment of a neural injury that comprises hippocampal nerves.
The recitation “wherein the treating is neural regeneration, increase in the number of neurons, or neural repair” in claim 6 necessarily occurs upon performing the positively recited steps.
The recitation “when administered nasally, can penetrate the blood-brain barrier to enter the brain” in claim 7 is an intended use of an optional limitation.
Thus, the disclosure of Kim et al. anticipates claims 1 and 3-7 of the present application.
Claim Rejections - 35 USC § 103
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 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.
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.
Claim(s) 1-7 are rejected under 35 U.S.C. 103 as being unpatentable over Maekawa et al. (cited above) in view of Kim et al. (cited above) and further in view of Patel et al. (Nutritional Neuroscience, 2022, vol. 25, no. 5, pp. 920-930, published September 2020, cited in PTO-892).
Maekawa et al. teach as discussed above.
Maekawa et al. do not expressly disclose isorhoifolin (present claim 1) or narirutin (present claim 2).
Kim et al. teach hesperidin has a variety of biological properties that include antioxidant and anti-inflammatory action (abstract). These properties have been observed in models of cardiovascular disease, diabetes, and for preventing cancer (p.369). Hesperidin has also been observed to ameliorate symptoms in animal models of neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, depression, neuroimmunological multiple sclerosis, brain ischemia-reperfusion injury, and traumatic injury in central nervous system (CNS) tissues (p.369-370, bridging para). According to Table 1, studies have been performed where hesperidin was administered to mice with mild traumatic brain injury (see ref. 20). Kim et al. teach “The beneficial effects of citrus flavonoids, including hesperidin, have been reviewed in the context of their neuropharmacological properties and neuroprotective capabilities with a special focus on anti-depressive actions and protection against learning and memory deficits” (p.370). Hesperidin reduced TNF-α, in a model of neuroinflammation in the hippocampus (p.370). “Thus, it can be postulated that, similar to other antioxidant flavonoids, hesperidin activates radical scavenging activity and subsequently attenuates the inflammatory response to be ultimately protective against cell death” (p.370, last para). Hesperetin (aglycone of hesperidin) can permeate the blood brain barrier to influence neurons and neuroglial cells directly in damaged regions (p.373-374, bridging para). Kim et al. teach hesperidin protects neurons against death and promotes the survival of neuronal progenitor cells (p.374, first para).
Patel et al. disclose orally administering narirutin-rich fraction (NRF, 150, 300 mg/kg) to rats subjected to bilateral carotid artery occlusion to induce cerebral ischemia/reperfusion injury (abstract). They found seven-day NRF pre-treatment protected against neurobehavioral alterations. The structure of narirutin is shown in figure 1:
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. NRF pre-treatment groups showed significant reduction in neurological disability scale (p.923, Effect of NRF treatment on behavioral parameters). In the histopathological study, they found the 300 mg/kg NRF pre-treatment protected brain cells from ischemic damage (p.925-926, Histopathology). Patel et al. teach “The brain regions of narirutin-treated animals exhibited undamaged neuronal cells with distinctive cell nucleus and continuous cell membrane, indicating the protective effect of narirutin in cerebral ischemia” (p.929, first para). Patel et al. conclude “Collectively the data suggest that narirutin displays free radical scavenging property and the ability to modulate oxidative impairment caused by cerebral I/R. Narirutin can be effectively employed to abate the oxidative stress during ischemic injury in vivo.” (p.929, last para).
The structure of hesperidin is as follows:
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. Another view of narirutin is provided here:
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. The structure of isorhoifolin is also provided:
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.
The differences between the three flavonoid glycosides lie in the flavone/flavonone moiety. Hesperidin contains a 4’-OCH3,5’-OH flavonone; Narirutin contains a 4’-OH flavonone; while isorhoifolin contains a 4’0OH flavone.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to administer hesperidin, narirutin or isorhoifolin to treat neural injury.
From the combined teaching of Maekawa et al. and Kim et al., the ordinary artisan would have been motivated to administer hesperidin to treat neural injury, by administering the hesperidin to the subject, because Maekawa et al. teach the flavonone glycoside has a neuroprotective effect in a retinal injury mouse model. Additionally, Kim et al. teach hesperidin was effective in ameliorating symptoms in brain ischemia-reperfusion injury, and traumatic injury in central nervous system (CNS) tissues. Hesperidin was also found to have a therapeutic effect in a mild traumatic brain injury model. Hesperidin also reduced TNF-α, in a model of neuroinflammation in the hippocampus.
The ordinary artisan would have been motivated to substitute hesperidin with narirutin, because they are structurally similar, and recognized classes of flavonoid glycosides. Additionally, Patel et al. found 300 mg/kg narirutin-rich fraction pre-treatment protected brain cells from ischemic damage. Thus, the ordinary artisan would have had a reasonable expectation of success given their close structural similarity, similar chemical class, and similar therapeutic efficacy as hesperidin in brain-ischemia reperfusion injury model.
Similarly, the ordinary would have been motivated to substitute hesperidin with isorhoifolin, because it is also structurally similar to narirutin, differing only by a double bond in the flavone moiety. The ordinary artisan would have had a reasonable expectation of success given their close structural similarity, similar chemical class, and similar therapeutic efficacy of hesperidin and narirutin in brain-ischemia reperfusion injury model.
Thus, the claimed invention as a whole is prima facie obvious over the combined teaching of the prior art.
Conclusion
In view of the rejections to the pending claims set forth above, no claim is allowed.
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/BAHAR CRAIGO/
Primary Examiner
Art Unit 1699
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