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 .
Status of the Claims
The status of the Claims are as follows:
Claims 1-10 are under consideration.
Claims 1-10 are rejected.
Priority
Acknowledgement is made that instant application 18/720,446, filed on 2024, Jun. 24, is a national stage entry of PCT/JP2022/046046, filed on 2022, Dec. 14, which claims foreign priority to JP2021-203424, filed on 2021, Dec. 15.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 2024, Jun. 14 and 2025, Nov. 20 is/are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement(s) is/are being considered by the examiner.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
Claim 5 and 10 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treatment of meteoropathy by administering kaempferol in a subject, does not reasonably provide enablement for prevention of said condition. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims. This is a scope of enablement rejection.
In this regard, the application disclosure and claims have been compared per the factors indicated in the decision In re Wands, 8 USPQ 2nd 1400 (Fed. Cir. 1988) as to undue experimentation. The factors include: (a) The nature of the invention; (b) The breadth of the claims; (c) The relative skill of those in the art; (d) Status of the prior art/predictability or unpredictability of the art (e) the amount of direction or guidance presented; (f) the presence or absence of working examples and (g) the quantity of experimentation necessary. Each factor is addressed below on the basis of comparison of the disclosure, the claims and the state of the art in the assessment of undue experimentation.
The nature of the invention: The invention is directed to methods of using kaempferol and/or glycosides thereof in regulating the autonomic nervous system.
The breadth of the claim: The scope of the claims includes a method for alleviation, prevention, or treatment of meteoropathy, comprising administering kaempferol and/or a glycoside thereof to a subject in need thereof.
The relative skill of those in the art: The level of skill is high comparable to that of an M.D. or Ph.D.
Status of the prior art/predictability or unpredictability of the art: It is known in the art that patients with rheumatoid arthritis, fibromyalgia, and other disorders often experience pain when atmospheric pressure decreases (see Bando, Weather-related pain or meteoropathy has been attracting attention. J Health Care and Res. 2021, 2(3)153-156. Doi 10.36502/2021/hcr.6201). Bando discusses a large survey on weather-related pain conducted in Japan for 16,482 cases, wherein 25% of eligible participants reported chronic pain that becomes worse with weather deterioration and 47% reported chronic pain that becomes worse with cold weather (page 154, right left column, paragraph 2). Participants indicated a diverse range of symptoms including headache (51.0%), neck and shoulder pain (13.4%), arthralgia (12.8%), and low back pain (7.2%) (page 154, left column, paragraph 2). Bando also teaches that mice who were exposed to lowered barometric pressure experienced greater activation of superior vestibular nuclei through higher c-Fos expression (page 154, left column, paragraph 4). It is noted that similar mechanisms may possibly contribute to the meteoropathic mechanism in humans, which highlights our current lack of understanding of the mechanism of action. Bando also teaches that psychosocial factors, such as fear of movement, self-efficacy, coping, and catastrophizing are involved with pain and discomfort in the head, neck, shoulder, and back (page 154, right column, paragraph 1). Bando also teaches exercise therapy as an effective treatment, such as stretching, muscle endurance, and muscle strengthening, depending on the afflicted region (page 155, left column, paragraph 1). As such, the etiology and pathophysiology of the described meteoropathic conditions are highly unpredictable, so one could not accurately predict the correct indication and severity to administer the correct dosage for preventative treatment.
The amount of direction or guidance presented: In the instant case, Applicant has not provided guidance as to how one skilled in the art would accomplish the objective of preventing meteoropathy by administering kaempferol, nor are any references provided that teach the same. Therefore, the instant application is viewed as lacking an adequate enablement of where meteoropathy or weather-related pain may actually be prevented by administering kaempferol.
The present or absence of working examples: No working examples are provided for preventing meteoropathy by administering kaempferol, for example, in a patient in the specification. The applicant has not provided any competent evidence or disclosed any tests that are highly predictive for the preventative effects of the instant composition. Note that in cases involving physiological activity such as the instant case, "the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved." See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
The quantity of experimentation necessary: The quantity of experimentation would be an undue burden to one of ordinary skill in the art. Thus, factors such as “sufficient working examples,” “the level of skill in the art" and "predictability," etc. have been demonstrated to be sufficiently lacking in the instant case for the instant method claim”. In view of the breadth of the claims, the chemical nature for the instant claims and unpredictability of preventing all meteoropathy, and the lack of working examples regarding the activity as claimed, one skilled in the art would have to undergo an undue amount of experimentation to use the instantly claimed invention commensurate in scope with the claims.
In consideration of the Wands factors, it is apparent that there is undue experimentation because of variability in prediction of outcome that is not addressed by the present application disclosure, examples, teaching and guidance presented. Absent factual data to the contrary, the amount and level of experimentation needed is undue.
Claim Rejections - 35 USC § 102/§ 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 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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
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.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
Claim(s) 1-4 is/are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Qu, et al. (hereafter, Qu. CN 106963754 A; published 2017, Jul., 21), and/or are rejected under 35 U.S.C. 103 as being unpatentable over Qu.
Instant claims 1 and 3 are directed to a method for improving sleep quality, comprising administering kaempferol and/or a glycoside thereof to a subject in need, wherein the sleeping heart rate of the subject is lowered.
Qu teaches the application of luteolin or its analogues for the preparation of medicines or health products for regulating the biological rhythm of the body (title, abstract). Qu measured the effect of luteolin on heart rate by daily gavage administration to rats in a closed and isolated compound environment at 25 mg/kg, 50 mg/kg, or 100 mg/kw BW and found that heart rate was significantly reduced during the first week of treatment (Figure 2A, pages 6-7, paragraph 0060). Prior to the effective filing date of the current invention, it was known in the art that sleep quality can be improved by reducing heart rate as evidenced by Qu (page 3, paragraph 0002). Therefore, one of ordinary skill in the art would reasonably conclude that use of luteolin and its analogues to induce a reduced heart rate would directly cause an improvement of sleep quality.
Qu does not explicitly teach an embodiment in which kaempferol is administered to a subject and sleep quality is improved, however, Qu teaches luteolin analogues can be used for the same purpose, wherein the analogue is selected from a list comprising kaempferol and its glycosides (abstract, page 3, paragraph 0007). As such, a person of ordinary skill in the art would at once envisage the claimed invention from the disclosed finite list of functionally equivalent compounds.
In the alternative, it would have been prima facie obvious to arrive at the claimed compound by applying the prong (B) rationale of In re KSR Int’l Co., 550 U.S. 398 (2007), in which obviousness entails simple substitution of one known element for another to obtain predictable results, it would have been obvious for a person of ordinary skill in the art to substitute kaempferol for luteolin to achieve the desired result with a reasonable expectation of success. Also in the alternative, one could apply KSR prong (E) and choose from a finite list to arrive at the instant claims in a predictable manner since the taught compounds are analogs of the tested compound.
Instant claim 2 is drawn to a method of lowering the sleeping heart rate comprising administering kaempferol and/or a glycoside thereof to a subject in need.
As stated above, Qu teaches the use of luteolin to reduce the heart rate of rats (Figure 2A, pages 6-7, paragraph 0060) and the application of luteolin analogues, including kaempferol and its glycosides, for use in the same (abstract, page 3, paragraph 0007). Qu further teaches that luteolin can regulate the biological rhythm of rats, including regulating the heart rate and heart rate rhythm (page 8, paragraph 0079). Qu further teaches that luteolin showed improvement in sleep quality, as reflected by animal activity (Figure 2F, page 5, paragraph 0035). As Qu states that a reduced heart rate aids in improved sleep quality (page 3, paragraph 0002), a person of ordinary skill in the art would therefore have found it obvious that luteolin and its analogues can improve the quality of sleep by lowering the sleeping heart rate of the subject.
Instant claim 4 is drawn to a method for regulating the autonomic nervous system, comprising administering kaempferol and/or a glycoside thereof to a subject in need.
As stated above, Qu teaches the use of luteolin to reduce the heart rate of rats (Figure 2A, pages 6-7, paragraph 0060) and the application of luteolin analogues, including kaempferol and its glycosides, for use in the same (abstract, page 3, paragraph 0007). Qu further teaches that luteolin modulates biological rhythms by regulating oxidative stress in supraoptic nucleus of the central hypothalamus (Figure 3D).
Claim(s) 6-9 is/are rejected under 35 U.S.C. 103 as being unpatentable over Qu in view of Chen, et al. (hereafter, Chen. A review of the dietary flavonoid, kaempferol on human health and cancer chemoprevention. Food Chemistry, 2013, 138, 2099-2107. dx.doi.org/10.1016/j.foodchem.2012.11.139).
Instant claims 6-9 are directed to methods of administering kaempferol and/or a glycoside thereof in the form of a food, beverage, drug, or quasi-drug.
As discussed above, Qu teaches the use of luteolin and its analogues, including kaempferol and its glycosides, to reduce heart rate and improve sleep quality to a patient in need thereof. Qu further teaches gavage administration for regulating said biological rhythms in rats.
The difference between the teachings of Qu and the instant application is that Qu fails to teach administration of kaempferol in the form of a food, beverage, drug, or quasi-drug.
However, Chen, teaches that kaempferol is abundantly found in natural foods, such as tea, broccoli, apples, strawberries, and beans (page 2100, paragraph 2). Therefore, it would have been prima facie obvious to administer to a subject kaempferol in the form of a food or beverage to achieve the same effects as taught by Qu. A skilled artisan would have been motivated to do so because gavage administration is not ideal for administration to a human subject, so providing the dose in a more palatable form would be optimal.
Claim(s) 5 is/are rejected under 35 U.S.C. 103 as being unpatentable over Qu in view of Sato, et al. (hereafter, Sato. Lowering barometric pressure induces neuronal activation in the superior vestibular nucleus in mice. PLOS ONE, 2019, 14(1), e0211297. doi.org/10.1371/journal.pone.0211297) in view of Tang, et al. (hereafter, Tang. CN 109453160 A; published 2019, Mar. 12), as evidenced by Nadjar, et al. (hereafter, Nadjar. Inactivation of the cerebral NFkB pathway inhibits interleukin-1-β-induced sickness behavior and c-fos expression in various brain nuclei. Neuropsychopharmacology, 2005, 30, 1491-1499. Doi: 10.1038/sj.npp.1300755).
Instant claim 5 is drawn to a method for alleviating, preventing, or treating meteoropathy, comprising administering kaempferol and/or a glycoside thereof to a subject.
The teachings of Qu are discussed above and incorporated herein by reference.
While Qu teaches luteolin and its analogues, including kaempferol and its glycosides, are CNS-penetrant and enters the hypothalamus, it fails to teach its use as a treatment option for meteoropathy.
However, Tang teaches the application of kaempferol in a treatment drug for osteoarthritis via reducing environmental inflammation through modulation of NF-κB and MAPK (title, abstract). Tang further teaches that NF-κB inhibition results in reduced expression levels of c-Fos protein (abstract, Figure 7B). As evidenced by Nadjar, the same correlation between NF-κB inhibition and c-Fos expression is found in the brain, whereby a specific inhibitor of NF-κB results in dramatically reduced interleukin-1β-induced c-Fos expression in various brain regions (abstract).
While the combined teachings of Qu and Tang as evidenced by Nadjar demonstrate kaempferol can enter the brain and inhibit c-Fos expression, they fail to teach how downregulation of c-Fos protein is an effective treatment for meteoropathy.
However, Sato teaches meteoropathy is linked to weather changes accompanied by decreases in barometric pressure (abstract). Neuronal activation in the superior vestibular nucleus was determined by using c-Fos protein as an activity marker (abstract). Sato found significant activation in the superior vestibular nucleus following a drop in barometric pressure by 40 hPa from 1013 hPa for 50 min (abstract). The findings showed that low-pressure stimulation increases c-Fos expression in the superior vestibular nucleus suggesting a barometric sensing system that contribute to meteoropathy generation (page 8, paragraph 3).
One of ordinary skill in the art would have been motivated to combine the teachings of Qu, Tang as evidenced by Nadjar, and Sato because they show a direct link between kaempferol and the amelioration of meteoropathy symptoms. Qu teaches brain exposure of luteolin and its analogues, including kaempferol and its glycosides, while Tang as evidenced by Nadjar teaches that the upregulation of c-Fos protein is indirectly stymied by kaempferol-induced inhibition of NF-κB. Sato then teaches that meteoropathy symptoms are likely to arise from a neural barometric sensing system that is activated by enhanced c-Fos expression, and therefore meteoropathy symptoms can be ameliorated by its reduction. Therefore, there was a reasonable expectation of success prior to the effective filing date of the current invention for said artisan to administer kaempferol as a treatment option for meteoropathy. for one to alleviate, prevent, or treat, meteoropathy by administering kaempferol to a patient in need.
Claim(s) 10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Qu in view of Tang as evidenced by Nadjar, in view of Sato, and in further view of Chen.
Instant claims 10 is directed to methods of administering kaempferol and/or a glycoside thereof in the form of a food, beverage, drug, or quasi-drug for the treatment of meteoropathy.
The combined teachings of Qu in view of Tang as evidenced by Nadjar, in view of Sato are discussed above and incorporated herein by reference.
The above combined teachings fail to teach administration in the form of a food, beverage, drug, or quasi-drug. However, this would have been prima facie obvious for a skilled artisan to implement in view of the teachings and argument related to Chen as discussed above.
Conclusion
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/P.A./ Examiner, Art Unit 1621
/CLINTON A BROOKS/ Supervisory Patent Examiner, Art Unit 1621
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