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 .
Claims 2, 3, 10-18 have been canceled. Claims 1, 4-9 are pending and under consideration.
Applicant's arguments filed 11-13-25 have been fully considered but they are not persuasive.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim Objections
Claim 1 is elliptical and convoluted with a patchwork of elements that can be written more simply and concisely. Claim 1 recites two active steps that can be delineated using “a)” and “b)” for ease of examination. Claim 1 requires two active steps but never results in a rat with constipation. The final active step does not have a functional limitation that require gavage feeding the rat loperamide results in constipation. The phrase “caused by liver depression and spleen deficiency” in the phrase “constipation caused by liver depression and spleen deficiency” is a mechanism of action and does not distinguish the constipation obtained in the rat from any other form of constipation. The term “min” in claim 1 should be ---minutes---. Claim 1 can be written more clearly as ---A method of making a rat model of constipation, the method comprising:
a) clamping the tail of a Sprague Dawley rat 2-4 times for 30 minutes for 4 continuous days;
b) gavage feeding the rat obtained in step a) with 3.5-7 mg/kg of loperamide the next day such that rat becomes constipated---.
Citations
The reference cited as Bowsu (“Effect of Recovery on Brain Intestinal Peptides of Functionally Constipated Gas Pogged Rats”, Bulletin of Beijing University of Chinese Medicine, 2021, Vol. 44, No. 7, pp. 615-624) in the office action sent 9-8-25 is more accurately cited as Tang (“Effects of Liqi Tongbian Formula on Brain-Gut Peptides in rats with functional constipation of qi stagnation pattern”, Journal of Beijing University of Traditional Medicine, 2021, Vol. 44, No. 7, pg 615-624). A translation has been attached herewith.
The reference cited as King Lemna (Chinese Journal of Experimental Protocols, 2021, Vol. 27, No. 20, pp. 200-205) in the office action sent 9-8-25 is more accurately cited as Wang (“Analysis of Animal Models of constipation based on characteristics of clinical symptoms of traditional Chinese and western medicine”, Chinese J. Experimental Traditional Medicine Formulae, 2021, Vol. 27, No. 20, pg 1-6). A translation has been attached herewith.
The reference cited as Clinical District Thought PBL tutorial of Chinese medicine, Ed. Lee China, Chinese Chinese Medical Press, page 198, publication date 2018-05-31 in the office action sent 9-8-25 is more accurately cited as Li (Clinical Dialectical Thinking PBL Tutorial, Chinese Medical Press, 2018, pg 198).
Claim Rejections - 35 USC § 101
The rejection of claims 10-17 under 35 U.S.C. 101 has been withdrawn because the claims have been canceled.
Claim Rejections - 35 USC § 112
Written Description
Claims 1, 4-9 remain rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The specification lacks written description for clamping the tail of a rat 2-4 times a day for 30 min for 4 continuous days followed by gavaging the rat with 3.5-7 mg/kg of loperamide the next day such that a “rat model of constipation caused by liver depression and spleen deficiency” is obtained as required in claim 1.
Claim 1 is drawn to a construction method for a rat model of constipation caused by liver depression and spleen deficiency, comprising: clamping the tail of the rat with a clamp 2-4 times every day, wherein the clamping performed for 30 min each time and is performed continuously for 4 days; and after the tail-clamping irritation treat, gavaging the rat with 3.5-7 mg/kg of loperamide the next day, wherein the rat is a Sprague Dawley rat.
Tang (“Effects of Liqi Tongbian Formula on Brain-Gut Peptides in rats with functional constipation of qi stagnation pattern”, Journal of Beijing University of Traditional Medicine, 2021, Vol. 44, No. 7, pg 615-624) made a constipated rat model by administering 10 mg/kg gavage of a co-diphenoxylate suspension diluted with normal saline 4 ml/day according to rat body weight, once a day for 1 session for 7 d, an intercourse rest for 1 d, and a continuous molding for 2 sessions. Meanwhile, in conjunction with the tail-clip irritation method, a gas-lagged rat model was established by wrapping each group of rats with gauze-tapped rat tails with pineapple clips, keeping the whole cage rats in irritation for 30 min each stimulation, twice daily, 8 h apart for 14 consecutive stimulations. The functional constipation gas stagnation model was successfully modeled when rats presented with irritability, irritability, hard stool dry on regular feed, prolonged first-grain black stool expulsion time, and the like (see section 2.1 of Tang). The constipation in the rat of Tang must be caused "liver-depression and spleen deficiency" as required in the preamble of claim 1 because it has the same structure as the rat described by Tang, i.e. it is constipated.
Wang (“Analysis of Animal Models of constipation based on characteristics of clinical symptoms of traditional Chinese and western medicine”, Chinese J. Experimental Traditional Medicine Formulae, 2021, Vol. 27, No. 20, pg 1-6) disclosed that the mechanism of action of the combined diphenoxylate constipation modeling approach is, constipation by exciting gut smooth muscle, inhibiting gut motility, slowing down the transport of contents, utilizing adverse effects; whereas the loperamide constipation modeling method acts by inhibiting intestinal water secretion and colonic peristalsis, delaying fecal egress time and intestinal lumen transit (see Wang Table 2). It can be seen that co-diphenoxylate acts similarly to loperamide and inhibits intestinal motility and slows down the transport of contents. Thus, Wang taught gavaging with loperamide instead of co-diphenoxylate to construct a constipation model.
CN 114788827 taught clamping the tail of a rat to make a model of irritable bowel syndrome (para 40, 72, 94).
The specification and the art at the time of filing did not teach constipation from loperamide and tail clamping was “caused by liver depression and spleen deficiency” as required in claim 1.
The specification uses the phrase frequently, specifically in the examples (pg 7, line 7-8, Example 1, and throughout pg 10-19). For example, paragraph 75 sets forth 9 phenotypes in the rat and somehow concludes they indicate tail-clamping irritation and loperamide treatment can make a rat model of liver depression and spleen deficiency. However, the specification and the art never define when a liver is “depressed”, and the specification never test the liver of the constipated rat for anything, especially for a “depressed” liver. The specification and the art never define when a spleen is “deficient”, and the specification never test the spleen of the constipated rat for anything, especially for whether it is “deficient”. Moreover, none of the 9 phenotypes observed in the rat (items 1-9 in para 75) have anything to do with liver depression or spleen deficiency. Accordingly, the concept lacks written description.
Response to arguments
Applicants argue the specification uses the phrase in paragraph 75 which says the results indicate tail-clamping irritation and loperamide treatment can make a rat model of liver depression and spleen deficiency. Applicants’ argument is not persuasive. The specification never test the liver or spleen of the constipated rat for anything, especially for a “depressed” liver or “deficient” spleen. The specification and the art never define when a liver is “depressed” or a spleen is “deficient”. None of the 9 phenotypes observed in the rat (items 1-9 in para 75) have anything to do with liver depression or spleen deficiency.
Enablement
Claims 1, 4-9 remain 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 clamping the tail of a rat followed by gavaging the rat with loperamide such that constipation occurs in the rat, does not reasonably provide enablement for obtaining constipation “caused by liver depression and spleen deficiency” as required in claim 1. 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/use the invention commensurate in scope with these claims.
The specification does not enable clamping the tail of a rat repeatedly for 3-5 days followed by gavaging the rat with 3.5-7 mg/kg of loperamide the next day such that a “rat model of constipation caused by liver depression and spleen deficiency” is obtained as required in claim 1.
Claim 1 is recited above.
Tang and Wang and CN 114788827 are described above.
The specification and the art at the time of filing did not teach constipation from loperamide and tail clamping was “caused by liver depression and spleen deficiency” as required in claim 1.
The specification uses the phrase frequently, specifically in the examples (pg 7, line 7-8, Example 1, and throughout pg 10-19). For example, paragraph 75 sets forth 9 phenotypes in the rat and somehow concludes they indicate tail-clamping irritation and loperamide treatment can make a rat model of liver depression and spleen deficiency. However, the specification and the art never define when a liver is “depressed”, and the specification never test the liver of the constipated rat for anything, especially for a “depressed” liver. The specification and the art never define when a spleen is “deficient”, and the specification never test the spleen of the constipated rat for anything, especially for whether it is “deficient”. Moreover, none of the 9 phenotypes observed in the rat (items 1-9 in para 75) have anything to do with liver depression or spleen deficiency. Given the lack of guidance in the specification taken with the art at the time of filing, it would have required those of skill undue experimentation to determine how to do so.
Response to arguments
Applicants argue the specification uses the phrase in paragraph 75 which says the results indicate tail-clamping irritation and loperamide treatment can make a rat model of liver depression and spleen deficiency. Applicants’ argument is not persuasive. The specification never test the liver or spleen of the constipated rat for anything, especially for a “depressed” liver or “deficient” spleen. The specification and the art never define when a liver is “depressed” or a spleen is “deficient”. None of the 9 phenotypes observed in the rat (items 1-9 in para 75) have anything to do with liver depression or spleen deficiency.
Indefiniteness
Claims 1, 4-9 remain 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 metes and bounds of constipation “caused by liver depression and spleen deficiency” after clamping the tail of a rat followed by gavaging with loperamide as required in claim 1 cannot be determined. The metes and bounds of when a liver is “depressed” and a spleen is “deficient” are not defined in the specification or the art at the time of filing. It is unclear how constipation caused by a “depressed liver” and “deficient” spleen (as a result of clamping the tail of a rat followed by gavaging with loperamide) differs from constipation caused by clamping the tail of a rat followed by gavage with loperamide. It is unclear whether it is enough for the rat to be constipated (after clamping the tail of a rat followed by gavaging with loperamide) or if a mechanism of action must occur to meet the limitation claimed. If clamping the tail of a rat followed by gavaging with loperamide inherently MUST cause “liver depression and spleen deficiency”, then the phrase “caused by liver depression and spleen deficiency” does not further limit how the rat was made; it is simply a mechanism of action that inherently MUST occur. If the amount of time for tail clamping and gavaging with loperamide is essential to cause liver “depression” and spleen “deficiency”, then clarification is required.
Response to arguments
Applicants argue the specification uses the phrase in paragraph 75 which says the results indicate tail-clamping irritation and loperamide treatment can make a rat model of liver depression and spleen deficiency. Applicants’ argument is not persuasive. The specification never test the liver or spleen of the constipated rat for anything, especially for a “depressed” liver or “deficient” spleen. The specification and the art never define when a liver is “depressed” or a spleen is “deficient”. None of the 9 phenotypes observed in the rat (items 1-9 in para 75) have anything to do with liver depression or spleen deficiency.
B) The metes and bounds of “irritating a rat via a tail-clamping irritation treatment, comprising clamping a tail of the rat with a clamp 2-4 times every day, wherein the clamping is performed for 30 min each time and is performed continuously for 4 days” in claim 1 are unclear which makes the claim indefinite. While the tail of a rat may be clamped, and the clamp may be “irritating”, it is unclear the “irritation treatment” must be more than just the clamp 2-4 times every day for 30 min each time and is performed continuously for 4 days. It is unclear if the claim is limited to clamping the tail or if the claim is clamping the tail for 30 minutes 2-4 times a day for at least 4 continuous days or if something more is required, i.e. a chemical irritant. Furthermore, the phrase “performed continuously for 4 days” does not make sense with the phrase “2-4 times a day for 30 min each time”. Clamping cannot occur “2-4 times a day for 30 min each time” and while clamping is “performed continuously for 4 days” as claimed. While clamping for 30 minutes may be performed 2-4 times a day for 4 continuous days, claim 1 does not say that. Overall, the way the clamping step is written is indefinite because the metes and bounds are unclear.
Response to arguments
Applicants argue the amendment overcomes the rejection. Applicants’ argument is not persuasive for reasons set forth above.
Claim Rejections - 35 USC § 103
A) Claims 1, 4-9 as newly amended are rejected under 35 U.S.C. 103 as being unpatentable over Tang (“Effects of Liqi Tongbian Formula on Brain-Gut Peptides in rats with functional constipation of qi stagnation pattern”, Journal of Beijing University of Traditional Medicine, 2021, Vol. 44, No. 7, pg 615-624) in view of Itanomi (Sci. Rep., 2021, Vol. 11, No. 24098, pg 1-9), Choi (Experimental and Therap., 2014, Vol. 8, No. 1847-1854), Choi (Evidence-Based Complementary and Alternative Med., 2014, No. 878503, pg 1-12), Bustos (Acta Gastroenterol Latinoam. 1991;21(1):3-9), Wang (“Analysis of Animal Models of constipation based on characteristics of clinical symptoms of traditional Chinese and western medicine”, Chinese J. Experimental Traditional Medicine Formulae, 2021, Vol. 27, No. 20, pg 1-6), and Li (Clinical Dialectical Thinking PBL Tutorial, Chinese Medical Press, 2018, pg 198).
Tang made a rat model of constipation by administering 10 mg/kg gavage of a co-diphenoxylate suspension diluted with normal saline 4 ml/day/body weight to a Wistar Rat, once a day for 1 session for 7 d, an intercourse rest for 1 d, and a continuous molding for 2 sessions. Meanwhile, in conjunction with the tail-clip irritation method, a gas-lagged rat model was established by wrapping each group of rats with gauze-tapped rat tails with pineapple clips, keeping the whole cage rats in irritation for 30 min each stimulation, twice daily, 8 h apart for 14 consecutive days. The functional constipation gas stagnation model was successfully modeled when rats presented with irritability, irritability, hard stool dry on regular feed, prolonged first-grain black stool expulsion time, and the like (see section 2.1 of Tang). The constipation in the rat of Tang must be caused "liver-depression and spleen deficiency" as required in the preamble of claim 1 because Tang clamped for 30 min each stimulation, twice daily, 8 h apart for 14 consecutive days, because the rat of it has the same structure as the rat described by Tang, i.e. it is constipated.
Tang did not teach the rat was a Sprague Dawley rat or that the rat was given loperamide (Tang is limited to using co-diphenoxylate) as required in claim 1.
However, Inatomi induced constipation in Sprague Dawley rats by oral administration of loperamide (pg 5, “Constipation induction in the rats”) using the methods of citations 32-35 (Choi (Exp. Ther. Med. 2014), Choi (Evid. Based Complement. Alternat. Med. 2014), Bustos, Wintola).
Choi (Exp. Ther. Med. 2014) induced constipation in Sprague Dawley rats by “oral administration” of loperamide (pg 1848, “Animals”) using the methods of citations 22, 23 (Bustos, Wintola).
Choi (Evid. Based Complement. Alternat. Med. 2014) induced constipation in Sprague Dawley rats by “oral administration” of loperamide (pg 1848, “Animals”) using the methods of citations 36, 37 (Bustos, Wintola).
Wintola induced constipation in rats by “oral administration” of loperamide (pg 5, “Constipation induction in the rats”) using the methods of citation 16 (Bustos).
Bustos induced constipation in rats by “oral administration” of loperamide (pg 4, “Materials and Methods”).
Wang taught that the mechanism of action of using loperamide and to replicate the blood deficiency constipation, yin deficiency constipation, and yang deficiency constipation rat models respectively, which can be used to carry out basic research on deficiency constipation [45].” (pg 7 of translation).
Thus, it would have been obvious to those of ordinary skill in the art at the time of filing to make a rat model of constipation using a chemical combined with tail clamping as described by Tang using loperamide as described by Wang. Those of ordinary skill in the art at the time of filing would have been motivated to switch co-diphenoxylate with loperamide because Wang taught it inhibited intestinal water secretion and colonic peristalsis and delayed fecal egress time and intestinal lumen transit. Using a Sprague Dawley rat as a model of constipation using loperamide was taught by Inatomi, Choi, and Choi. Using a Sprague Dawley rat instead of a Wistar rat was merely a matter of design choice.
Tang did not teach the tail was clamped 2-4 times/day for 30 min each for 4 continuous days as encompassed by claim 1. However, specific clamping times are determined by routine experimentation by those skilled in the art depending on the particular animal strain, physiological condition of the animal, and the like. Those of ordinary skill in the art at the time of filing would have been motivated to clamp 2-4 times/day for 25-35 min each continuously for 3-5 days as required in claim 1 as a matter of design choice. The clamping is determined by routine experimentation by those skilled in the art depending on the particular animal strain, physiological condition of the animal, and the like.
Claim 4 is obvious because the number of tail clipping, the length of tail clipping and the continuous treatment time are determined by routine tests by those skilled in the art depending on the particular animal strain, the physiological condition of the animal and the like.
Claim 5 is obvious because the pathology specimen is obtainable by a person skilled in the art by routine selection according to actual needs.
Claims 6-8 are obvious because both the clipping position and the application of the wounded site with an iodophor are conventional technical means.
Claim 9 is obvious because Tang does not recite a special diet, the rat in Tang is considered to be in a free diet state.
Claims 10-18 require use of a liver-depression spleen imaginary constipation rat model constructed according to any one of claims 1 to 9 for screening and/or evaluating a medicament for anti-liver-depression spleen imaginary constipation. The person skilled in the art knows that hepatic depression virtual constipation is mainly manifested by symptoms such as irritability and constipation (cf. Common general knowledge 1, Clinical District Thought PBL tutorial of Chinese medicine, Ed. Lee China, Chinese Chinese Medical Press, page 198, publication date 2018-05-31). From the disclosures of Tang and Wang, it is known that treatment with caudal irritation and gavage of loperamide can cause symptoms such as irritability, irritability and constipation in rats. Accordingly, it will be apparent to those skilled in the art that a rat model constructed according to the methods of claims 1-9 is used for screening or evaluation of liver-depressed spleen imaginary type constipation drugs as required in claims 10-18.
Response to arguments
Applicants argue constipation is more difficult to establish in Sprague Dawley rats (pg 10). Applicants quotes a reference that says “Sprague Dawley (SD) rats were bred from Wistar rats. SD rats are more aggressive in temperament than Wistar rats, and possess stronger adaptability and disease resistance. (Experimental Animal Center, Tsinghua Univ. Differences between wistar rats and SD rats [EB/OL]; https://larc.tsinghua.ed.cn/post/334” (pg 11). Applicants’ argument is not persuasive. Using a Sprague Dawley rat as a model of constipation using loperamide was taught by Inatomi, Choi, and Choi. Using a Sprague Dawley rat instead of a Wistar rat was merely a matter of design choice. The claims do not require obtaining any amount of efficiency in obtaining constipation in the rat; any amount will do. The reference mentioned by applicants is improperly cited because it is missing the author, journal title, volume and page numbers. The website address was attempted but did not result in anything similar to the quote used by applicants. The sentence cited by applicants cannot be used to determine what was known at the time of filing because it was published in 2024. The sentence cited by applicants actually shows the advantage of using SD rats because they have “stronger adaptability and disease resistance”, so the citation does not help applicants’ argument.
Applicants argue the claimed invention uses a method with an irritation intensity that is weaker than those used in Tang. Applicants’ argument is not persuasive. The claims are not limited to clamping the tails of the rats for only 4 days; the claims encompass clamping the tails for 4 or more days. Tang clamped the tails for 30 min twice daily, 8 h apart for 14 consecutive days. Modifying the clamping schedule was well-within the skill of the ordinary artisan at the time of filing and obvious to do so for reasons set forth in the rejection.
Applicants argue the dosage of loperamide required to establish constipation is higher than diphenoxylate. Applicants’ argument is not persuasive. The amount of loperamide required to establish constipation in rats was well-known and described by Inatomi, Choi (Exp. Ther. Med. 2014), Choi (Evid. Based Complement. Alternat. Med. 2014), Wintola, and Bustos (see citations above).
Applicants somehow conclude those of skill would not think of replacing co-diphenoxylate with loperamide (pg 13). Applicants’ argument is not persuasive because the conclusion does not naturally or logically flow from the art at the time of filing. It was well-known to compare various means of inducing constipation in rats as described by Wintola compares aqueous leaf extract “Aloe ferox Mill.” vs. Loperamide. Those of ordinary skill in the art at the time of filing would have been motivated to switch co-diphenoxylate with loperamide because Wang taught it inhibited intestinal water secretion and colonic peristalsis and delayed fecal egress time and intestinal lumen transit.
Applicants point to para 4-6 which teaches the method claimed is different than the one described by Tang. Applicants’ argument is not persuasive. Tang does not teach all the limitations claimed, so that’s why this is an obviousness rejection.
Conclusion
No claim is allowed.
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.
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Michael C. Wilson
/MICHAEL C WILSON/
Primary Examiner, Art Unit 1638
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