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 .
DETAILED ACTION
Preliminary amendment filed on 04/22/2024 are acknowledged. Claims 3 and 8 were amended. Claims 1-8 are pending in the instant application and are examined on the merits herein.
Priority
This application claims benefit to provisional application 63/497,515 filed on 04/21/2023.
Information Disclosure Statement
The information disclosure statement (IDS) dated 04/19/2024 complies with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609. Accordingly, the IDS document has been placed in the application file and the information therein has been considered as to the merits.
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.
Claims 1-20 are 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.
In claim 1, the phrase “at least one of a pharmaceutically acceptable excipient thereof and a food excipient thereof” renders the claim indefinite because it is unclear whether the composition must include at least one of both a pharmaceutically acceptable excipient and a food excipient, or “at least one of a pharmaceutically acceptable excipient thereof or a food excipient thereof”. For the purposes of applying prior art, the examiner will interpret the claim as “at least one of a pharmaceutically acceptable excipient thereof or a food excipient thereof.” Claims 2-20 are rejected for being dependent on a rejected claim base.
Claim Rejections - 35 USC § 112(a)
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.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
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 of carrying out his invention.
Claims 1-20 are rejected under 35 U.S.C. 112(a), because the specification, while being enabling for inhibiting precocious puberty in a subject, it does not reasonably provide enablement for preventing precocious puberty in a subject. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
With respect to the claimed method, attention is directed to In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. (1) the nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary.
All of the Wands factors have been considered and those most relevant to the cited claims are discussed below.
Nature of the invention: The invention is drawn to a method of preventing precocious puberty in a subject in thereof, comprising administering an effective amount of a composition to the subject, wherein the composition comprises glycyrrhizin or a salt or derivative thereof and at least one of a pharmaceutically acceptable excipient thereof and a food excipient thereof.
Relative skill of those in the art: The relevant art is pharmaceutical formulations, which is a mature art where practitioners receive specialized training and earn advanced degrees during the course of their study. There is a voluminous amount of published material describing research, best practices and practical application of compositions and techniques to the medical field. The relative skill of those in the art is high.
Breadth of claims: The claims are broad with respect to the concept of prevention. The full scope of the instant claims covers the entire definition of treatment and prevention as well any adverse effects from precocious puberty. The instant specification defines prevention to include avoiding, preventing, or postponing the occurrence of the disease or the symptoms or conditions of the disease. The instant specification defines “treating” as encompassing partially or completely preventing, ameliorating, mitigating, and/or managing a symptom, a disorder, or a condition associated with a disease (instant specification pages 7-8).
Amount of guidance/Existence of working examples: The instant specification provides a data analysis of 1,014 subjects and showed that glycyrrhizin consumption was shown to reduce the risk of PP, whereas added sugar was associated with increased PP (Table 2). The direction of effect of glycyrrhizin was established by observing the whole estrous cycle. It was found that monoammonium glycyrrhizin (MAG) inhibited PP in a danazol induced PP rat model following a dose-dependent manner, in which the most obvious effects were observed with Low- and Medium-MAG groups (Table 3 and FIG. 3, instant specification page 20-21).
State of the prior art/Predictability or unpredictability of the art:
De Vries et al. (The Journal of Pediatrics, published 03/2010, PTO-892) is drawn to the study of whether age at premature thelarche (PT) onset affects the clinical characteristics, course, and risk of progression to precocious puberty (PP). De Vries concludes that Clinical and anthropometric characteristics at admission and risk of PP were similar in all girls with PT, regardless of age at onset. There are currently no clinical or laboratory tests that can predict the risk of progression to PP at presentation (page 466).
Quantity of experimentation: Prevention is difficult to determine due to the inability to control who will contract the condition. There is no disclosure or suggestion in the art or the specification on how to determine prevention. One of ordinary skill in the art would have to conduct a myriad number of experiments comprising trial and error administration of the claimed compositions to both healthy individuals and individuals with PP to determine if the claimed compositions can be used in the fully claimed scope prevent PP. Genetech, 108 F.3d at 1366, states that “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion” and “[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable”.
Therefore, in view of the Wands factors as discussed above, e.g., the breadth of the claims, the amount of guidance provided, the state/unpredictability of the art and the lack of working examples, one of skill in the art would be burdened with undue experimentation to practice the invention commensurate in the scope of the claims, with no assurance of success. Instant claims 2-20 are rejected for being dependent on a rejected claim base.
Claims 7 is 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.
Claim 7 is drawn to a method of treating precocious puberty in a subject in need thereof, comprising administering an effective amount of a composition to the subject, wherein the composition comprises glycyrrhizin or a salt or derivative thereof and at least one of a pharmaceutically acceptable excipient thereof and a food excipient thereof and wherein the glycyrrhizin or a salt or derivative thereof is the sole active ingredient.
The instant disclosure, however, does not describe an experiment with that establishes a predictable dose dependent response. Table 3 (instant specification page 21) shows that in a danazol induced PP model, the low- and medium-dose MAG saw a log-rank test statistical difference between the danazol, however, the high-dose MAG did not have a statistical difference with the danazol alone treatment. Further, while there was a statistical difference versus the danazol group using the log-rank test, there was also a statistical difference between the control group and the MAG only group, indicating that MAG administered alone in a non-danazol induced PP model had an inhibitory effect on puberty-related time points of the rats (Instant specification, Table 3).
Al-Muala et al. (Journal of Biotechnology Research Center, published 2010, PTO-892) is drawn to the study of the effect of licorice root extract on ovulation induction in immature female mice (title). Al-Muala showed that there was a significant precocious estrus cycle in animals that treated with 1g/kg bwt/day and a non-significant precocity with 0.5g/kg bwt/day, as compared to the control group (abstract). The results indicate that licorice extract could cause symptoms of precocious puberty. As evidenced by Al-Jiboori et al. (IRAQI J MED SCI, published 2010, PTO-892), the two major chemical constituents of licorice root extract are glycyrrhizin and flavonoid (page 14). Therefore, the prior art teaches that glycyrrhizin can cause symptoms of precocious puberty.
Therefore, the state of the art prior to the effective filing date of the claimed invention demonstrates that effect of glycyrrhizin on inhibiting or improving precocious puberty unpredictable.
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.
Claims 1-6, 8-18, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Ha (KR 20140004159 A, published 07/22/2015, PTO-892) and Hennell et al. (Journal of Pharmaceutical and Biomedical Analysis, published 02/02/2008, PTO-892).
Ha is drawn to extract concentrations of medicinal herbs that can be used to inhibit precocious puberty (PP) (abstract). Ha teaches that the most common cause of PP is a hormone that regulates secondary sexual characteristics, and it is believed that various causes such as obesity, stress, and environmental changes due to malnutrition cause a hormone imbalance (paragraph 0006). Ha teaches a concentrated extract by extracting a herbal medicine containing sex hormone inhibitory and regulating substances contained in a plurality of natural substances as an active ingredient, and is effective for the growth of the body and promotes the normal balance development of the endocrine system and the reproductive organs (paragraph 0008). The instant specification defines central precocious puberty (CPP) as early sexual development prompted by production and release of gonadotropins and/or sex steroids from normal endogenous sources including the hypothalamus or pituitary (instant specification page 2). Therefore, a “containing sex hormone inhibitory and regulating substances” would meet the limitations of CPP. The composition comprises 3-5 wt% Glycyrrhiza uralensis (abstract). The composition was hot water extracted with purified water and concentrated to 200cc (paragraph 0056). The purified water meets the limitations of a pharmaceutical excipient that is a solvent. The composition is to be consumed as a drink (paragraph 0012). Ha exemplified administering to subjects ages 6-16 years old the herbal extract every 20 out of 30 days for a dosing period of 1-3 years. The experiment was divided by the amount taken per day based on the weight of the child as a test subject. When the subject is 14-18kg body weight a 30 vol% based on the total volume of the herbal extract concentrate for delaying premature maturation prepared according to the present invention is administered, 40 vol% if 22-30kg body weight, 50 vol% if 18-22kg body weight, 70% by volume if 30 ~ 42kg body weight, 100% by volume if 42kg or more body weight wherein 100% by volume is the entire herbal extract concentrate 200cc for early maturation delay (paragraphs 0057-0063). Ha teaches that administering the composition to girls delayed menarche from 6 months to 2 years and extended the final height by 3cm or more (paragraph 0066).
Ha does not specifically teach that glycyrrhizin is present in the composition and selected from the group consisting of glycyrrhizic acid, glycyrrhetic acid, monoammonium glycyrrhizinate, dipotassium glycyrrhizinate, sodium glycyrrhizinate, and calcium glycyrrhizinate.
Hennell is drawn to the determination of glycyrrhizic acid in Glycyrrhiza uralensis dried aqueous extract (title). Hennel teaches that the principle pharmacologically active ingredient in the root of the plant is glycyrrhizic acid. Hennel teaches that the concentration of glycyrrhizic acid in the dried aqueous extract was found to be 40.4±0.3 mg/g (abstract).
It would have been prima facie obvious to combine the teachings of Ha and Hennell before the effective filing date of the claimed invention by substituting the glycyrrhiza uralensis extract in the composition taught by Ha with glycyrrhizic acid as taught by Hennell to arrive at the claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to substitute the glycyrrhiza uralensis extract in the composition taught by Ha with glycyrrhizic acid as taught by Hennell because Hennell teaches that glycyrrhizic acid is the principle pharmacologically active ingredient in glycyrrhiza uralensis. One of ordinary skill in the art would have a reasonable expectation of success because Hennell teaches that glycyrrhizic acid is the principle pharmacologically active ingredient in glycyrrhiza uralensis.
Regarding instant claims 8 and 9, it would have been prima facie obvious before the effective filing date of the claimed invention to combine the teachings of Ha and Hennell before the effective filing date of the claimed invention by optimizing the amount of the glycyrrhizc acid administered to the subject to be between about 0.1 mg/day to about 2000 mg/day to arrive at the claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to optimize the amount of the glycyrrhizc acid administered to the subject to be between 0.1 mg/day to about 2000 mg/day because Ha exemplified administering up to 200cc of a composition comprising 3-5 w% Glycyrrhiza uralensis daily to subjects that resulted in delayed menarche and Hennel teaches that Glycyrrhiza uralensis comprises about 40 mg glycyrrhizic acid per gram Glycyrrhiza uralensis which equates to about 400 mg glycyrrhizic acid administered per day when 200cc of the concentrated composition is administered. Furthermore, in the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). (MPEP § 2144.05(I)) Moreover, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here 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.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). (MPEP § 2144.05(II)) “The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.” In re Peterson, 315 F.3d 1325, 1330, 65 USPQ2d 1379, 1382-83 (Fed. Cir. 2003).
Regarding instant claim 5 it is noted that Ha does not expressly teach that administration of the composition comprising Glycyrrhiza uralensis inhibitor would result in an increased level of at least one of Dialister, Atopobium, Granulicatella, family Carnobacteriaceae, Romboutsia, and Allobaculum in the subject. However, since the teachings of the prior art teach the administration of the same actives, Glycyrrhiza uralensis which comprises glycyrrhinnic acid, with the same amount of glycyrrhinnic acid as described in the instant specification (instant specification page 15, Low-MAG 100 µg/kg/day and High-MAG 400 µg/kg/day) to the same population having a risk of PP, the results would necessarily flow, thereby meeting the instant claim limitations. The instantly claimed results are merely a mechanism of action resulting from the administration step. MPEP 2112(II) makes clear that there is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. Furthermore, MPEP 2145 states that mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention. Applicant’s recitation of a new mechanism of action for the prior art method would not, by itself, distinguish the instant claims over the prior art teaching the same or nearly the same method steps.
Regarding instant claim 6 it is noted that Ha does not expressly teach that administration of the composition comprising Glycyrrhiza uralensis inhibitor would result in a decreased level of at least one of Lachnospirace, Prevotellaceae, Coprococcus, and Ruminococcaceae in the subject. However, since the teachings of the prior art teach the administration of the same actives, Glycyrrhiza uralensis with comprises glycyrrhinnic acid, with the same amount of glycyrrhinnic acid as described in the instant specification (instant specification page 15, Low-MAG 100 µg/kg/day and High-MAG 400 µg/kg/day) to the same population having a risk of PP, the results would necessarily flow, thereby meeting the instant claim limitations. The instantly claimed results are merely a mechanism of action resulting from the administration step. MPEP 2112(II) makes clear that there is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. Furthermore, MPEP 2145 states that mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention. Applicant’s recitation of a new mechanism of action for the prior art method would not, by itself, distinguish the instant claims over the prior art teaching the same or nearly the same method steps.
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Ha (KR 20140004159 A, published 07/22/2015, PTO-892) and Hennell et al. (Journal of Pharmaceutical and Biomedical Analysis, published 02/02/2008, PTO-892) as applied to claim 1 above, and further in view of Ryu (WO 2017/200224 A1, published 11/23/2017, PTO-892).
Claim 1 is rejected as discussed above.
The combined teachings of Ha and Hennel are discussed above.
The combined teachings of Ha and Hennel does not teach a pharmaceutically acceptable excipient or food excipient listed in instant claim 19.
Ryu is drawn to compositions comprising a combined extract for treating abnormal regulation of female hormones (Title). The pharmaceutical composition comprises at least two combined herbs of mulberry fruit, asparagi radix and lycii Fructus (claim 5). The composition may further comprise glycyrrhizin (paragraph 70). The composition may be used to treat an abnormal regulation of female hormone that may be precocious puberty (claim 8). The composition according to the present invention can be provided as a pharmaceutical composition containing pharmaceutically acceptable carriers, adjuvants or diluents, e.g., lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, polyvinyl pyrrlidone, water, methylhydroxy benzoate, propylhydroxy benzoate, talc, magnesium stearate and mineral oil. The formulations may additionally include fillers, anti-agglutinating agents, lubricating agents, wetting agents, flavoring agents, emulsifiers, preservatives and the like (paragraph 56).
It would have been prima facie obvious to combine the combined teachings of Ha and Hennell with the teachings of Ryu by modifying the composition for treating PP taught by the combined teachings of Ha and Hennell to further comprise a pharmaceutically acceptable excipient or food excipient such as xylitol as taught by Ryu to arrive at the claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to modify the composition for treating PP taught by the combined teachings of Ha and Hennell to further comprise a pharmaceutically acceptable excipient or food excipient such as xylitol as taught by Ryu, because both the compositions taught by the combined teachings of Ha and Hennell and teachings of Ryu are for treating PP in a subject in need. One of ordinary skill in the art would have a reasonable expectation of success because both the compositions taught by the combined teachings of Ha and Hennell and teachings of Ryu are for treating PP in a subject in need.
Conclusion
No claims are allowed.
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/S.L.S./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693
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