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 .
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The instant application, filed August 1, 2023, claims foreign priority to applications filed in the Republic of Korea, Korean Patent Application Nos. KR10-2022-0095425, filed on August 1, 2022, and KR10-2023-0059573, filed on May 9, 2023. Receipt is acknowledged of certified copies of the foreign applications. Certified copies of the translations of the foreign applications have not been received.
Applicant cannot rely upon the certified copies of the foreign priority applications because translations of said applications have not been made of record in accordance with 37 CFR 1.55. When an English language translation of a non-English language foreign application is required, the translation must be that of the certified copy (of the foreign application as filed) submitted together with a statement that the translation of the certified copy is accurate. See MPEP §§ 215 and 216.
Because English translations of the certified copies of the foreign priority applications have not been made of record, the examiner cannot establish whether or not what is now claimed was properly disclosed in the foreign priority applications. Therefore, benefit to the foreign priority applications is not granted; the effective filing date of the instant application is August 1, 2023, corresponding to filing date of the instant application, U.S. Patent Application No. 18/363,123.
Status of Claims
Claims 1-22 are pending.
Information Disclosure Statement
The Information Disclosure Statement (“IDS”) submitted on September 17, 2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Claim Interpretation
All claims are generally directed to compositions exhibiting certain anti-inflammatory properties. The specification discloses certain embodiments of compositions, viz. anti-inflammatory compositions (see, e.g., Specification at paragraphs [00012] – [0024]), cosmetic compositions (see, e.g., Specification at paragraphs [0028] – [0036], [0066] – [0067], [0133] et seq., and FIGS. 9-11), pharmaceutical compositions (see, e.g., Specification at paragraphs [0037] – [0045]), and medicinal compositions (see, e.g., Specification at paragraphs [0046] – [0055]). The Specification does not provide a special definition for a composition, or for any of the aforementioned disclosed embodiments. See, e.g., Specification at paragraphs [0025] – [0027] (describing exemplary embodiments of “the composition”), see also supra identified sections. Accordingly, the term “composition” is given its broadest reasonable interpretation consistent with the specification. See MPEP 2173.01(I). Therefore, the plain and ordinary meaning of the term “composition” includes compositions of matter, such as compounds, and articles of food, such as garlic.
Further, the claims are drawn to the various disclosed embodiments of the compositions, wherein:
claims 1-7 are drawn to anti-inflammatory compositions,
claims 8-11 are drawn to cosmetic compositions for ameliorating atopic dermatitis,
claims 12-16 are drawn to pharmaceutical compositions for preventing or treating rheumatoid arthritis, and
claims 17-22 are drawn to medicinal compositions for treatment of ulcerative colitis.
Please note that “[i]f the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction.” MPEP 2111.02(II).
Furthermore, while the claims are drawn to various compositions, many of the limitations recited in the claims include functional language that are merely recitations of intended use. Please note that a recitation of intended use does not distinguish over the prior art since a product claim covers what a product is and not what it is used for. Therefore, as long as the prior art teaches the claimed structural features of the product, it reads on the claim. See MPEP 2114.
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 3-7 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.
Claim 3 is Indefinite
Regarding claim 3, the term “a therapeutic effect on an inflammatory disease an inflammatory disease” renders the claim indefinite. The term “a therapeutic effect on an inflammatory disease” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Turning to the Specification, the term “therapeutic effect” is used once.
In one embodiment, the anti-inflammatory composition has a therapeutic effect on an inflammatory disease including atopic dermatitis, rheumatoid arthritis, or ulcerative colitis.
Specification at page 3, paragraph [0020] (emphasis added).
Notably, in this context, the therapeutic effect 1) modifies only the anti-inflammatory composition, and not the cosmetic, pharmaceutical, or medicinal compositions, and 2) relates to a therapeutic effect on certain inflammatory diseases, including atopic dermatitis, rheumatoid arthritis, or ulcerative colitis. The Specification further discusses various embodiments of the anti-inflammatory composition at pages 2-4 paragraphs [00012] – [0024]. However, these sections only describe compounds of the anti-inflammatory composition, see paragraphs [0012] – [0019], and other embodiments of the anti-inflammatory composition, see paragraphs [0021] – [0024].
Absent a special definition of the therapeutic effect term, Nicholas T. Lappas & Courtney M. Lappas, Appendix B - Principles of Pharmacodynamics, in Forensic Toxicology Principles and Concepts 275-76 (Elizabeth Brown ed., 1st ed. 2016), hereinafter “Lappas 2016”, explains that therapeutic effects are a term of art in the field of pharmacodynamics:
The effects of a drug can be characterized as therapeutic effects, side effects, or toxic effects. The therapeutic effects of a drug are defined as the specific, desired effects of drug administration. For example, a physician may prescribe a narcotic to relieve pain; the relief of pain is the therapeutic effect. The dose of a drug that is anticipated to produce the desired effects, for instance, the relief of pain, without resulting in significant adverse or undesired effects, is called the therapeutic or effective dose. Side effects are defined as all of the effects that are produced by a therapeutic dose of a drug and that are not the desired therapeutic effects. For instance, if an opioid is prescribed for the relief of pain, the therapeutic dose may achieve the desired effect of analgesia, but it may also result in the side effect of constipation. If, however, an opioid is prescribed to treat diarrhea, constipation would be the therapeutic effect and pain relief would become a side effect. It is therefore important to note that the therapeutic effects and the side effects of a drug are dependent upon the purpose of drug administration. Whereas side effects are produced at the therapeutic dose of a drug, toxic effects occur only when doses greater than the normal therapeutic dose of a drug are administered. If a therapeutic dose of aspirin is administered, the side effect of an upset stomach may result. However, if a dose exceeding the therapeutic dose of aspirin is administered, tinnitus may occur. Because tinnitus occurs only as the result of the administration of a greater than therapeutic dose of aspirin, and not as a result of the administration of a normal, therapeutic dose of the drug, it is considered to be a toxic effect rather than a side effect. The occurrence of toxic effects indicates that a dose exceeding the normal therapeutic dose has been taken. It is therefore evident that the dose of a drug influences the effects elicited by drug administration (i.e., a therapeutic dose elicits therapeutic effects, whereas an elevated dose may produce toxic effects). As Paracelsus famously proclaimed, “the dose makes the poison.”
Lappas 2016 at 275-276 (emphasis added) (the “Lappas 2016 excerpt”).
As the proceeding excerpt makes clear, the therapeutic effects of a drug are the specific, desired effects of drug administration. Under this definition, claim 3 reads as follows:
An anti-inflammatory composition containing, as an active ingredient, a compound represented by a following Chemical Formula 1 … wherein the anti-inflammatory composition has a specific, desired effect of drug administration on an inflammatory disease including atopic dermatitis, rheumatoid arthritis, or ulcerative colitis.
On its face, the claim fails to set forth any specific, desired effect of drug administration on the recited inflammatory diseases, and instead leaves the scope of the claim open to the unrestrained, subjective opinion of a particular individual purported to be practicing the invention.
Moreover, applying the Lappas 2016 excerpt, a physician intending to prescribe the anti-inflammatory composition of claim 3, would have to determine what are the specific, desired effects of administering the drug, i.e., the active ingredient represented by a following Chemical Formula 1, contained in the anti-inflammatory composition, on an inflammatory disease.
In order to make this determination, the physician would have to first determine the inflammatory disease that the anti-inflammatory composition would have a therapeutic effect on. Here, the claim recites three specific inflammatory diseases, viz. atopic dermatitis, rheumatoid arthritis, or ulcerative colitis, but leaves open the possibility that other inflammatory diseases may be covered under the scope of the claim.
Second, the physician would have to consider the various modes of administering drug contained in the anti-inflammatory composition, such as orally, topically, subcutaneously, intravenously, parenterally, rectally, and so on. A person of ordinary skill in the art would understand that the mode of administration changes, inter alia, the metabolism of the drug and the effects that its administration elicits.
Third, the physician would have to determine what are the specific and desired effects of administering the drug in the context of a specific inflammatory disease. As the Lappas 2016 excerpt explains, administering a drug may elicit desired and undesired effects. Further, Lapas 2016 explains that whether or not an effect is desired or undesired depends on the purpose of drug administration, i.e., the specific issue that the physician is seeking to treat. See, e.g., supra Lappas 2016 excerpt (discussing the use of opioids to treat pain or diarrhea).
Fourth, the physician would then need to determine the dose appropriate to elicit a therapeutic effect without the drug’s administration resulting in significant adverse or undesired effects. See, e.g., supra Lappas 2016 excerpt (discussing the therapeutic or effective dose). Here, the claim does not specify a dose required to achieve a therapeutic on an inflammatory disease.
The four steps explained above generalize the process a physician would have to consider when determining if the anti-inflammatory composition has a therapeutic effect on an inflammatory disease. At each step where a physician must make a determination, another reasonable physician may make an entirely different determination, and the result of those determinations may lead to different conclusions as to whether the anti-inflammatory composition has a therapeutic effect on an inflammatory disease. Moreover, this determination may change over time, as the claim uses the verb “has”, which implies that the therapeutic effect is assessed as it is presenting, and the claim provides no means for differentiating past from present therapeutic effects. In sum, without specific delineation as to what therapeutic effects the scope of claim 3 covers, and how to assess those effects, the metes and bounds of the claim are unclear.
As the metes and bounds of the claim limitations are unclear, claim 3 is rejected for indefiniteness.
Claim 4 is Indefinite
Claim 4 depends from claim 1 and recites “wherein the anti-inflammatory composition inhibits activation, expression and production of p38 MAP kinase and JNK induced by lipopolysaccharide, and inhibits an inflammation-related signal transduction pathway linked to p38 MAPK-MK2.” The terms “inhibits activation, expression and production of p38 MAP kinase and JNK induced by lipopolysaccharide” and “inhibits an inflammation-related signal transduction pathway linked to p38 MAPK-MK2” (collectively, the “intended use of claim 4”) render the claim indefinite, because the specification does not provide a standard for ascertaining the requisite degree of when the intended use is met, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
The Specification refers to the intended use of claim 4 in paragraphs [0021] and [0084]. In these sections, the Specification generally discusses that this intended use pertains to one embodiment of the anti-inflammatory composition, Specification at paragraph [0021], and that the intended use was derived from its observation after administering BMDA (FMJ-G0) and DMMA (FMJ-G4) in vitro to human THP-1 monocytic cell lines, Specification at paragraphs [0080-0084].
Further, while the Specification also discusses in vitro results obtained from THP-1 cell line pretreatment with FMJ-G0 --– FMJG4, wherein pretreatment inhibited phosphorylation of p38 MAP kinase, JNK, and MK2 resulting from LPS, it is not clear if this result pertains to the same intended use of claim 4, because the recited inflammation-related signal transduction pathway linked to p38 MAPK-MK2 is not defined.
While the Specification provides various concentrations where the intended use of claim 4 was observed in vitro, it does not explain if the same inhibition results in vivo, and if so, under what circumstances. A person having ordinary skill therefore would not be reasonably apprised of the scope of the invention, because the claim implies that it is not restricted only to in vitro uses under specific conditions. Furthermore, neither the Specification, nor the claims, define what transduction signally pathway is inhibited by the anti-inflammatory composition.
Therefore, the metes and bounds of the claim limitations of claim 4 are unclear, and claim 4 is rejected for indefiniteness.
Claim 5 is Indefinite
Claim 5 depends from claim 1 and recites “wherein the anti-inflammatory composition inhibits production of a pro-inflammatory cytokine selected from TNF-α, IL-1 or IL-6, and inhibits activity of a transcription factor NF-κB.” The terms “inhibits production of a pro-inflammatory cytokine selected from TNF-α, IL-1 or IL-6”, and “inhibits activity of a transcription factor NF-κB” (collectively, the “intended use of claim 5”) render the claim indefinite, because the specification does not provide a standard for ascertaining the requisite degree of when the intended use is met, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
The Specification refers to the intended use of claim 5 in paragraphs [0022] and [0085]. In these sections, the Specification generally discusses that this intended use pertains to one embodiment of the anti-inflammatory composition, Specification at paragraph [0022], and that the intended use was derived from its observation after administering BMDA (FMJ-G0) and DMMA (FMJ-G4) in vitro to human THP-1 monocytic cell lines, Specification at paragraphs [0080-0085].
Similar to claim 4, while the Specification provides various concentrations where the intended use of claim 5 was observed in vitro, it does not explain if the same inhibition results in vivo, and if so, under what circumstances. A person having ordinary skill therefore would not be reasonably apprised of the scope of the invention, because the claim implies that it is not restricted only to in vitro uses under specific conditions.
Therefore, the metes and bounds of the claim limitations of claim 5 are unclear, and claim 5 is rejected for indefiniteness.
Claim 6 is Indefinite
Claim 6 depends from claim 1 and recites “wherein the anti-inflammatory composition increases expression of HO-1 (Heme oxygenase 1) or Nrf2 (nuclear factor erythroid-related factor 2), thereby achieving an antioxidant effect.” The terms “increases expression of HO-1 (Heme oxygenase 1) or Nrf2 (nuclear factor erythroid-related factor”, and “thereby achieving an antioxidant effect” (collectively, the “intended use of claim 6”) render the claim indefinite, because the specification does not provide a standard for ascertaining the requisite degree of when the intended use is met, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
The Specification refers to the intended use of claim 6 in paragraphs [0023] and [0103]. In these sections, the Specification generally discusses that this intended use pertains to one embodiment of the anti-inflammatory composition, Specification at paragraph [0023], and that the intended use was derived from its observation after administering BMDA (FMJ-G0) and DMMA (FMJ-G4) in vivo (oral, rats), Specification at paragraphs [0094] – [0103].
While the Specification explains that the intended use was observed in vivo from oral administration of FMJ-G0 and FMJ-G4 to rats, it does not explain if the same inhibition results in any other circumstances, and if so, under what circumstances.
Furthermore, the Specification gives an example of “an antioxidant effect”, by referring to FIG. 6B, but does not specifically define the effect, leaving the scope of the effect delimitated in claim 6 unclear – merely stating that the anti-inflammatory composition increases expression of HO-1 (Heme oxygenase 1) or Nrf2 (nuclear factor erythroid-related factor 2), does not sufficiently define “an antioxidant effect”, as claim 6 demands, because there are no clear limits or context set in the claim on how to determine if and when the anti-inflammatory composition increased expression of HO-1 or Nrf2. A person having ordinary skill therefore would not be reasonably apprised of the scope of the invention, because the claim implies that it is not restricted only to in vivo uses under specific conditions.
Therefore, the metes and bounds of the claim limitations of claim 6 are unclear, and claim 6 is rejected for indefiniteness.
Claim 7 is Indefinite
Claim 7 depends from claim 1 and recites “wherein the anti-inflammatory composition inhibits production of chemokine CINC-3.” The term “inhibits production of chemokine CINC-3” (the “intended use of claim 7”) renders the claim indefinite, because the specification does not provide a standard for ascertaining the requisite degree of when the intended use is met, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
The Specification refers to the intended use of claim 7 in paragraphs [0024] and [0090]. In these sections, the Specification generally discusses that this intended use pertains to one embodiment of the anti-inflammatory composition, Specification at paragraph [0024], and that the intended use was derived from its observation after administering BMDA (FMJ-G0) and DMMA (FMJ-G4) in vivo (rectal, rats), Specification at paragraphs [0086] – [0090]. The Specification at paragraph [0055] also discusses suppression of production of CINC-3 in the context of the medicinal composition.
While the Specification explains that the intended use was observed in vivo from rectal administration of FMJ-G0 and FMJ-G4 to rats, it does not explain if the same inhibition results in any other circumstances, and if so, under what circumstances. A person having ordinary skill therefore would not be reasonably apprised of the scope of the invention, because the claim implies that it is not restricted only to in vivo uses under specific conditions.
Therefore, the metes and bounds of the claim limitations of claim 7 are unclear, and claim 7 is rejected for indefiniteness.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-9, 12-18, and 20-22 are rejected under 35 U.S.C. 101 because the claimed inventions are directed to a judicial exception (i.e., a product of nature) without significantly more.
Compounds of the Claimed Invention
Claim 1 is generally directed to an anti-inflammatory composition containing, as an active ingredient, a compound represented by Chemical Formula 1. Compounds represented by Chemical Formula 1 encompass several known naturally occurring alkaloids, such as the disclosed compounds represented by Chemical Formulas 1-1 and 1-4, reproduced below.
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Chemical Formula 1-1, BMDA, or FMJ-G0
Chemical Formula 1-4, or FMJ-G2
The compound represented by Chemical Formula 1-1 is named benzyl-decyl-methyl-amine, and is also referred to as BMDA and FMJ-G0 throughout the Specification. See Specification at page 12, paragraphs [0076] – [0077]. This compound, hereinafter referred to as “BMDA”, is an alkaloid extracted from garlic. See, e.g., Jeong et al., “N-benzyl-N-methyldecan-1-amine, a phenylamine derivative isolated from garlic cloves, induces G2/M phase arrest and apoptosis in U937 human leukemia cells,” Oncology Reports, vol. 32, no. 1, pp. 373-381 (2014), hereinafter referred to as “Jeong 2014”. For example, Jeong 2014 provides the structure for BMDA (which Jeong 2014 refers to as NBNMA):
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Jeong 2014 at 375.
Jeong 2014 also explains that:
We isolated the novel phenylamine derivative N-benzyl-N-methyldecan-1-amine (NBNMA) from garlic cloves during the course of our bioactive natural product screening program of medicinal foods.
Jeong 2014 at 374.
Garlic is generally known to impart many health benefits. See Khatua et al., “Garlic and cardioprotection: insights into the molecular mechanisms,” Can. J. Physiol. Pharmacol, vol. 91, no. 6, pp. 448-458 (2013), hereinafter referred to as “Khatua 2013”. For example, Khatua 2013 discloses garlic’s use in treating rheumatoid arthritis, which, inter alia, is an inflammatory condition that compounds of Chemical-Formula 1 have an anti-inflammatory effect on:1
Garlic (Allium sativum L., family Alliaceae) is one of the best researched and best-selling herbal remedies, and is commonly used in food as a spice. Garlic has been used all over the world to treat arthritis, asthma, toothaches, baldness, athlete's foot, plague, cancer, and cardiovascular disease. Around 300 BC, Charak, the father of Ayurvedic medicine, described the uses of garlic to maintain the fluidity of blood and strengthen the heart. Similar uses were also reported in the Codex Ebers, an Egyptian medical manuscript from approximately 3500 years ago. Experimentally, garlic has been shown to exert antilipidemic, antihypertensive, antineoplastic, antibacterial, antiviral, antifungal, antiparasitic, antidiabetic, and immunostimulant activity. Clinically, garlic has been evaluated for a number of conditions, including hypertension, hypercholesterolemia, intermittent claudication, diabetes, rheumatoid arthritis, common cold, and for the prevention of arteriosclerosis and cancer.
Khatua 2013 at 449 (emphases added).
Turing to the compound represented by Chemical Formula 1-4, it is named benzyl-dodecyl-methyl-amine, and is also referred to as FMJ-G2 throughout the Specification. See Specification at page 17, paragraphs [0107] and [0109]. This compound, hereinafter referred to as “FMJ-G2”, is an alkaloid that may be extracted from propolis obtained from the North Sinai area. See, e.g., Abdelsattar et al., “Enhancement of wound healing via topical application of natural products: In vitro and in vivo evaluations,” Arabian Journal of Chemistry, vol. 15, no. 6, article 103869, pp 1-20 (available online March 29, 2022), hereinafter referred to as “Abdelsattar 2022”. See, for example, Table 4 of Abdelsattar 2022, which lists N-methyl-N-benzyldodecanamine (i.e., FMJ-G2) as a component of propolis:
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Abdelsattar 2022 at 8.
Regarding propolis, Abdelsattar 2022 further explains that:
Propolis is a resinous compound with a dark color and is collected from nectars by honeybees from the flora and trees buds of the area surrounding the hives and used to maintain the hive structure (Hannan et al., 2015). Hence, its chemical composition varies from one place to another. Propolis is mainly composed of wax (30%), resin (50%), pollen (5%), essential oils (10%), and other substances (5%), including minerals, debris, and organic compounds (El-Guendouz et al., 2018). A broad spectrum of biological activities such as antioxidant, antifungal, anticancer, antibacterial, and anti-inflammatory responses has been linked to propolis active compounds (Hannan et al., 2015; Fernandes Júnior et al., 2005).
Abdelsattar 2022 at 2 (emphasis added).
Claim 1 Recites a Product of Nature
“If the claim includes a nature-based product that does not exhibit markedly different characteristics from its naturally occurring counterpart in its natural state, then the claim recites a "product of nature" exception ….” MPEP 2106.04(c). “The markedly different characteristics analysis compares the nature-based product limitation to its naturally occurring counterpart in its natural state. Markedly different characteristics can be expressed as the product’s structure, function, and/or other properties, and are evaluated based on what is recited in the claim on a case-by-case basis.” See MPEP 2106.04(c)(II).
Regarding claim 1, the nature-based products it includes, viz. BMDA from garlic and FMJ-G2 from propolis, do not exhibit markedly different characteristics from their naturally occurring counterparts in their natural state, because 1) the products’ chemical structures are the same as their naturally occurring counterparts in their natural state, 2) the products’ functions as anti-inflammatory agents are the same as their naturally occurring counterparts in their natural state, and 3) and the products’ other properties, which are tied to their chemical structures, are the same as their naturally occurring counterparts in their natural state. Therefore, claim 1 recites a product of nature exception.
Claim 1 is Directed to a Product of Nature
This judicial exception is not integrated into a practical application. In particular, the claim only recites one additional element – an anti-inflammatory composition recited in the preamble of the claim. However, a preamble is not a limitation where a claim is directed to a product and the preamble merely recites a property inherent in an old product defined by the remainder of the claim. See Kropa v. Robie, 187 F.2d 150, 152, 88 USPQ2d 478, 480-81 (CCPA 1951).
Here, as explained above, claim 1 recites a product, viz., a product of nature wherein the compound of Chemical-Formula 1 is BMDA or FMJ-02. These products of nature naturally occur in garlic and propolis, which as explained above, are known to possess anti-inflammatory properties. Therefore, the preamble of claim 1, i.e., “an anti-inflammatory composition”, merely recites the known anti-inflammatory properties of the products of nature. Accordingly, the preamble is not a limitation for claim 1, and is thus not an element to consider as to whether claim 1 integrates the recited product of nature into a practical application.
Furthermore, even if the preamble is considered necessary to give life, meaning, and vitality to the claim, it is recited at a high-level of generality such that it amounts to no more than merely indicating the field of use of the natural products. “[A] claim directed to a judicial exception cannot be made eligible "simply by having the applicant acquiesce to limiting the reach of the patent for the formula to a particular technological use." Diamond v. Diehr, 450 U.S. 175, 192 n.14, 209 USPQ 1, 10 n. 14 (1981). Thus, limitations that amount to merely indicating a field of use or technological environment in which to apply a judicial exception do not amount to significantly more than the exception itself, and cannot integrate a judicial exception into a practical application.” See MPEP 2106.05(h).
Here, the preamble of claim 1 merely indicates that the natural products BMDA or FMJ-02 may be applied in the field of anti-inflammatory compositions. It neither specifies any particular anti-inflammatory conditions in which to apply the natural products, or places any limitations on their use in the field of anti-inflammatory compositions. Accordingly, even if the preamble is considered to be a necessary element of claim 1, it fails to integrate the recited product of nature into a practical application, because it merely indicates the field of use in which to apply the natural products.
Thus, claim 1, as a whole, is directed to a product of nature.
Claim 1 is not Patent Eligible
The claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception, because it lacks an inventive concept.
An inventive concept "cannot be furnished by the unpatentable law of nature (or natural phenomenon or abstract idea) itself." Genetic Techs. Ltd. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016). See also Alice Corp., 573 U.S. at 21-18, 110 USPQ2d at 1981 (citing Mayo, 566 U.S. at 78, 101 USPQ2d at 1968 (after determining that a claim is directed to a judicial exception, "we then ask, ‘[w]hat else is there in the claims before us?") (emphasis added))…. Instead, an "inventive concept" is furnished by an element or combination of elements that is recited in the claim in addition to (beyond) the judicial exception, and is sufficient to ensure that the claim as a whole amounts to significantly more than the judicial exception itself. Alice Corp., 573 U.S. at 27-18, 110 USPQ2d at 1981 (citing Mayo, 566 U.S. at 72-73, 101 USPQ2d at 1966).
MPEP 2106.05(I).
As discussed above, either 1) the preamble bears no weight and claim 1 is solely directed to a product of nature, or 2) the additional element of an anti-inflammatory composition amounts to no more than merely indicating the field of use in which to apply the natural products. In the first case, since there is nothing remaining in the claim other than the product of nature, the claim as a whole fails to amount to anything more than the judicial exception. In the latter case, merely indicating the field of use in which to apply the natural products fails to provide an inventive concept, and therefore the claim does not amount to significantly more than the exception itself. See MPEP 2106.05(h).
Thus, claim 1, as a whole, is not patent eligible.
Claim 2 is not Patent Eligible
Claim 2 depends from claim 1 and selects several compounds as compounds represented by Chemical Formula 1, two of which are BMDA and FMJ-G2. As explained above for claim 1, BMDA and FMJ-G2 are products of nature, and an anti-inflammatory composition containing, as an active ingredient, those compounds, without additional elements, is not patent eligible.
Thus, claim 2, as a whole, is not patent eligible.
Claim 3 is Directed to a Product of Nature
Claim 3 depends from claim 1, and adds the element that “wherein the anti-inflammatory composition has a therapeutic effect on an inflammatory disease including atopic dermatitis, rheumatoid arthritis, or ulcerative colitis” (emphasis added). This therapeutic effect element merely states an inherent effect of applying the judicial exception, i.e., the natural products BMDA and FMJ-G2, in an anti-inflammatory composition. “A claim having broad applicability across many fields of endeavor may not provide meaningful limitations that integrate a judicial exception into a practical application or amount to significantly more. For instance, a claim that generically recites an effect of the judicial exception or claims every mode of accomplishing that effect, amounts to a claim that is merely adding the words "apply it" to the judicial exception.” MPEP 2106.05(f)(3).
Here, the additional therapeutic effect element generically recites a therapeutic effect resulting from applying the products of nature. While the claim specifies three particular anti-inflammatory conditions, viz. atopic dermatitis, rheumatoid arthritis, or ulcerative colitis, it does not place any limitations on using the products of nature to obtain those therapeutic effects, and thereby claims every mode of accomplishing those therapeutic effects. Therefore, claim 3 amounts to a claim merely adding the words “apply it” to the judicial exception. Accordingly, the therapeutic effect element fails to integrate the recited products of nature into a practical application, because it fails to provide any meaningful limitations on its application.
Thus, claim 3, as a whole, is directed to a product of nature.
Claim 3 is not Patent Eligible
The claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception, because it lacks an inventive concept. As discussed above in claim 1 with respect to the integration of the natural product into a practical application, the preamble amounts to no more than merely indicating the field of use in which to apply the natural products. Likewise, as discussed immediately above, the therapeutic effect element amounts to no more than merely reciting the inherent effects of the products of nature. Neither can provide an inventive concept.
Thus, claim 3, as a whole, is not patent eligible.
Claim 4 is Directed to a Product of Nature
Claim 4 depends from claim 1, and adds the element that “wherein the anti-inflammatory composition inhibits activation, expression and production of p38 MAP kinase and JNK induced by lipopolysaccharide, and inhibits an inflammation-related signal transduction pathway linked to p38 MAPK-MK2” (emphasis added). These inhibiting elements merely state inherent effects of applying the judicial exception, i.e., the natural products BMDA and FMJ-G2, in an anti-inflammatory composition.
Specifically, these inhibiting elements generically recite inhibition effects of the products of nature on enzymes and pathways generally related to inflammation. While the claim specifies the inhibition of several specific enzymes and pathways generally related to inflammation, it does not place any limitations on using the products of nature to obtain those effects, and thereby claims every mode of accomplishing those effects. Therefore, claim 4 amounts to a claim merely adding the words “apply it” to the judicial exception. Accordingly, the inhibiting elements fail to integrate the recited products of nature into a practical application, because they fail to provide any meaningful limitations on its application.
Thus, claim 4, as a whole, is directed to a product of nature.
Claim 4 is not Patent Eligible
The claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception, because it lacks an inventive concept. As discussed above in claim 1 with respect to the integration of the natural product into a practical application, the preamble amounts to no more than merely indicating the field of use in which to apply the natural products. Likewise, as discussed immediately above, the inhibiting elements amount to no more than merely reciting the inherent effects of the products of nature. Neither can provide an inventive concept.
Thus, claim 4, as a whole, is not patent eligible.
Claim 5 is Directed to a Product of Nature
Claim 5 depends from claim 1, and adds the element that “wherein the anti-inflammatory composition inhibits production of a pro-inflammatory cytokine selected from TNF-α, IL-1 or IL-6, and inhibits activity of a transcription factor NF-κB” (emphases added). Similar to claim 4, these inhibiting elements merely state inherent effects of applying the judicial exception, i.e., the natural products BMDA and FMJ-G2, in an anti-inflammatory composition.
Specifically, these inhibiting elements generically recite inhibition effects of the products of nature on enzymes and pathways generally related to inflammation. While the claim specifies the inhibition of several specific enzymes and pathways generally related to inflammation, it does not place any limitations on using the products of nature to obtain those effects, and thereby claims every mode of accomplishing those effects. Therefore, claim 5 amounts to a claim merely adding the words “apply it” to the judicial exception. Accordingly, the inhibiting elements fail to integrate the recited product of nature into a practical application, because it fails to provide any meaningful limitations on its application.
Thus, claim 5, as a whole, is directed to a product of nature.
Claim 5 is not Patent Eligible
The claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception, because it lacks an inventive concept. As discussed above in claim 1 with respect to the integration of the natural product into a practical application, the preamble amounts to no more than merely indicating the field of use in which to apply the natural products. Likewise, as discussed immediately above, the inhibiting elements amount to no more than merely reciting the inherent effects of the products of nature. Neither can provide an inventive concept.
Thus, claim 5, as a whole, is not patent eligible.
Claim 6 is Directed to a Product of Nature
Claim 6 depends from claim 1, and adds the element that “wherein the anti-inflammatory composition increases expression of HO-1 (Heme oxygenase 1) or Nrf2 (nuclear factor erythroid-related factor 2), thereby achieving an antioxidant effect” (emphasis added). However, this increasing expression of HO-1 or Nrf2 element merely states the inherent effects of applying the judicial exception, i.e., the natural products BMDA and FMJ-G2, in an anti-inflammatory composition.
Specifically, this increasing expression of HO-1 or Nrf2 element generically recites the effects of the products of nature on enzymes and pathways involved in antioxidant response. While the claim specifies the increased expression of HO-1 and Nrf2, it does not place any limitations on using the products of nature to obtain those effects, and thereby claims every mode of accomplishing those effects. Therefore, claim 6 amounts to a claim merely adding the words “apply it” to the judicial exception. Accordingly, the increasing expression of HO-1 or Nrf2 element fails to integrate the recited product of natures into a practical application, because it fails to provide any meaningful limitations on its application.
Thus, claim 6, as a whole, is directed to a product of nature.
Claim 6 is not Patent Eligible
The claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception, because it lacks an inventive concept. As discussed above in claim 1 with respect to the integration of the natural product into a practical application, the preamble amounts to no more than merely indicating the field of use in which to apply the natural products. Likewise, as discussed immediately above, the increasing expression of HO-1 or Nrf2 element amounts to no more than merely reciting the inherent effects of the products of nature. Neither can provide an inventive concept.
Thus, claim 6, as a whole, is not patent eligible.
Claim 7 is Directed to a Product of Nature
Claim 7 depends from claim 1, and adds the element that “wherein the anti-inflammatory
composition inhibits production of chemokine CINC-3.” (emphasis added). However, this inhibiting element merely states the inherent effect of applying the judicial exception, i.e., the natural products BMDA and FMJ-G2, in an anti-inflammatory composition.
Specifically, this inhibiting element generically recites the effect of the products of nature on chemokine CINC-3. While the claim is specific to inhibiting production of chemokine CINC-3, it does not place any limitations on using the products of nature to obtain those effects, and thereby claims every mode of accomplishing those effects. Therefore, claim 7 amounts to a claim merely adding the words “apply it” to the judicial exception. Accordingly, this inhibiting element fails to integrate the recited products of nature into a practical application, because it fails to provide any meaningful limitations on its application.
Thus, claim 7, as a whole, is directed to a product of nature.
Claim 7 is not Patent Eligible
The claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception, because it lacks an inventive concept. As discussed above in claim 1 with respect to the integration of the natural product into a practical application, the preamble amounts to no more than merely indicating the field of use in which to apply the natural products. Likewise, as discussed immediately above, this inhibiting element amounts to no more than merely reciting the inherent effects of the products of nature. Neither can provide an inventive concept.
Thus, claim 7, as a whole, is not patent eligible.
Claim 8 Recites a Product of Nature
Claim 8 is generally directed to a cosmetic composition for ameliorating atopic dermatitis, containing, as an active ingredient, a compound represented by Chemical Formula 2. Atopic dermatitis is an inflammatory disease. See Specification at page 9, paragraph [0056].
Compounds represented by Chemical Formula 2 encompass BMDA. As explained above in claim 1, a claim generally directed to an anti-inflammatory composition containing, as an active ingredient, BMDA, recites a product of nature exception. For the same reasons, a claim generally directed to a cosmetic composition for ameliorating atopic dermatitis, i.e., an inflammatory disease, containing, as an active ingredient, BMDA, also recites a product of nature exception.
Therefore, claim 8 recites a product of nature exception.
Claim 8 is Directed to a Product of Nature
This judicial exception is not integrated into a practical application. In particular, the claim, as it pertains to embodiments wherein the compound of Chemical Formula 2 is BMDA, only recites one additional element – a cosmetic composition for ameliorating atopic dermatitis, recited in the preamble of the claim. However, the preamble is recited at a high-level of generality such that it amounts to no more than merely indicating the field of use of the natural product.
Here, the preamble of claim 8 merely indicates that the natural product BMDA may be applied in the field of cosmetic compositions for ameliorating atopic dermatitis. It places no limitations on the use of BMDA in the field of cosmetic composition for ameliorating atopic dermatitis. Accordingly, it fails to integrate the recited product of nature into a practical application, because it merely indicates the field of use in which to apply the natural product.
Thus, claim 8, as a whole, is directed to a product of nature.
Claim 8 is not Patent Eligible
The claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception, because it lacks an inventive concept.
As discussed above, the additional element of a cosmetic composition for ameliorating atopic dermatitis amounts to no more than merely indicating the field of use in which to apply the natural product. Merely indicating the field of use in which to apply the natural product fails to provide an inventive concept, and therefore the claim does not amount to significantly more than the exception itself. See MPEP 2106.05(h).
Thus, claim 8, as a whole, is not patent eligible.
Claim 9 is not Patent Eligible
Claim 9 depends from claim 8 and selects several compounds as compounds represented by Chemical Formula 2, one of which is BMDA. As explained above for claim 8, BMDA is a product of nature, and a cosmetic composition for ameliorating atopic dermatitis, containing, as an active ingredient, BMDA, without additional elements, is not patent eligible.
Thus, claim 9, as a whole, is not patent eligible.
Claim 12 Recites a Product of Nature
Claim 12 is generally directed to a pharmaceutical composition for preventing or treating rheumatoid arthritis, the pharmaceutical composition containing, as an active ingredient, a compound represented by a following Chemical Formula 1 or a pharmaceutically acceptable salt thereof. Rheumatoid arthritis is an inflammatory disease. See Specification at page 9, paragraph [0056].
Regarding claim 12, Chemical Formula 1 encompasses encompass several known naturally occurring alkaloids, viz. BMDA from garlic and FMJ-G2 from propolis. See supra discussion of claim 1. As explained above in claim 1, a claim generally directed to an anti-inflammatory composition containing, as an active ingredient, BMDA or FMJ-G2, recites a product of nature exception. For the same reasons, a claim generally directed to a pharmaceutical composition for preventing or treating rheumatoid arthritis, i.e., an inflammatory disease, the pharmaceutical composition containing, as an active ingredient, BMDA or FMJ-G2, also recites a product of nature exception.
Therefore, claim 12 recites a product of nature exception. However, the examiner notes that certain pharmaceutically acceptable salts of BMDA or FMJ-G2 may not be products of nature.
Claim 12 is Directed to a Product of Nature
This judicial exception is not integrated into a practical application. In particular, the claim, as it pertains to embodiments wherein the compound of Chemical Formula 1 is BMDA or FMJ-G2, only recites one additional element – a pharmaceutical composition for preventing or treating rheumatoid arthritis, recited in the preamble of the claim. However, the preamble is recited at a high-level of generality such that it amounts to no more than merely indicating the field of use of the natural products.
Here, the preamble of claim 12 merely indicates that the natural products BMDA or FMJ-G2 may be applied in the field of pharmaceutical compositions for preventing or treating rheumatoid arthritis. It places no limitations on the use of BMDA in the field of pharmaceutical compositions for preventing or treating rheumatoid arthritis. Accordingly, it fails to integrate the recited product of nature into a practical application, because it merely indicates the field of use in which to apply the natural products.
Thus, claim 12, as a whole, is directed to a product of nature.
Claim 12 is not Patent Eligible
The claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception, because it lacks an inventive concept.
As discussed above, the additional element of a pharmaceutical composition for preventing or treating rheumatoid arthritis amounts to no more than merely indicating the field of use in which to apply the natural products. Merely indicating the field of use in which to apply the natural products fails to provide an inventive concept, and therefore the claim does not amount to significantly more than the exception itself. See MPEP 2106.05(h).
Thus, claim 12, as a whole, is not patent eligible.
Claim 13 is not Patent Eligible
Claim 13 depends from claim 12 and selects two compounds as compounds represented by Chemical Formula 1, one of which is BMDA. As explained above for claim 12, BMDA is a product of nature, and a pharmaceutical composition for preventing or treating rheumatoid arthritis, the pharmaceutical composition containing, as an active ingredient, BMDA, without additional elements, is not patent eligible.
Thus, claim 13, as a whole, is not patent eligible.
Claim 14 is not Patent Eligible
Claim 14 depends from claim 13 and selects BMDA as the compound represented by Chemical Formula 1. As explained above for claim 12, BMDA is a product of nature, and a pharmaceutical composition for preventing or treating rheumatoid arthritis, the pharmaceutical composition containing, as an active ingredient, BMDA, without additional elements, is not patent eligible.
Thus, claim 14, as a whole, is not patent eligible.
Claim 15 is Directed to a Product of Nature
Claim 15 depends from claim 12, and specifies that the pharmaceutical composition of claim 12 is administered orally. As explained above, claim 12 recites a product of nature.
This judicial exception is not integrated into a practical application. As explained for the parent claim, claim 12 is not integrated into a practical application. Regarding claim 15, the claim the claim, as it pertains to embodiments wherein the compound of Chemical Formula 1 is BMDA or FMJ-G2, only recites one additional element – that the pharmaceutical composition of claim 12 is administered orally. However, this element is recited at a high-level of generality such that it amounts to no more than merely indicating the field of use of the natural products.
Here, the additional element merely indicates that the natural products BMDA or FMJ-G2 may be applied in the field of orally administered pharmaceutical compositions for preventing or treating rheumatoid arthritis. It places no limitations on the use of BMDA or FMJ-G2 in the field of pharmaceutical compositions for preventing or treating rheumatoid arthritis. Accordingly, it fails to integrate the recited products of nature into a practical application, because it merely indicates the field of use in which to apply the natural products.
Thus, claim 15, as a whole, is directed to a product of nature.
Claim 15 is not Patent Eligible
The claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception, because it lacks an inventive concept.
As discussed above, the additional element of an orally administered pharmaceutical composition for preventing or treating rheumatoid arthritis amounts to no more than merely indicating the field of use in which to apply the natural products. Merely indicating the field of use in which to apply the natural products fails to provide an inventive concept, and therefore the claim does not amount to significantly more than the exception itself. See MPEP 2106.05(h).
Thus, claim 15, as a whole, is not patent eligible.
Claim 16 Recites a Product of Nature
Claim 16 depends from claim 15, and further specifies that the compound represented by the Chemical Formula 1 is formulated in a unit dosage form suitable for oral administration at a dose of 15 to 25 mg/kg. Claim 15 depends from claim 12, and both recite products of nature, viz. BMDA or FMJ-G2. Whether or administration of BMDA or FMJ-G2 at a dosage of 15 to 25 mg/kg also recites products of nature requires determining if oral administration at that dosage exhibits markedly different characteristics from their naturally occurring counterparts in their natural state.
Here, the Specification does not indicate that the concentration of BMDA or FMJ-G2 in the recited composition differs from those found in their naturally occurring counterparts in their natural state. Accordingly, administration at the claimed dosage does not exhibit markedly different characteristics from their naturally occurring counterparts in their natural state. Therefore, claim 16 recites a product of nature exception.
Claim 16 is Directed to a Product of Nature
This judicial exception is not integrated into a practical application. As explained for the parent claims, claims 12 and 15 are not integrated into a practical application. Regarding claim 16, the claim, as it pertains to embodiments wherein the compound of Chemical Formula 1 is BMDA or FMJ-G2, only recites one additional element – that the BMDA or FMJ-G2 is formulated in a unit dosage form suitable for oral administration at a dose of 15 to 25 mg/kg of BMDA or FMJ-G2. However, this element is recited at a high-level of generality such that it amounts to no more than merely indicating the field of use of the natural products.
Here, the additional element merely indicates that the natural products BMDA or FMJ-G2 may be applied in the field of orally administered pharmaceutical compositions for preventing or treating rheumatoid arthritis. While the claim limits the dosage of BMDA or FMJ-G2 in the orally administered pharmaceutical compositions for preventing or treating rheumatoid arthritis, it fails to distinguish the recited dosage from the concentration of the products of nature in their naturally occurring counterparts in their naturally occurring states. Accordingly, it fails to integrate the recited products of nature into a practical application, because it merely indicates the field of use in which to apply the natural products.
Thus, claim 16, as a whole, is directed to a product of nature.
Claim 16 is not Patent Eligible
The claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception, because it lacks an inventive concept.
As discussed above, the additional element, that the BMDA or FMJ-G2 is formulated in a unit dosage form suitable for oral administration at a dose of 15 to 25 mg/kg of BMDA or FMJ-G2, amounts to no more than merely indicating the field of use in which to apply the natural products. Merely indicating the field of use in which to apply the natural products fails to provide an inventive concept, and therefore the claim does not amount to significantly more than the exception itself. See MPEP 2106.05(h).
Thus, claim 16, as a whole, is not patent eligible.
Claim 17 Recites a Product of Nature
Claim 17 is generally directed to a medicinal composition for treatment of ulcerative colitis, the composition containing, as an active ingredient, a compound represented by a following Chemical Formula 1 or a pharmaceutically acceptable salt thereof. Rheumatoid arthritis is an inflammatory disease. See Specification at page 9, paragraph [0056].
Regarding claim 17, Chemical Formula 1 encompasses encompass several known naturally occurring alkaloids, viz. BMDA from garlic and FMJ-G2 from propolis. See supra discussion of claim 1. As explained above in claim 1, a claim generally directed to an anti-inflammatory composition containing, as an active ingredient, BMDA or FMJ-G2, recites a product of nature exception. For the same reasons, a claim generally directed to a medicinal composition for treatment of ulcerative colitis, i.e., an inflammatory disease, the pharmaceutical composition containing, as an active ingredient, BMDA or FMJ-G2, also recites a product of nature exception.
Therefore, claim 17 recites a product of nature exception. However, the examiner notes that certain pharmaceutically acceptable salts of BMDA or FMJ-G2 may not be products of nature.
Claim 17 is Directed to a Product of Nature
This judicial exception is not integrated into a practical application. In particular, the claim, as it pertains to embodiments wherein the compound of Chemical Formula 1 is BMDA or FMJ-G2, only recites one additional element – a medicinal composition for treatment of ulcerative colitis, recited in the preamble of the claim. However, the preamble is recited at a high-level of generality such that it amounts to no more than merely indicating the field of use of the natural products.
Here, the preamble of claim 17 merely indicates that the natural products BMDA and FMJ-G2 may be applied in the field of medicinal composition for treatment of ulcerative colitis. It places no limitations on the use of BMDA or FMJ-G2 in the field of medicinal composition for treatment of ulcerative colitis. Accordingly, it fails to integrate the recited products of nature into a practical application, because it merely indicates the field of use in which to apply the natural products.
Thus, claim 17, as a whole, is directed to a product of nature.
Claim 17 is not Patent Eligible
The claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception, because it lacks an inventive concept.
As discussed above, the additional element of a medicinal composition for treatment of ulcerative colitis amounts to no more than merely indicating the field of use in which to apply the natural products. Merely indicating the field of use in which to apply the natural products fails to provide an inventive concept, and therefore the claim does not amount to significantly more than the exception itself. See MPEP 2106.05(h).
Thus, claim 17, as a whole, is not patent eligible.
Claim 18 is not Patent Eligible
Claim 18 depends from claim 17 and selects two compounds as compounds represented by Chemical Formula 1, one of which is BMDA. As explained above for claim 17, BMDA is a product of nature, and a medicinal composition for treatment of ulcerative colitis, the pharmaceutical composition containing, as an active ingredient, BMDA, without additional elements, is not patent eligible.
Thus, claim 18, as a whole, is not patent eligible.
Claim 20 is Directed to a Product of Nature
Claim 20 depends from claim 17, and specifies that the medicinal composition for treatment of ulcerative colitis of claim 17 is administered in an enema manner. As explained above, claim 17 recites a product of nature.
This judicial exception is not integrated into a practical application. As explained for the parent claim, claim 17 is not integrated into a practical application. Regarding claim 20, the claim, as it pertains to embodiments wherein the compound of Chemical Formula 1 is BMDA or FMJ-G2, only recites one additional element – that the medicinal composition for treatment of ulcerative colitis of claim 17 is administered in an enema manner. However, this element is recited at a high-level of generality such that it amounts to no more than merely indicating the field of use of the natural products.
Here, the additional element merely indicates that the natural products BMDA or FMJ-G2 may be applied in the field of medicinal compositions for treatment of ulcerative colitis administered in an enema manner. It places no limitations on the use of BMDA or FMJ-G2 in the field of medicinal compositions for treatment of ulcerative colitis administered in an enema manner. Accordingly, it fails to integrate the recited products of nature into a practical application, because it merely indicates the field of use in which to apply the natural products.
Thus, claim 20, as a whole, is directed to a product of nature.
Claim 20 is not Patent Eligible
The claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception, because it lacks an inventive concept.
As discussed above, the additional element, that the medicinal composition for treatment of ulcerative colitis of claim 17 is administered in an enema manner, amounts to no more than merely indicating the field of use in which to apply the natural products. Merely indicating the field of use in which to apply the natural products fails to provide an inventive concept, and therefore the claim does not amount to significantly more than the exception itself. See MPEP 2106.05(h).
Thus, claim 20, as a whole, is not patent eligible.
Claim 21 Recites a Product of Nature
Claim 21 depends from claim 20, and further specifies that the medicinal composition is administered directly to an ulcerative colitis patient in the enema manner at 0.4 mg/kg or smaller as an effective dosage per day. Claim 20 depends from claim 17, and both recite products of nature, viz. BMDA or FMJ-G2. Whether administration of BMDA or FMJ-G2 in the enema manner at 0.4 mg/kg or smaller as an effective dosage per day also recites products of nature requires determining if administration at that dosage exhibits markedly different characteristics from their naturally occurring counterparts in their natural state.
Here, the Specification does not indicate that the concentration of BMDA or FMJ-G2 differs from those found in their naturally occurring counterparts in their natural state. Accordingly, administration at the claimed dosage does not exhibit markedly different characteristics from their naturally occurring counterparts in their natural state. Therefore, claim 21 recites a product of nature exception.
Claim 21 is Directed to a Product of Nature
This judicial exception is not integrated into a practical application. As explained for the parent claims, claims 17 and 20 are not integrated into a practical application. Regarding claim 21, the claim, as it pertains to embodiments wherein the compound of Chemical Formula 1 is BMDA or FMJ-G2, only recites one additional element – that the medicinal composition for treatment of ulcerative colitis of claim 20 is administered in an enema manner at 0.4 mg/kg or less of BMDA or FMJ-G2. However, this element is recited at a high-level of generality such that it amounts to no more than merely indicating the field of use of the natural products.
Here, the additional element merely indicates that the natural products BMDA or FMJ-G2 may be applied in the field of medicinal compositions for treatment of ulcerative colitis administered in an enema manner. While the claim limits the dosage of BMDA or FMJ-G2 in the medicinal compositions for treatment of ulcerative colitis administered in an enema manner, it fails to distinguish the recited dosage from the concentration of the products of nature in their naturally occurring counterparts in their naturally occurring states. Accordingly, it fails to integrate the recited products of nature into a practical application, because it merely indicates the field of use in which to apply the natural products.
Thus, claim 21, as a whole, is directed to a product of nature.
Claim 21 is not Patent Eligible
The claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception, because it lacks an inventive concept.
As discussed above, the additional element, that the medicinal composition for treatment of ulcerative colitis of claim 17 is administered in an enema manner at 0.4 mg/kg or smaller as an effective dosage per day, amounts to no more than merely indicating the field of use in which to apply the natural products. Merely indicating the field of use in which to apply the natural products fails to provide an inventive concept, and therefore the claim does not amount to significantly more than the exception itself. See MPEP 2106.05(h).
Thus, claim 21, as a whole, is not patent eligible.
Claim 22 is Directed to a Product of Nature
Claim 22 depends from claim 17, and specifies that administration of the medicinal composition in an enema manner suppresses production of chemokine CINC-3 (the “suppression effect”) (emphasis added).
As explained for the parent claim, claim 17 is not integrated into a practical application. Similar to claim 20, that the claim, as it pertains to embodiments wherein the compound of Chemical Formula 1 is BMDA or FMJ-G2, is administered in an enema manner, merely indicates the field of use of the natural productions.
Regarding the remaining element – that administration suppresses production of chemokine CINC-3, the suppression effect element merely recites an effect of using the products of nature in a medicinal composition administered in an enema manner. The claim places no limitations on using the natural products to obtain the suppression effect, other than merely reciting the field of use of the natural products. Therefore, claim 22 amounts to a claim merely adding the words “apply it” to the judicial exception. Accordingly, the suppression effect element fails to integrate the recited products of nature into a practical application, because it fails to provide any meaningful limitations on its application.
Thus, claim 22, as a whole, is directed to a product of nature.
Claim 22 is not Patent Eligible
The claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception, because it lacks an inventive concept.
As discussed above, that the medicinal composition for treatment of ulcerative colitis of claim 17 is administered in an enema manner, amounts to no more than merely indicating the field of use in which to apply the natural products. Likewise, as discussed above, the suppression effect element amounts to no more than merely reciting the inherent effects of the products of nature. Neither can provide an inventive concept.
Thus, claim 22, as a whole, is not patent eligible.
Claim Rejections - 35 USC § 102
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.
Claims 1-18, 20 - 22 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Korean Patent Application Publication No. 10-2015-0059029, published May 29, 2015, hereinafter “KR’029” (page references to “KR’029” herein refer to the pages from the attached Google Machine Translated Copy of the Korean Patent Application Publication, unless otherwise noted. A second translation was obtained through KIPRIS, which is also attached hereto and is indicated when referenced). KR’029 is the publication of Korean Patent Application No. 10-2013-0142486, filed on November 21, 2013.
KR’029
KR’029 teaches BMDA, its isolation from garlic, and use in as the active ingredient in a pharmaceutical composition for preventing or treating cancer. See KR’029 at page 3, claims 1-3, reproduced below.
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KR’029 at 3.
KR’029 further teaches various doses and concentrations of BMDA contained within the disclosed pharmaceutical compositions. See, e.g.,
KR’029 at page 3, claim 4 (“A pharmaceutical composition for preventing or treating cancer, characterized in that the composition is administered at 0.1 to 10 mg/kg.”),
id. at page 6 (“In one embodiment of the present invention, the composition may be administered at 0.1 to 10 mg/kg.”),
id. at page 12 (explaining that 13.2 mg of pure compound was obtained from 1 kg of dried garlic),
id. at page 14 (“Treatment was performed for 24 hours to reach 3.125, 6.25, 12.5, 25, 50, and 100 ÿg/ml.”) (ÿg/ml refers to μg/ml in the untranslated text),
id. at 14 (listing IC50 values of BMDA against cancer lines ranging from 1.74 to 3.95 (ÿ/ÿ), which is μg/ml in the untranslated copy),
KR’029 KIPRIS Translation at page 44/49 (“Twenty-four hours after tumor induction, mice were orally administered 1, 5, 10, and 20 mg/kg of n-benzyl-n-methyldecan-1-amine once every 3 days for 16 days.”),
id. at page 45/49 (“On the other hand, when n-benzyl-n-methyldecan-1-amine was administered at concentrations of 1 mg/kg and 5 mg/kg, respectively, the tumor inhibition rates were 28% and 43%, respectively, but when treated with 10 mg/kg and 20 mg/kg, it was confirmed that the tumor inhibition rate rather decreased (data not shown).”),
KR’029 at page 18, Drawing 5 (showing dosages of BMDA at 0.312, 0.625, 1.25, 2.5, 3.75, and 5 μg/ml),
id. at page 18, Drawing 6 (showing BMDA treatment at 1 mg and 5 mg),
id. at page 19, Drawing 7 and Drawing 8 (showing treatment at 1 and 5 mg/kg of BMDA).
KR’029 teaches that the compositions, shapes, and types of dosage forms of the disclosed pharmaceutical compositions “generally vary widely.” See, e.g., KR’029 KIPRIS Translation at pages 21-22:
The compositions, shapes, and types of dosage forms of the present invention generally vary widely depending on their use. For example, the dosage form used for acute treatment of a disease may contain a greater amount of one or more active ingredients it comprises than the dosage form used for chronic treatment of the same disease. Similarly, parenteral dosage forms may contain lower amounts of one or more active ingredients it comprises than oral dosage forms used to treat the same disease. These and other ways of the particular dosage forms encompassed by the present invention are each very diverse and are apparent to those skilled in the art to which the present invention pertains.
KR’029 KIPRIS Translation at pages 21-22 (emphases added).
KR’029 further teaches components of the disclosed pharmaceutical compositions. See, e.g., KR’029 KIPRIS Translation at pages 31-32:
Suitable additives (e.g., carriers and excipients) and other substances that may be used to provide topical and mucosal dosage forms encompassed by the present invention are well known to those skilled in the pharmaceutical art and depend on the particular tissue to which a given pharmaceutical composition or dosage form is to be applied. With this fact in mind, typical additives for forming solutions, emulsions or gel agents include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil and mixtures thereof, which are non-toxic and pharmaceutically acceptable. Moisturizers or humectants may also be added to the pharmaceutical compositions and dosage forms, if desired. Examples of such additional components are well known to those skilled in the art to which the present invention pertains.
KR’029 KIPRIS Translation at 31-32 (emphases added).
KR’029 further teaches additional excipients of the disclosed pharmaceutical compositions. See, e.g., KR’029 KIPRIS Translation at pages 23-24:
The general oral dosage forms of the present invention are prepared by mixing the active ingredient with at least one excipient in a dense mixture according to conventional pharmaceutical mixing techniques. Excipients may be in a wide variety of forms, depending on the form of formulation desired for administration. For example, excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, perfume ingredients, preservatives, and coloring ingredients. Examples of excipients suitable for use in solid oral dosage forms (e.g., powders, tablets, capsules and caplets) include, but are not limited to, starches, sugars, microcrystalline cellulose, excipients, granulants, glidants, binders, and disintegrants.
KR’029 KIPRIS Translation at 23-24 (emphases added).
KR’029 further teaches dosage forms of the disclosed pharmaceutical composition. See, e.g., KR’029 KIPRIS Translation at pages 20-21:
A single unit dosage form of the invention is suitable for oral, mucosal (e.g., nasal, sublingual, vaginal, bucal, or rectal), parenteral (e.g., subcutaneous, intravenous, bolus infusion, intramuscular, or intraarterial), topical (e.g., eye), transdermal, or transcutaneous administration to a patient. Examples of dosage forms are tablets; Caplets Capsules such as soft elastic gelatin capsules; Cachets; Troches; Lozenges Dispersing agents; Suppositories; Powder; Aerosols (e.g., nasal sprays or enholers); Gels; A liquid dosage form suitable for oral or mucosal administration to a patient comprising a suspension formulation (e.g., an aqueous or non-aqueous liquid suspension formulation, an oil-in-water emulsion, or a water-in-oil emulsion) solution formulation and an elixil formulation. A liquid dosage form suitable for injection administration to a patient And sterile solid preparations (e.g., crystalline or amorphous solids) that can be reconstituted to provide a liquid dosage form suitable for injection administration to a patient, but are not limited thereto.
KR’029 KIPRIS Translation at 20-21 (emphases added).
KR’029 further teaches that the disclosed embodiments are illustrative and not restrictive.
So far, the present invention has been described focusing on preferred embodiments thereof. Those skilled in the art to which the present invention pertains will understand that the present invention may be implemented in a modified form without departing from the essential characteristics of the present invention. Therefore, the disclosed embodiments should be considered in an illustrative sense and not a restrictive sense.
KR’029 KIPRIS Translation at 46.
Claims Anticipated by KR’029
Regarding the instant claims 1 and 2, KR’029 teaches a pharmaceutical composition for preventing or treating cancer, comprising BMDA, hereinafter, the “the pharmaceutical composition of KR’029” (KR’029 at claim 3). The pharmaceutical composition of KR’029 reads on an anti-inflammatory composition containing, as an active ingredient, a compound represented by a following Chemical Formula 1, wherein the Chemical Formula 1 is BMDA (i.e., Chemical Formula 1-1).
Regarding claims 3-7, their respective recitations of intended use, as discussed above in the section pertaining to indefiniteness, do not distinguish the claims over the pharmaceutical composition of KR’029, because the pharmaceutical composition of KR’029 could be used for the same purposes recited in claims 3-7.
Regarding claims 8 and 9, the pharmaceutical composition of KR’029 reads on a cosmetic composition for ameliorating atopic dermatitis, the composition containing, as an active ingredient, a compound represented by a following Chemical Formula 2, wherein the Chemical Formula 2 is BMDA (i.e., Chemical Formula 1-1).
Regarding claim 10, KR’029 teaches that moisturizers may be additives to the pharmaceutical composition of KR’029. See KR’029 KIPRIS Translation at 31-32, excerpted above. KR’029 further teaches water, perfume, and preservatives as excipients. See KR’029 KIPRIS Translation at 23-24, excerpted above.
Regarding claim 11, KR’029 teaches that the pharmaceutical composition of KR’029 may be in the form of powder, gels, suspension, emulsion, and sprays. See KR’029 KIPRIS Translation at 20-21, excerpted above.
Regarding claims 12-14, the pharmaceutical composition of KR’029 reads on a pharmaceutical composition for preventing or treating rheumatoid arthritis, the composition containing, as an active ingredient, a compound represented by a following Chemical Formula 1, wherein the Chemical Formula 1 is BMDA (i.e., Chemical Formula 1-1).
Further, the disclosure of KR’029 encompasses pharmaceutically acceptable salts. See KR’029 KIPRIS Translation at 21-22 (“The compositions, shapes, and types of dosage forms of the present invention generally vary widely depending on their use.…These and other ways of the particular dosage forms encompassed by the present invention are each very diverse and are apparent to those skilled in the art to which the present invention pertains.”).
Regarding claim 15, KR’029 teaches that the pharmaceutical composition of KR’029 is suitable for oral administration. See KR’029 KIPRIS Translation at 20-21, excerpted above.
Regarding claim 16, KR’029 teaches that the pharmaceutical composition of KR’029 was administered orally at 20 mg/kg. See KR’029 KIPRIS Translation at page 44/49, excerpted above. KR’029 further teaches single unit dosage forms suitable for oral administration. See KR’029 KIPRIS Translation at page 20-21, excerpted above.
Regarding claims 17-18, the pharmaceutical composition of KR’029 reads on a medicinal composition for treatment of ulcerative colitis, the composition containing, as an active ingredient, a compound represented by a following Chemical Formula 1, wherein the Chemical Formula 1 is BMDA (i.e., Chemical Formula 1-1).
Further, the disclosure of KR’029 encompasses pharmaceutically acceptable salts. See KR’029 KIPRIS Translation at 21-22 (“The compositions, shapes, and types of dosage forms of the present invention generally vary widely depending on their use.…These and other ways of the particular dosage forms encompassed by the present invention are each very diverse and are apparent to those skilled in the art to which the present invention pertains.”).
Regarding claim 20, KR’029 teaches that the pharmaceutical composition of KR’029 “is suitable for … mucosal (e.g., … rectal) … administration to a patient.” See KR’029 KIPRIS Translation at page 20-21, excerpted above.
Regarding claim 21, KR’029 further teaches that the amount of active ingredients in the pharmaceutical composition of KR’029 “generally vary widely”. See KR’029 KIPRIS Translation at pages 21-22, excerpted above. KR’029 further teaches ranges of 0.1 to 10 mg/kg BMDA. KR’029 Google Machine Translation at page 6. KR’029 further teaches concentrations of 3.125 to 100 μg/ml BMDA.
Regarding claim 22, it recites that the intended use of administering the medicinal composition of claim 17 in an enema manner is to suppress production of chemokine CINC-3. As discussed above, recitations of intended use do not distinguish the claims over the prior art. Therefore, the pharmaceutical composition of KR’029 anticipates claim 22, because the pharmaceutical composition of KR’029 could be used for the same purposes recited in claim 22.
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.
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.
Claims 1 and 2 are obvious over KR’029 in view of Kaowinn 2018 and Sisto 2021
Claims 1 and 2 are rejected under 35 U.S.C. 103 as being unpatentable over KR’029 in view of Kaowinn et al., “N-Benzyl-N-methyl-dodecan-1-amine, a novel compound from garlic, exerts anti-cancer effects on human A549 lung cancer cells overexpressing cancer upregulated gene (CUG)2,” European journal of Pharmacology, vol. 841, pp. 19-27 (2018), hereinafter “Kaowinn 2018”, and Sisto et al., “Organ Fibrosis and Autoimmunity: The Role of Inflammation in TGFβ-Dependent EMT,” Biomolecules, vol. 11, no. 2: 310, pp. 1-26 (2021), hereinafter “Sisto 2021”.
As explained above in the section regarding anticipation, KR’029 teaches a pharmaceutical composition for preventing or treating cancer, comprising BMDA (KR’029 at claim 3) (referred to as the “pharmaceutical composition of KR’029” above). KR’029 further teaches that BMDA, i.e., a disclosed embodiment of Chemical Formula 1, is a component of garlic. See, e.g., KR’029 at claim 2. Furthermore, KR’029 discloses that the subject matter of its disclosure was supported by an award granted to a research project which was named, in part, “Anti-diabetic, anti-inflammatory, and hangover-preventing activity of garlic - Pure separation and standardization of components.” See KR’029 at page 2/19 (emphasis added).
One of ordinary skill in the art would have a reasonable expectation of success in using the pharmaceutical composition of KR’029 in the anti-inflammatory compositions recited in claims 1 and 2, because Kaowinn 2018 discloses that administration of BMDA inhibits certain molecular mechanisms and pathways, such as transforming growth factor TGF-β, NF-κB, and epithelial-mesenchymal transition (“EMT”), which Sisto 2021 explains are factors that are linked to and elevated in rheumatoid arthritis patients.
Kaowinn 2018
Kaowinn 2018 discloses in vivo results from the administration of BMDA to mice injected with A549-CUG2 cells and in vitro studies of A549-CUG2 cell lines treated with BMDA. Kaowinn 2018 explains that for the CUG2 cells, CUG2 expression induces EMT through TGF-β signalling:
Cancer upregulated gene 2 (CUG2) is commonly enhanced in various types of cancers, including lung, colon, liver, and ovarian cancers (Lee et al., 2007). The transplantation of CUG2 induces tumor similar to that of mutant Ras in nude mice (Lee et al., 2007). Furthermore, CUG2 is considered a centromeric component necessary for chromosomal segregation during mitosis (Hori et al., 2008; Kim et al., 2009). The overexpression of CUG2 induces the activation of Ras and enhances the phosphorylation of ERK, JNK, and p38MAPK (Park et al., 2010). The enhanced CUG2 expression also induces epithelial-mesenchymal transition (EMT) through transforming growth factor (TGF)-β signaling (Kaowinn et al., 2017b).
Kaowinn 2018 at 20 (emphases added).
Regarding the in vitro results obtained from treatment with BDMA, Kaowinn 2018 explains that the results are applicable to non-CUG2 cells:
[T]reatment with BMDA significantly reduced the level of NF-κB P65 in A549-CUG2 cells, but it moderately decreased their levels in A549-Vec cells (Fig. 2B).
Kaowinn 2018 at 22 (emphasis added).
Kaowinn 2018 further explains the effect of BMDA treatment on EMT:
To investigate whether BMDA treatment inhibits CUG2-induced cancer stem cell-like phenotypes, we examined its effects on EMT, an essential process for tumor development. The treatment with BMDA inhibited cell migration induced by CUG2 in the wound healing assay. It also inhibited cell invasion into the lower well through a Matrigel-coated membrane (Fig. 5A and B). Furthermore, A549-Vec cells exhibited significantly slower cell migration and invasion than A549-CUG2 cells.
…
We examined the potential downregulation of E-cadherin levels, which is a biochemical feature of EMT; the level of N-cadherin or vimentin is usually upregulated. The treatment with BMDA increased the level of E-cadherin and decreased the expression of vimentin and N-cadherin, supporting the inhibitory effect of BMDA on EMT (Fig. 5D).
Kaowinn 2018 at 24.
Kaowinn 2018 further discloses the link between TGF-β and EMT, and the effects of BMDA on target molecules of TGF-β signaling (Snail and Twist):
We observed that BMDA treatment inhibited CUG2-induced cancer stem cell-like phenotypes (Fig. 5) and therefore sought to determine the underlying mechanisms mediating these effects. Recently, we reported that TGF-β signaling plays an important role in EMT, stemness (in submission) and drug resistance (Kaowinn et al., 2017a, Kaowinn et al., 2017b). Therefore, we evaluated the inhibitory effects of BMDA on TGF-β signaling activity. A549-CUG2 cells exhibited reduced TGF-β reporter activity during BMDA treatment (Fig. 6A), thus, reducing the synthesis of TGF-β (Fig. 6B). Furthermore, in A549-CUG2 cells, BMDA treatment decreased the level of phospho-Smad2, as well as the level of Snail and Twist, which are target molecules of TGF- β signaling (Fig. 6B). Furthermore, the immunohistochemistry analysis showed that BMDA treatment significantly decreased Twist staining in the tumor section from A549-CUG2-transplanted Balb/C nude mice compared with that from mock-treated mice (Fig. 6C).
…
These results indicate that BMDA inhibits TGF-β, Akt–ERK, and β-catenin signaling involved in EMT or stemness.
Kaowinn 2018 at 24-25 (emphases added).
Kaowinn 2018 summarizes the results of the studies as follows:
Furthermore, the treatment with BMDA inhibited EMT, stemness, and Twist expression in vivo, which are likely mediated by the inhibition of TGF-ß transcription and protein synthesis.
…
Overall, our results suggest that BMDA isolated from garlic has potential to be developed as a novel anticancer drug that acts by inhibiting TGF-ß, Akt-ERK, and ß-catenin signaling.
Kaowinn 2018 at 26.
Sisto 2021
Sisto 2021 generally discloses the link between TGF-β, NF-κB, and EMT in rheumatoid arthritis, and explains that blocking TGF-β results in neutralization of rheumatoid arthritis symptoms.
Rheumatoid arthritis (RA) is an autoimmune and chronic inflammatory disease featuring synovial hyperplasia and progressive joint destruction [134]. Synovial hyperplasia is caused by the influx and proliferation of inflammatory cells, due to an increased neo-angiogenesis within the hyperplastic tissue [135], as well as by the increased proliferation and survival of resident cells [135].
In this context of an enhanced, prolonged production of inflammatory cytokines, TGF-β and NF-κB signalling are crucial regulatory pathways in RA [136]. In RA, TGF-β1 performs actions that range from a pro-angiogenic role in the synovial membrane (SM) [137] to the induction and synthesis of pro-inflammatory cytokines [138], MMPs [139], and various agents responsible for fibrinolysis and tissue remodelling, such as aggrecanase [140] and urokinase-type plasminogen activator [141]. The importance of TGF-β in the pathogenesis of RA has been highlighted by numerous studies conducted on animal models. The abundant expression of TGF-β1, 2, and 3 and of TGFBR1 and -2 in rat synovium, acts as a potent inducer of collagen-linked arthritis (CIA) [142], while the intra-articular injection of TGF-β1 or TGF-β2 induces symptoms typical of RA, resulting in synovial inflammation and hyperplasia [143]. On the contrary, when TGF-β activity was blocked, the neutralization of acute and chronic RA symptoms triggered by streptococcal cell walls (SCW) occurred [144]. …
Sisto 2021 at page 9 of 26 (emphases added).
Sisto 2021 further discloses links between TGF-β expression in rheumatoid arthritis and EMT, as well as the observed activation of key EMT regulators:
The great variety of experimental data collected prompted many authors to investigate a possible link between TGF-β expression in RA and EMT, in view of the key role of TGF-β in EMT induction. During EMT, the phenotype of cells changes, becoming more aggressive, invasive, and resistant to apoptosis [4]. These processes, which are characteristic of metastatic processes in tumours, determine pannus tissue invasion and destruction in RA [27]. In RA patients and in the CIA mice model, the synovial membrane or synovial fluid shows increased levels of EMT-inducing molecules, including TGF-β [150].
…
This complex network of inducers/pathways leads to the activation of key EMT regulators, such as the transcription factors Snail/Slug, Twist, Zeb, and E47, which organize a concerted modulation of EMT [26].
…
These recently published findings support the hypothesis that Snail mediates ECM degradation by human and rat synovial cells, and is involved in cartilage degradation detected in a CIA model [152]. However, despite growing evidence of an involvement of TGF-β/EMT in RA, some important reservations need to be kept in mind, because in the synovium few cells have epithelial characteristics, and classical E-cadherins are poorly expressed due to the lack of a basement membrane [157]. These key points need to be solved to clearly identify the critical role likely played by EMT in RA joints. Nevertheless, the presence of α-SMA in the synovial lining layer of RA patients and the expression of fibrotic factors in healthy FLSs after stimulation with synovial fluid from RA patients [158] indicate that a modulated process like EMT might play a role in the development of RA synovium.
Sisto 2021 at page 10/26 (emphases added).
Claims 1 and 2 were Obvious at the Time of Filing
One having ordinary skill in the art at the time of filing would be motivated by the disclosure of Sisto 2021 to target the treatment of rheumatoid arthritis, i.e., an inflammatory disease, by using a drug that inhibited TGF-β, reduced the levels of NF-κB, reduced the levels of key EMT regulators Snail and Twist, and inhibited EMT, because Sisto 2021 explains that the elevation of the levels and expression of these factors and mechanisms are linked to the pathogenesis of rheumatoid arthritis. One having ordinary skill in the art at the time of filing would have a reasonable expectation of success in using BMDA in an anti-inflammatory composition designed to treat an inflammatory disease such as rheumatoid arthritis, because Kaowinn 2018 teaches that BMDA administration inhibited TGF-β, reduced the levels of NF-κB, reduced the levels of key EMT regulators Snail and Twist, and inhibited EMT.
Therefore, claim 1 was obvious at the time of filing.
Regarding claim 2, it generally recites the anti-inflammatory composition of claim 1, wherein the anti-inflammatory composition contains one of compounds represented by Chemical Formulas 1-1 – 1-5. Claim 2 is wherein the compound represented by Chemical Formula 1 is BMDA, i.e., Chemical Formula 1-1, as for the same reasons claim 1 is obvious.
Therefore, claim 2 was obvious at the time of filing.
Claim 2 is obvious over KR’029 in view of Kaowinn 2018 and Sisto 2021, in further view of Masato 2006, Njardarson 2022, Topliss 1972, Richardson 2021, and Topliss 1977
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over KR’029 in view of Kaowinn 2018 and Sisto 2021, in further view of Abe Chinomura Masato, “Chemical components of phytoncides and their antioxidant effects”, Aroma Research No.25, vol 7, no. 1, pp. 56-62 (2006) (Machine Translation also attached, and referred to as “Masato 2006”), Kevin A. Scott, Philip B. Cox, and Jon T. Njardarson, “Phenols in Pharmaceuticals: Analysis of a Recurring Motif”, Journal of Medicinal Chemistry, vol. 65, no. 10, pp. 7044-7072 (published May 9, 2022), hereinafter “Njardarson 2022”, John G. Topliss, “Utilization of Operational Schemes for Analog Synthesis in Drug Design”, Journal of Medicinal Chemistry, vol. 15, no. 10, pp. 1006-1011 (1972), hereinafter “Topliss 1972”, Paul Richardson, “Applications of fluorine to the construction of bioisosteric elements for the purposes of novel drug discovery”, Expert Opinion on Drug Discovery, vol. 16, no. 11, pp. 1261-1286 (2021), hereinafter “Richardson 2021”, and John G. Topliss, "A manual method for applying the Hansch approach to drug design." J. Med. Chem., vol. 20, no. 4, pp. 463-469 (1977), hereinafter “Topliss 1977”.
KR’029, Kaowinn 2018 and Sisto 2021 are relied upon as above.
While KR’029, Kaowinn 2018 and Sisto 2021 render claim 2 obvious wherein the compound represented by Chemical Formula 1 is BMDA, i.e., Chemical Formula 1-1, the references do not expressly teach the anti-inflammatory composition of claim 1, wherein the anti-inflammatory composition contains Chemical Formulas 1-2, 1-3, 1-4, or 1-5.
Chemical Formula 1-2
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As shown above in the chemical structures for BMDA (Chemical Formula 1-1) and Chemical Formula 1-2, the structures differ by substitution at the nitrogen of the amine functional group, wherein in BMDA, one group is benzyl, and in Chemical Formula 1-5, one group is 4-methoxybenzyl.
One of ordinary skill in the art would have a reasonable expectation of success in preparing such a composition, wherein the composition contains Chemical Formula 1-2, because
1) one of ordinary skill in the art at the time of filing would recognize that BMDA would be expected to possess beneficial properties when used as an active ingredient in an anti-inflammatory composition, for the reasons stated in claim 1,
2) the 4--methoxy substituent is a routine and recommended modification of a benzene ring for analog synthesis in drug design (see, e.g., Topliss 1972), and
3) the methyl phenyl ether group is generally known to provide optimal physiochemical properties in small-molecule drugs (see, e.g., Njardarson 2022).
Topliss 1972
Topliss 1972 discloses an operational scheme for aromatic substitution that is used for finding the optimum substitution on a benzene ring in an active lead compound for maximization of drug potency. See Topliss 1972 at 1006. “The scheme [is] based on a fundamental assumption of the Hansch method that a particular substituent may modify activity relative to the parent compound by virtue of resulting changes in hydrophobic, electronic, and steric effects.” Topliss 1972 at abstract. The general scheme is reproduced below.
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Topliss 1972 at 1007.
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When considering a lead compound with an unsubstituted benzene ring, Topliss 1972 generally recommends assessing the activity of the 4-chloro analog of the lead compound as a starting point, i.e., at tier 0 in the above chart. Depending on the activity of the 4-choloro analog, Topliss 1972 generally recommends, at tier 1, further assessing the activity the 4-methoxy, 4-methyl, and 3,4-dicholoro analogs.
Topliss 1972 further discloses the hydrophobic (π), electronic (σ), and steric (Es) parameters used in assessing potential substitutions to the base benzene ring. The 4-methoxy group is notable insofar as it has a minimal impact on the hydrophobic (i.e., lipophilic) properties of the lead compound, while still being able to impart solubility through hydrogen bonding. See Topliss 1972 at Table 1, page 1009, reproduced herein.
Njardarson 2022
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Njardarson 2022 generally discloses the analysis of the structures of FDA approved molecules containing phenol or phenolic ether fragments. As evident upon review of the article, the methyl phenyl ether group is a common structural motif of many FDA approved drugs, see, e.g., Njardarson 2022, Figure 21 et seq. With respect to the instant compound represented by Chemical Structure 1-4 which possess a methyl phenyl ether, its particular 4-methoxy linkage appears in 8 of 14 approved drugs containing a mono-substituted methyl ether. See Njardarson 2022 at Figure 21, page 7052, reproduced herein.
Njardarson 2022 further discusses that drugs possessing a methyl phenyl ether group tend to exhibit potentially beneficial phase I metabolism, wherein the methyl group is cleaved, exposing a phenol functional group. In certain cases, the resulting phenol bearing compound may be the active form of the drug, and therefore the methoxy group can serve to protect the active form of the drug from unwanted metabolism prior to binding to the receptor target. See Njardarson 2022 at 7067 (discussing the example of codeine metabolism).
Regarding the selection of methoxy over hydroxy substitution, Njardarson 2022 discloses that:
In contrast to phenolic drugs, phenolic ether drugs have a significantly higher percentage approved for oral delivery (84%), and this is reflected in their comparatively superior physicochemical properties. Given this fact, overall Ro5 compliance is high (86%), with a very slight enhancement in Ro5 compliance (87%) for oral phenol ether drugs versus other routes of administration.
Njardarson 2022 at 7062.
Claim 2 wherein Chemical Formula 1-2 is the Active Ingredient is Obvious
One of ordinary skill in the art at the time of filing, would recognize that BMDA would be expected to possess beneficial properties when used as an active ingredient in an anti-inflammatory composition, for the reasons stated in claim 1. One of ordinary skill in the art at the time of filing would be motivated to synthesize the 4-methoxy analog of BMDA, i.e., the compound represented by Chemical Structure 1-2, because Topliss 1972 recommends synthesizing that specific analog in order to find the optimum substitution on the benzene ring of BMDA for maximization of drug potency. One of ordinary skill in the art at the time of filing would be further motivated to synthesize the 4-methoxy analog of BMDA, because Topliss 1972 inherently teaches that the 4-methoxy analog would maintain desirable lipophilicity while imparting beneficial solubility properties through the ability to accept a hydrogen bond. One of ordinary skill in the art at the time of filing would be further motivated to incorporate the general methyl phenyl ether moiety into the structure of BMDA, because Njardarson 2022 discloses that such moieties impart beneficial physicochemical properties, which is reflected in their abundant appearance in FDA approved pharmaceuticals. Therefore, one of ordinary skill in the art at the time of filing would have a reasonable expectation of success in using the compound represented by Chemical Formula 1-2 as the active ingredient in an anti-inflammatory composition, because Topliss 1972 and Njardarson 2022 collectively teach that the 4-methoxy analog of BMDA may exhibit physicochemical properties superior to those of BMDA, which one of ordinary skill in the art at the time of filing would recognize would be expected to possess beneficial properties when used as an active ingredient in an anti-inflammatory composition, for the reasons stated in claim 1.
Therefore, claim 2, as it pertains to Chemical Formula 1-2, was obvious at the time of filing.
Chemical Formula 1-3
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As shown above in the chemical structures for BMDA (Chemical Formula 1-1) and Chemical Formula 1-3, the structures differ by substitution at the nitrogen of the amine functional group, wherein in BMDA, one group is methyl, and in Chemical Formula 1-3, one group is ethyl. These chemicals are homologs, and therefore there is a presumed expectation that such compounds possess similar properties. See, MPEP 2144.09(II):
Compounds which are … homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977).
MPEP 2144.09(II).
The presumed expectation that Chemical Formula 1-3 would possess properties similar to BMDA’s properties entails the motivation to make Chemical Formula 1-3. See MPEP 2144.09(I).
A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties." In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979). See In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA 1963) … and In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990)….
MPEP 2144.09(I).
Therefore, one of ordinary skill in the art at the time of filing would be motivated make Chemical Formula 1-3, in the expectation that it would have similar properties to the known and expected properties of BMDA, because the two chemicals are homologs. One of ordinary skill in the art at the time of filing would have a reasonable expectation of success in using Chemical Formula 1-3 as an active ingredient in an anti-inflammatory composition, because one of ordinary skill in the art at the time of filing would have a reasonable expectation of success in using BMDA in such a manner. See supra discussion of obviousness of claim 1.
Therefore, claim 2, as it pertains to Chemical Formula 1-3, was obvious at the time of filing.
Chemical Formula 1-4
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As shown above in the chemical structures for BMDA (Chemical Formula 1-1) and Chemical Formula 1-4, the structures differ by substitution at the nitrogen of the amine functional group, wherein in BMDA, one group is decyl, and in Chemical Formula 1-4, one group is dodecyl. BMDA and the compound represented by Chemical Formula 1-4 are therefore homologs.
First, regarding a matter of clarity, the examiner notes that Kaowinn 2018 discloses the use of Chemical Formula 1-4, although perhaps in error. In the title, abstract, and throughout the article, Kaowinn 2018 refers to the chemical named “N-benzyl-N-methyl-dodecan-1-amine”. One of ordinary skill in the art at the time of filing would attribute that chemical name to the chemical structure of Chemical Formula 1-4, and not BMDA. However, throughout the manuscript, the authors provide the structure of BMDA, and not Chemical Formula 1-4. See also Kaowinn 2018 at 22 (describing the synthesis of BMDA using decanal, not dodecanal). Therefore, the examiner does not consider Kaowinn 2018 as expressly teaching Chemical Formula 1-4.
Turning now to the prior art that expressly teaches Chemical Formula 1-4, one of ordinary skill in the art would be motivated to use the compound represented by Chemical Structure 1-4 as an active ingredient in an anti-inflammatory composition, because Masato 2006 taught that the compound was classified in a group known to possess excellent radical scavenging properties.
Masato 2006
Masato 2006 discloses certain chemical components of phytoncides and their antioxidant effects. In particular, Masato 2006 at Table 3, page 60, lists compound (22) – N-Benzyl-N-methyl-dodecyl amine, as a compound identified in “Type D”. The chemical structure is provided in Masato 2006 at 61, and is reproduced below. This compound is the compound represented by Chemical Formula 1-4 in the instant claims.
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Masato 2006 at 61.
Compounds in “Type D” phytoncide were obtained from “flower-based plant extracts”. Masato 2006 at 57. Regarding results from DPPH quenching studies, Masato 2016 discloses that “Type D phytoncide, derived primarily from flowering plants, was found to exhibit the highest radical scavenging rate (100%). Furthermore, when the 50% radical scavenging concentration (SC50) was examined, Type D phytoncide solution demonstrated a value equivalent to that of α-tocopherol, demonstrating its excellent radical scavenging effect.” See also Masato 2016 at 58, last paragraph (disclosing the antioxidant effect of the studied phytoncides with respect to active oxygen scavenging) and 59 at Table 2 (listing the active oxygen scavenging effect of Type-D phytoncide).
Therefore, one of ordinary skill in the art would have a reasonable expectation of success in using the compound represented by Chemical Structure 1-4 as an active ingredient in an anti-inflammatory composition, because 1) Masato 2006 taught that the compound was classified in a group known to possess excellent radical scavenging properties, and therefore would function as an antioxidant, and 2) BMDA and the compound represented by Chemical Formula 1-4 are homologs and therefore, claim 2, as it pertains to Chemical Formula 1-4, is obvious for at least the same reasons the claim, as it pertains to Chemical Formula 1-3, is obvious.
Therefore, claim 2, as it pertains to Chemical Formula 1-4, was obvious at the time of filing.
Chemical Formula 1-5
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As shown above in the chemical structures for BMDA (Chemical Formula 1-1) and Chemical Formula 1-5, the structures differ by substitution at the nitrogen of the amine functional group, wherein in BMDA, one group is benzyl, and in Chemical Formula 1-5, one group is p-fluorobenzyl.
One of ordinary skill in the art would have a reasonable expectation of success in preparing such a composition, wherein the composition contains Chemical Formula 1-5, because
1) one of ordinary skill in the art at the time of filing would recognize that BMDA would be expected to possess beneficial properties when used as an active ingredient in an anti-inflammatory composition, for the reasons stated in claim 1,
2) aryl fluorination is known to impart beneficial physiochemical properties in small molecule drugs (Richardson 2021 and Topliss 1977).
Richardson 2021
Richardson 2021 reviews the generally applicability and certain applications of fluorine substitution in the design and development of bioisosteres in medicinal chemistry. In general, a medicinal chemist may incorporate fluorine into the structure of an active drug compound in order to reduce in vivo metabolism, block unwanted reactive metabolism, increase drug half-life and exposure, influence lipophilicity, improve solubility, and more. See Richardson 2021 at 1261, right column.
Regarding aryl fluorination, Richardson 2021 discloses that aryl-fluoro compounds comprise the largest group of the reviewed 340 registered fluoro-pharmaceuticals registered since 1954. Richardson 2021 at 1262. Richardson 2021 further discloses an exemplary case of aryl fluorination through describing the development of Ezetimibe, wherein fluorination was successfully employed to block unwanted metabolism of a 4-methoxyphenyl group present in a lead compound. See Richardson 2021 at 1265-66, and Figure 2 at 1266, reproduced below.
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Richardson 2021 at 1266.
Topliss 1977
Topliss 1977 provides a batch approach for applying the decision tree disclosed in Topliss 1977. Regarding 4-fluoro substitution, Topliss 1977 discloses the additional recommendation of synthesizing the 4-fluoro analog of the parent compound (i.e., possessing a 4-H) to avoid metabolic hydroxylation:
The 4-F analogue, which provides minimal change in π and σ effects compared to the unsubstituted compound, should prove advantageous in the event that the initial analysis indicates the unsubstituted compound may be essentially optimal in terms of π and σ but subject to rather rapid metabolic transformation by 4-hydroxylation.
Topliss 1977 at 468 (note that π and σ effects correspond to hydrophobic and electronic effects, respectively).
Claim 2 wherein Chemical Formula 1-5 is the Active Ingredient is Obvious
One of ordinary skill in the art at the time of filing, would recognize that BMDA would be expected to possess beneficial properties when used as an active ingredient in an anti-inflammatory composition, for the reasons stated in claim 1. One of ordinary skill in the art at the time of filing would be motivated to synthesize the 4-fluoro analog of BMDA, i.e., the compound represented by Chemical Structure 1-5, because Topliss 1977 recommends synthesizing that specific analog in order to find the optimum substitution on the benzene ring of BMDA for maximization of drug potency – by maintaining the hydrophobic and electronic character while reducing the risk of unwanted metabolic hydroxylation. One of ordinary skill in the art at the time of filing would be further motivated to synthesize the 4-fluoro analog of BMDA, because Richardson 2021 discloses that such moieties impart beneficial physicochemical properties, which is reflected in their abundant appearance in FDA approved pharmaceuticals. Therefore, one of ordinary skill in the art at the time of filing would have a reasonable expectation of success in using the compound represented by Chemical Formula 1-5 as the active ingredient in an anti-inflammatory composition, because Topliss 1977 and Richardson 2021 collectively teach that the 4-fluoro analog of BMDA may exhibit physicochemical properties superior to those of BMDA, which one of ordinary skill in the art at the time of filing would recognize would be expected to possess beneficial properties when used as an active ingredient in an anti-inflammatory composition, for the reasons stated in claim 1.
Moreover, the examiner notes that the above analysis also applies to considering modification of the compound represented by Chemical Formula 1-2 to arrive at the compound represented by Chemical Formula 1-5, insofar as fluorination may also serve to block oxidative metabolism of the compound represented by Chemical Formula 1-2.
Therefore, claim 2, as it pertains to Chemical Formula 1-5, was obvious at the time of filing.
Claim 3 is obvious over KR’029 in view of Kaowinn 2018 and Sisto 2021, in further view of Weissler 2021 and Atreya 2008
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over KR’029 in view of Kaowinn 2018 and Sisto 2021, in further view of Katherine A Weissler and Pamela A Frischmeyer-Guerrerio, “Genetic evidence for the role of transforming growth factor in atopic phenotypes”, Current Opinion in Immunology, vol. 60, pp. 54-62 (2021), hereinafter “Weissler 2021”, and I. Atreya et al., "NF-κB in inflammatory bowel disease," Journal of Internal Medicine, vol. 263, no. 6, pp. 591-596 (2008), hereinafter ‘Atreya 2008”.
Claim 3 recites the anti-inflammatory composition of claim 1, wherein the anti-inflammatory composition has a therapeutic effect on an inflammatory disease including atopic dermatitis, rheumatoid arthritis, or ulcerative colitis.
Regarding the claim as it pertains to rheumatoid arthritis, the obviousness analyses in claims 1 and 2 apply, and therefore render claim 3 obvious as well.
Atopic Dermatitis
Regarding the claim as it pertains to atopic dermatitis, one of ordinary skill in the art would have a reasonable expectation of success in using the pharmaceutical composition of KR’029 in such a manner, because Kaowinn 2018 discloses that administration of BMDA inhibits certain molecular mechanisms and pathways, such as transforming growth factor TGF-β, which Weissler 2021 explains is a factor that affects the pathology of atopic dermatitis.
Weissler 2021
Weissler 2021 generally discloses the role of TGF-β in atopic phenotypes, including atopic dermatitis. The role of TGF-β in atopic phenotypes is summarized in Figure 1, Weissler 2021 at 55, reproduced below.
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Weissler 2021 at 55.
As depicted in the above figure, TGF-β may both promote and inhibit allergic outcomes. Regarding Figure 1 and atopic dermatitis specifically, Weissler 2021 discloses:
Finally, TGF-β is important in the resolution of tissue damage following an allergic episode, and its con-tinued presence can lead to fibrosis, which can worsen symptoms in asthma, atopic dermatitis, and EoE. The various and contradictory roles of TGF-β in allergy development and progression are summarized in Figure 1.
Weissler 2021 at 59.
One having ordinary skill in the art at the time of filing would be motivated by the disclosure of Weissler 2021 to target the treatment of atopic dermatitis, i.e., an inflammatory disease, by using a drug that inhibited TGF-β, because, Weissler 2021 explains that the continued presence of TGF-β following an allergic episode can worsen the symptoms of atopic dermatitis. One having ordinary skill in the art at the time of filing would have a reasonable expectation of success in using BMDA in an anti-inflammatory composition designed to have a therapeutic effect on an inflammatory disease such as atopic dermatitis, because Kaowinn 2018 teaches that BMDA administration inhibited TGF-β.
Therefore, claim 3 as it pertains to atopic dermatitis was obvious at the time of filing.
Ulcerative Colitis
Regarding the claim as it pertains to ulcerative colitis, one of ordinary skill in the art would have a reasonable expectation of success in using the pharmaceutical composition of KR’029 in such a manner, because Kaowinn 2018 discloses that administration of BMDA inhibits certain molecular mechanisms and pathways, such as NF-κB, which Atreya 2008 explains are factors that affect the pathology of ulcerative colitis.
Atreya 2008
Atreya 2008 generally discloses the role of NF-κB in inflammatory bowel disease, including ulcerative colitis. For example,
In general, the family of nuclear transcription factor kappaB (NF-κB) proteins consists of five different members, which are namely p65 (RelA), c-Rel, RelB, p50 and p52.
…
[I]nhibitors of NF-κB are able to mask the motif within the amino acid sequence of NF-κB, which is responsible for the nuclear localization of NF-κB.…
Atreya 2008 at 591.
Atreya 2008 further summarizes the goals of targeting NF-κB as a potential therapeutic strategy for patients with IBD, including ulcerative colitis.
By carefully targeting specific NF-κB subunits or signalling components that are particularly involved in the pathogenesis of IBD, it might be possible to further minimize systemic toxic effects [1]. Considering these principles of local administration and high specificity, the therapeutical targeting of NF-κB activation probably represents a promising tool for future therapy of IBD.
Atreya 2008 at 594 (emphasis added).
One having ordinary skill in the art at the time of filing would be motivated by the disclosure of Atreya 2008 to target the treatment of ulcerative colitis, i.e., an inflammatory disease, by using a drug that inhibited NF-κB, because, Atreya 2008 explains that “the therapeutical targeting of NF-κB activation probably represents a promising tool for future therapy of IBD.” Atreya 2008 at 594. One having ordinary skill in the art at the time of filing would have a reasonable expectation of success in using BMDA in an anti-inflammatory composition designed to have a therapeutic effect on an inflammatory disease such as ulcerative colitis, because Kaowinn 2018 teaches that BMDA administration inhibited NF-κB.
Therefore, claim 3 as it pertains to ulcerative colitis was obvious at the time of filing.
Claim 4 is obvious over KR’029 in view of Kaowinn 2018 and Sisto 2021
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over KR’029 in view of Kaowinn 2018 and Sisto 2021.
KR’029, Kaowinn 2018 and Sisto 2021 are relied upon as above.
Sisto 2021 further discloses the interaction between TGF-β and other molecular mechanisms and pathways, including p38 MAPK.
In addition to Smads pathways, TGF-β1 also utilizes a multitude of intracellular noncanonical, non-Smads TGF-β signals that are generally triggered by the binding of ligands not belonging to the TGF-β family to tyrosine kinase receptors [99]. The activated TGF-β1 receptors induce a response through signal transducers such as the mitogen-activated protein kinase (MAPK) pathways, for example, including extracellular signal-regulated kinases (Erks), c-Jun amino terminal kinase (JNK), p38 MAPK, as well as IκB kinase (IKK), phosphatidylinositol-3 kinase (PI3K) and Akt, and the Rho family GTPases, that could finally converge on the Smad activating cascade [76,99].
Sisto 2021 at page 6 of 26 (emphases added).
One having ordinary skill in the art at the time of filing would be motivated by the disclosure of Sisto 2021 to target the treatment of rheumatoid arthritis, i.e., an inflammatory disease, by using a drug that inhibited TGF-β, reduced the levels of NF-κB, reduced the levels of key EMT regulators Snail and Twist, and inhibited EMT, because Sisto 2021 explains that the elevation of the levels and expression of these factors and mechanisms are linked to the pathogenesis of rheumatoid arthritis. One having ordinary skill in the art at the time of filing would understand that inhibiting TGF-β would have a downstream effect on p38 MAPK, because Sisto 2021 teaches that activated TGF-β1 receptors induce a response through signal transducers such as p38 MAPK. One having ordinary skill in the art at the time of filing would have a reasonable expectation of success in using BMDA in an anti-inflammatory composition designed to treat an inflammatory disease such as rheumatoid arthritis, because Kaowinn 2018 teaches that BMDA administration inhibited TGF-β, reduced the levels of NF-κB, reduced the levels of key EMT regulators Snail and Twist, and inhibited EMT.
Therefore, claim 4 was obvious at the time of filing.
Claim 5 is obvious over KR’029 in view of Kaowinn 2018 and Sisto 2021, in further view of Atreya 2008
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over KR’029 in view of Kaowinn 2018 and Sisto 2021, in further view of Atreya 2008.
KR’029, Kaowinn 2018, Sisto 2021, and Atreya 2008 are relied upon as above.
Atreya 2008 further discloses the interaction between NF-κB and other molecular mechanisms and pathways, including TNF-α, IL-1 and IL-6:
In IBD patients, the increased NF-κB expression in mucosal macrophages is accompanied by an increased capacity of these cells to produce and secrete TNF-α, IL-1 and IL-6 [12].
Atreya 2008 at 592.
One having ordinary skill in the art at the time of filing would be motivated by the disclosure of Sisto 2021 to target the treatment of rheumatoid arthritis, i.e., an inflammatory disease, by using a drug that inhibited TGF-β, reduced the levels of NF-κB, reduced the levels of key EMT regulators Snail and Twist, and inhibited EMT, because Sisto 2021 explains that the elevation of the levels and expression of these factors and mechanisms are linked to the pathogenesis of rheumatoid arthritis. One having ordinary skill in the art at the time of filing would understand that inhibiting NF-κB would have a downstream effect on TNF-α, IL-1 and IL-6, because Atreya 2008 teaches that “[i]n IBD patients, NF-κB expression in mucosal macrophages is accompanied by an increased capacity of these cells to produce and secrete TNF-α, IL-1 and IL-6.” Atreya 2008 at 592. One having ordinary skill in the art at the time of filing would have a reasonable expectation of success in using BMDA in an anti-inflammatory composition designed to treat an inflammatory disease such as rheumatoid arthritis, because Kaowinn 2018 teaches that BMDA administration inhibited TGF-β, reduced the levels of NF-κB, reduced the levels of key EMT regulators Snail and Twist, and inhibited EMT.
Therefore, claim 5 was obvious at the time of filing.
Claim 6 is obvious over KR’029 in view of Kaowinn 2018 and Sisto 2021, in further view of Gao 2022
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over KR’029 in view of Kaowinn 2018 and Sisto 2021, in further view of Gao et al., “Dissecting the Crosstalk Between Nrf2 and NF-κB Response Pathways in Drug-Induced Toxicity,” Front. Cell Dev. Biol., vol. 9, article 809952, pp. 1-21 (published February 1, 2022), hereinafter “Gao 2022”.
KR’029, Kaowinn 2018 and Sisto 2021 are relied upon as above.
Goa 2022 generally discloses the crosstalk between Nrf2 and NF-κB. In particular, NF-κB p65 can directly inhibit Nrf2 at the transcriptional level, id. at page 4 of 21, and Nrf2 can inhibit the NF-κB path, id. at pages 4-5 of 21. These pathways further show crosstalk with HO-1. Id. at page 5 of 21. See also Gao 2022 at Figure 3, page 4 of 21 (illustrating crosstalk between Nrf2, HO-1 and NF-κB) (reproduced below).
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Gao 2022 at page 4 of 21.
One having ordinary skill in the art at the time of filing would be motivated by the disclosure of Sisto 2021 to target the treatment of rheumatoid arthritis, i.e., an inflammatory disease, by using a drug that inhibited TGF-β, reduced the levels of NF-κB, reduced the levels of key EMT regulators Snail and Twist, and inhibited EMT, because Sisto 2021 explains that the elevation of the levels and expression of these factors and mechanisms are linked to the pathogenesis of rheumatoid arthritis. One having ordinary skill in the art at the time of filing would understand that inhibiting NF-κB would have a downstream effect on Nrf2 at the transcriptional level, because Gao 2022 teaches that NF-κB p65 can directly inhibit Nrf2 at the transcriptional level. One having ordinary skill in the art at the time of filing would understand that this in turn would have an effect on HO-1, because Gao 2022 teaches that HO-1 is a downstream gene of Nrf2 that can inhibit NF-κB transcription. One having ordinary skill in the art at the time of filing would have a reasonable expectation of success in using BMDA in an anti-inflammatory composition designed to treat an inflammatory disease such as rheumatoid arthritis, because Kaowinn 2018 teaches that BMDA administration inhibited TGF-β, reduced the levels of NF-κB, reduced the levels of key EMT regulators Snail and Twist, and inhibited EMT.
Therefore, claim 6 was obvious at the time of filing.
Claim 7 is obvious over KR’029 in view of Kaowinn 2018 and Sisto 2021, in further view of Edamatsu 1997
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over KR’029 in view of Kaowinn 2018 and Sisto 2021, in further view of Edamatsu et al., “Induction of neutrophil chemotactic factor production by staurosporine in rat peritoneal neutrophils,” British Journal of Pharmacology, vol. 121, no. 8, pp. 1651-1658 (1997), hereinafter “Edamatsu 1997”.
KR’029, Kaowinn 2018 and Sisto 2021 are relied upon as above.
Edamatsu 1997 discloses that NF-κB is required for the induction of MIP-2, which is CINC-3:
The activation of nuclear factor-kB (NF-kB), which is indispen-sable for the induction of several chemokines (Kunsch & Rosen, 1993; Ohmori et al., 1995) including MIP-2 (Widmer et al., 1993), requires activation of certain protein kinases (Ishikawa et al., 1995).
Edamatsu 1997 at 1651.
One having ordinary skill in the art at the time of filing would be motivated by the disclosure of Sisto 2021 to target the treatment of rheumatoid arthritis, i.e., an inflammatory disease, by using a drug that inhibited TGF-β, reduced the levels of NF-κB, reduced the levels of key EMT regulators Snail and Twist, and inhibited EMT, because Sisto 2021 explains that the elevation of the levels and expression of these factors and mechanisms are linked to the pathogenesis of rheumatoid arthritis. One having ordinary skill in the art at the time of filing would understand that inhibiting NF-κB would have a downstream effect on CINC-3, because Edamatsu 1997 teaches that NF-κB is indispensable for the induction of MIP-2 (CINC-3). One having ordinary skill in the art at the time of filing would have a reasonable expectation of success in using BMDA in an anti-inflammatory composition designed to treat an inflammatory disease such as rheumatoid arthritis, because Kaowinn 2018 teaches that BMDA administration inhibited TGF-β, reduced the levels of NF-κB, reduced the levels of key EMT regulators Snail and Twist, and inhibited EMT.
Therefore, claim 7 was obvious at the time of filing.
Claims 8-11 are obvious over KR’029 in view of Kaowinn 2018 and Weissler 2021, in further view of Njardarson 2022, Topliss 1972, Richardson 2021, and Topliss 1977
Claims 8- - 11 are rejected under 35 U.S.C. 103 as being unpatentable over KR’029 in view of Kaowinn 2018 and Weissler 2021, in further view of Njardarson 2022, Topliss 1972, Richardson 2021, and Topliss 1977.
The references are relied upon as above.
Claim 8 recites a cosmetic composition for ameliorating atopic dermatitis containing an active ingredient represented by Chemical Formula 2, which encompasses the compounds represented by Chemical Formulas 1-1, 1-2, 1-3, and 1-5. Claim 9 depends from claim 8 and specifically recites the aforementioned compounds as the active ingredient in the cosmetic composition.
As explained above in the section regarding anticipation, KR’029 teaches a pharmaceutical composition for preventing or treating cancer, comprising BMDA (KR’029 at claim 3) (referred to as the “pharmaceutical composition of KR’029” above). KR’029 further teaches that BMDA, i.e., a disclosed embodiment of Chemical Formula 1, is a component of garlic. See, e.g., KR’029 at claim 2. Furthermore, KR’029 discloses that the subject matter of its disclosure was supported by an award granted to a research project which was named, in part, “Anti-diabetic, anti-inflammatory, and hangover-preventing activity of garlic - Pure separation and standardization of components.” See KR’029 at page 2/19 (emphasis added).
One of ordinary skill in the art would have a reasonable expectation of success in using the pharmaceutical composition of KR’029 in the cosmetic compositions for ameliorating atopic dermatitis recited in claims 8 and 9, because Kaowinn 2018 discloses that administration of BMDA inhibits certain molecular mechanisms and pathways, such as transforming growth factor TGF-β, which Weissler 2021 explains is a factor that affects the pathology of atopic dermatitis. See supra discussion of Kaowinn 2018 in the section regarding obviousness of claims 1 and 2, see also supra discussion of Weissler 2021 in the section regarding obviousness of claim 3 as it pertains to atopic dermatitis.
As further explained above in the section regarding obviousness of claims 1 and 2, the compounds represented by Chemical Formulas 1-2 and 1-5, are obvious in further view of the following references:
Chemical Formula 1-2 - Topliss 1972 and Njardarson 2022,
Chemical Formula 1-5 - Richardson 2021 and Topliss 1977.
As further explained above in the section regarding obviousness of claims 1 and 2, the compound represented by Chemical Formula 1-3 is a homolog of BMDA and was therefore obvious at the time of filing.
Therefore, claims 8 and 9 were obvious at the time of filing.
Regarding claim 10, it recites the cosmetic composition of claim 8, wherein the cosmetic composition further contains at least one selected from a group consisting of a skin moisturizing ingredient, a cosmetic formulation ingredient, a fragrance, a preservative, and a purified water.
KR’029 teaches that moisturizers may be additives to the pharmaceutical composition of KR’029. See KR’029 KIPRIS Translation at 31-32, excerpted above. KR’029 further teaches water, perfume, and preservatives as excipients. See KR’029 KIPRIS Translation at 23-24, excerpted above.
One of ordinary skill in the art would have a reasonable expectation of success in using the pharmaceutical composition of KR’029 in the cosmetic compositions for ameliorating atopic dermatitis recited in claim 8, because Kaowinn 2018 discloses that administration of BMDA inhibits certain molecular mechanisms and pathways, such as transforming growth factor TGF-β, which Weissler 2021 explains is a factor that affects the pathology of atopic dermatitis. One of ordinary skill in the art would have a reasonable expectation of success in using the pharmaceutical composition of KR’029 in such a manner with at least one selected from a group consisting of a skin moisturizing ingredient, a cosmetic formulation ingredient, a fragrance, a preservative, and a purified water, because KR’029 teaches moisturizers, water, perfume, and preservatives as excipients contained within the pharmaceutical composition of KR’029.
Therefore, claim 10 was obvious at the time of filing.
Regarding claim 11, it recites the cosmetic composition of claim 8, wherein a formulation of the cosmetic composition is lotion, cream, emulsion, essence, gel, serum, pack, powder, skin ointment, skin patch, suspension, spray, or cosmetic solution.
KR’029 teaches that the pharmaceutical composition of KR’029 may be in the form of powder, gels, suspension, emulsion, and sprays. See KR’029 KIPRIS Translation at 20-21, excerpted above.
One of ordinary skill in the art would have a reasonable expectation of success in using the pharmaceutical composition of KR’029 in the cosmetic compositions for ameliorating atopic dermatitis recited in claim 8, because Kaowinn 2018 discloses that administration of BMDA inhibits certain molecular mechanisms and pathways, such as transforming growth factor TGF-β, which Weissler 2021 explains is a factor that affects the pathology of atopic dermatitis. One of ordinary skill in the art would have a reasonable expectation of success in using the pharmaceutical composition of KR’029 in such a manner wherein a formulation of the cosmetic composition is lotion, cream, emulsion, essence, gel, serum, pack, powder, skin ointment, skin patch, suspension, spray, or cosmetic solution, because KR’029 teaches that the pharmaceutical composition of KR’029 may be in the form of powder, gels, suspension, emulsion, and sprays.
Therefore, claim 11 was obvious at the time of filing.
Claims 12-16 are obvious over KR’029 in view of Kaowinn 2018 and Sisto 2021, in further view of Njardarson 2022, Topliss 1972, Masato 2006, Richardson 2021, and Topliss 1977
Claims 12 - 16 are rejected under 35 U.S.C. 103 as being unpatentable over KR’029 in view of Kaowinn 2018 and Sisto 2021, in further view of Njardarson 2022, Topliss 1972, Masato 2006, Richardson 2021, and Topliss 1977.
The references are relied upon as above.
Claim 12 recites a pharmaceutical composition for preventing or treating rheumatoid arthritis containing an active ingredient represented by Chemical Formula 1, which encompasses the compounds represented by Chemical Formulas 1-1, 1-2, 1-3, 1-4, and 1-5, or a pharmaceutically acceptable salt thereof. Claim 13 depends from claim 12 and specifically recites the aforementioned compounds represented by Chemical Formulas 1-1 and 1-2 as the active ingredient in the pharmaceutical composition (the examiner notes that it is unclear if applicants intend for claim 13 to encompass the salts as well). Claim 14 depends from claim 13 and specifically recites the compound represented by Chemical Formula 1-1 (i.e., BMDA) as the active ingredient in the pharmaceutical composition.
As explained above in the section regarding anticipation, KR’029 teaches a pharmaceutical composition for preventing or treating cancer, comprising BMDA (KR’029 at claim 3) (referred to as the “pharmaceutical composition of KR’029” above). KR’029 further teaches that BMDA, i.e., a disclosed embodiment of Chemical Formula 1, is a component of garlic. See, e.g., KR’029 at claim 2. Furthermore, KR’029 discloses that the subject matter of its disclosure was supported by an award granted to a research project which was named, in part, “Anti-diabetic, anti-inflammatory, and hangover-preventing activity of garlic - Pure separation and standardization of components.” See KR’029 at page 2/19 (emphasis added).
Further, the disclosure of KR’029 encompasses pharmaceutically acceptable salts. See KR’029 KIPRIS Translation at 21-22 (“The compositions, shapes, and types of dosage forms of the present invention generally vary widely depending on their use.…These and other ways of the particular dosage forms encompassed by the present invention are each very diverse and are apparent to those skilled in the art to which the present invention pertains.”).
One of ordinary skill in the art would have a reasonable expectation of success in using the pharmaceutical composition of KR’029 in the pharmaceutical compositions for preventing or treating rheumatoid arthritis recited in claims 12 and 13, because Kaowinn 2018 teaches that BMDA administration inhibited TGF-β, reduced the levels of NF-κB, reduced the levels of key EMT regulators Snail and Twist, and inhibited EMT, which Sisto 2021 explains are factors and mechanisms linked to the pathogenesis of rheumatoid arthritis. See supra discussion of Kaowinn 2018 and Sisto 2021 in the section regarding obviousness of claims 1 and 2.
As further explained above in the section regarding obviousness of claims 1 and 2, the compound represented by Chemical Formulas 1-2, 1-4, and 1-5 are obvious in further view of the following references:
Chemical Formula 1-2 - Topliss 1972 and Njardarson 2022.
Chemical Formula 1-4 – Masato 2006.
Chemical Formula 1-5 - Richardson 2021 and Topliss 1977.
As further explained above in the section regarding obviousness of claims 1 and 2, the compound represented by Chemical Formula 1-3 is a homolog of BMDA and was therefore obvious at the time of filing.
Therefore, claims 12 - 14 were obvious at the time of filing.
Regarding claim 15, it recites the pharmaceutical composition of claim 12, wherein the pharmaceutical composition is administered orally.
KR’029 teaches that the pharmaceutical composition of KR’029 is suitable for oral administration. See KR’029 KIPRIS Translation at 20-21, excerpted above.
One of ordinary skill in the art would have a reasonable expectation of success in using the pharmaceutical composition of KR’029 in the pharmaceutical composition for preventing or treating rheumatoid arthritis recited in claim 12, because Kaowinn 2018 teaches that BMDA administration inhibited TGF-β, reduced the levels of NF-κB, reduced the levels of key EMT regulators Snail and Twist, and inhibited EMT, which Sisto 2021 are factors and mechanisms linked to the pathogenesis of rheumatoid arthritis. One of ordinary skill in the art would have a reasonable expectation of success in using the pharmaceutical composition of KR’029 in such a manner wherein the pharmaceutical composition is administered orally, because KR’029 teaches that the pharmaceutical composition of KR’029 is suitable for oral administration.
Therefore, claim 15 was obvious at the time of filing.
Regarding claim 16, it recites the pharmaceutical composition of claim 12, wherein the pharmaceutical composition is formulated in a unit dosage form suitable for oral administration at a dose of 15 to 25 mg/kg.
KR’029 teaches single unit dosage forms suitable for oral administration. See KR’029 KIPRIS Translation at page 20-21, excerpted above.
KR’029 teaches that the pharmaceutical composition of KR’029 was administered orally at 20 mg/kg. See KR’029 KIPRIS Translation at page 44/49, excerpted above.
KR’029 further teaches that the amount of active ingredients in the pharmaceutical composition of KR’029 “generally vary widely”. See KR’029 KIPRIS Translation at pages 21-22, excerpted above. KR’029 further teaches ranges of 0.1 to 10 mg/kg BMDA. KR’029 Google Machine Translation at page 6.
Kaowinn 2018 teaches intraperitoneal administration of BMDA at 40 mg/kg. Kaowinn 2018 at 21.
One of ordinary skill in the art would have a reasonable expectation of success in using the pharmaceutical composition of KR’029 in the pharmaceutical composition for preventing or treating rheumatoid arthritis recited in claim 12, because Kaowinn 2018 teaches that BMDA administration inhibited TGF-β, reduced the levels of NF-κB, reduced the levels of key EMT regulators Snail and Twist, and inhibited EMT, which Sisto 2021 are factors and mechanisms linked to the pathogenesis of rheumatoid arthritis. One of ordinary skill in the art would have a reasonable expectation of success in using the pharmaceutical composition of KR’029 in such a manner wherein the pharmaceutical composition is formulated in a unit dosage form suitable for oral administration at a dose of 15 to 25 mg/kg, because 1) KR’029 teaches that the pharmaceutical composition of KR’029 is suitable for oral administration in unit dosage form at 20 mg/kg, from and 0.1 to 10 mg/kg, and that dosages forms may vary, and 2) Kaowinn 2018 teaches intraperitoneal administration of BMDA at 40 mg/kg.
Therefore, claim 16 was obvious at the time of filing.
Claims 17-21 are obvious over KR’029 in view of Kaowinn 2018 and Atreya 2008, in further view of Njardarson 2022, Topliss 1972, Masato 2006, Richardson 2021, and Topliss 1977
Claims 17 - 21 are rejected under 35 U.S.C. 103 as being unpatentable over KR’029 in view of Kaowinn 2018 and Atreya 2008, in further view of in further view of Njardarson 2022, Topliss 1972, Masato 2006, Richardson 2021, and Topliss 1977.
The references are relied upon as above.
Claim 17 recites a medicinal composition for treatment of ulcerative colitis containing an active ingredient represented by Chemical Formula 1, which encompasses the compounds represented by Chemical Formulas 1-1, 1-2, 1-3, 1-4, and 1-5, or a pharmaceutically acceptable salt thereof. Claim 18 depends from claim 17 and specifically recites the aforementioned compounds represented by Chemical Formulas 1-1 and 1-2 as the active ingredient in the medicinal composition. Claim 19 depends from claim 18 and specifically recites the compound represented by Chemical Formula 1-2 as the active ingredient in the medicinal composition.
As explained above in the section regarding anticipation, KR’029 teaches a pharmaceutical composition for preventing or treating cancer, comprising BMDA (KR’029 at claim 3) (referred to as the “pharmaceutical composition of KR’029” above). KR’029 further teaches that BMDA, i.e., a disclosed embodiment of Chemical Formula 1, is a component of garlic. See, e.g., KR’029 at claim 2. Furthermore, KR’029 discloses that the subject matter of its disclosure was supported by an award granted to a research project which was named, in part, “Anti-diabetic, anti-inflammatory, and hangover-preventing activity of garlic - Pure separation and standardization of components.” See KR’029 at page 2/19 (emphasis added).
Further, the disclosure of KR’029 encompasses pharmaceutically acceptable salts. See KR’029 KIPRIS Translation at 21-22 (“The compositions, shapes, and types of dosage forms of the present invention generally vary widely depending on their use.…These and other ways of the particular dosage forms encompassed by the present invention are each very diverse and are apparent to those skilled in the art to which the present invention pertains.”).
One of ordinary skill in the art would have a reasonable expectation of success in using the pharmaceutical composition of KR’029 in the medicinal composition for treatment of ulcerative colitis recited in claims 17 and 18, because Kaowinn 2018 discloses that administration of BMDA inhibits certain molecular mechanisms and pathways, such as NF-κB, which Atreya 2008 explains are factors that affect the pathology of ulcerative colitis. See supra discussion of Kaowinn 2018 in the section regarding obviousness of claims 1 and 2, see also supra discussion of Atreya 2008 the section regarding obviousness of claim 3 as it pertains to ulcerative colitis.
As further explained above in the section regarding obviousness of claims 1 and 2, the compound represented by Chemical Formulas 1-2, 1-4, and 1-5 are obvious in further view of the following references:
Chemical Formula 1-2 - Topliss 1972 and Njardarson 2022.
Chemical Formula 1-4 – Masato 2006.
Chemical Formula 1-5 - Richardson 2021 and Topliss 1977.
As further explained above in the section regarding obviousness of claims 1 and 2, the compound represented by Chemical Formula 1-3 is a homolog of BMDA and was therefore obvious at the time of filing.
Therefore, claims 17 - 19 were obvious at the time of filing.
Regarding claim 20, it recites the medicinal composition of claim 17, wherein the medicinal composition is administered in an enema manner.
KR’029 teaches that the pharmaceutical composition of KR’029 “is suitable for … mucosal (e.g., … rectal) … administration to a patient.” See KR’029 KIPRIS Translation at page 20-21, excerpted above.
One of ordinary skill in the art would have a reasonable expectation of success in using the pharmaceutical composition of KR’029 in the medicinal composition for treatment of ulcerative colitis recited in claim 17, because Kaowinn 2018 discloses that administration of BMDA inhibits certain molecular mechanisms and pathways, such as NF-κB, which Atreya 2008 explains are factors that affect the pathology of ulcerative colitis. One of ordinary skill in the art would have a reasonable expectation of success in using the pharmaceutical composition of KR’029 in such a manner wherein the medicinal composition is administered in an enema manner, because KR’029 teaches that the composition of KR’029 is suitable for “mucosal (e.g., … rectal) … administration to a patient.”
Therefore, claim 20 was obvious at the time of filing.
Regarding claim 21, it recites the medicinal composition of claim 20, wherein the medicinal composition is administered directly to an ulcerative colitis patient in the enema manner at 0.4 mg/kg or smaller as an effective dosage per day.
KR’029 teaches that the composition of KR’029 “is suitable for … mucosal (e.g., … rectal) … administration to a patient.” See KR’029 KIPRIS Translation at page 20-21, excerpted above.
KR’029 further teaches that the amount of active ingredients in the pharmaceutical composition of KR’029 “generally vary widely”. See KR’029 KIPRIS Translation at pages 21-22, excerpted above. KR’029 further teaches ranges of 0.1 to 10 mg/kg BMDA. KR’029 Google Machine Translation at page 6. KR’029 further teaches concentrations of 3.125 to 100 μg/ml BMDA.
One of ordinary skill in the art would have a reasonable expectation of success in using the pharmaceutical composition of KR’029 in the medicinal composition for treatment of ulcerative colitis recited in claim 17, because Kaowinn 2018 discloses that administration of BMDA inhibits certain molecular mechanisms and pathways, such as NF-κB, which Atreya 2008 explains are factors that affect the pathology of ulcerative colitis. One of ordinary skill in the art would have a reasonable expectation of success in using the pharmaceutical composition of KR’029 in such a manner wherein the medicinal composition is administered directly to an ulcerative colitis patient in the enema manner at 0.4 mg/kg or smaller as an effective dosage per day, because 1) KR’029 teaches that the pharmaceutical composition of KR’029 is suitable for “mucosal (e.g., … rectal) … administration to a patient.”, and 2) KR’029 teaches that the pharmaceutical composition of KR’029 is suitable for administration at ranges from 0.1 to 10 mg/kg, at concentrations ranging from 3.125 to 100 μg/ml BMDA (note that because the volume of the dosage is not specified, this concentration range reads on “or smaller”), and that dosages forms may vary.
Therefore, claim 21 was obvious at the time of filing.
Claim 22 is obvious over KR’029 in view of Kaowinn 2018 and Atreya 2008, in further view of Edamatsu 1997, Njardarson 2022, Topliss 1972, Masato 2006, Richardson 2021, and Topliss 1977
Claim 22 is rejected under 35 U.S.C. 103 as being unpatentable over KR’029 in view of Kaowinn 2018 and Atreya 2008, in further view of Edamatsu 1997, Njardarson 2022, Topliss 1972, Masato 2006, Richardson 2021, and Topliss 1977.
Regarding claim 22, it recites the medicinal composition of claim 17, wherein administration of the medicinal composition in an enema manner suppresses production of chemokine CINC-3.
As explained above in the section regarding anticipation, KR’029 teaches a pharmaceutical composition for preventing or treating cancer, comprising BMDA (KR’029 at claim 3) (referred to as the “pharmaceutical composition of KR’029” above). KR’029 further teaches that BMDA, i.e., a disclosed embodiment of Chemical Formula 1, is a component of garlic. See, e.g., KR’029 at claim 2. Furthermore, KR’029 discloses that the subject matter of its disclosure was supported by an award granted to a research project which was named, in part, “Anti-diabetic, anti-inflammatory, and hangover-preventing activity of garlic - Pure separation and standardization of components.” See KR’029 at page 2/19 (emphasis added).
One of ordinary skill in the art would have a reasonable expectation of success in using the pharmaceutical composition of KR’029 in the medicinal composition for treatment of ulcerative colitis recited in claim 17, because Kaowinn 2018 discloses that administration of BMDA inhibits certain molecular mechanisms and pathways, such as NF-κB, which Atreya 2008 explains are factors that affect the pathology of ulcerative colitis. See supra discussion of Kaowinn 2018 in the section regarding obviousness of claims 1 and 2, see also supra discussion of Atreya 2008 the section regarding obviousness of claim 3 as it pertains to ulcerative colitis.
As further explained above in the section regarding obviousness of claims 1 and 2, the compound represented by Chemical Formulas 1-2, 1-4, and 1-5 are obvious in further view of the following references:
Chemical Formula 1-2 - Topliss 1972 and Njardarson 2022.
Chemical Formula 1-4 – Masato 2006.
Chemical Formula 1-5 - Richardson 2021 and Topliss 1977.
As further explained above in the section regarding obviousness of claims 1 and 2, the compound represented by Chemical Formula 1-3 is a homolog of BMDA and was therefore obvious at the time of filing.
One of ordinary skill in the art would have a reasonable expectation of success in using the pharmaceutical composition of KR’029 in as the medicinal composition as recited in claim 17 wherein the medicinal composition is administered in an enema manner, because KR’029 teaches that the pharmaceutical composition of KR’029 is suitable for “mucosal (e.g., … rectal) … administration to a patient.” One having ordinary skill in the art at the time of filing would understand that inhibiting NF-κB would have a downstream effect on CINC-3, because Edamatsu 1997 teaches that NF-κB is indispensable for the induction of MIP-2 (CINC-3). See supra discussion of Edamatsu 1997 in the section regarding obviousness of claim 7.
Therefore, claim 22 was obvious at the time of filing.
Prior art Cited but not Applied
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Moosavian et al., “The effects of garlic (Allium sativum) supplementation on inflammatory biomarkers, fatigue, and clinical symptoms in patients with active rheumatoid arthritis: A randomized, double-blind, placebo-controlled trial”, Phytotherapy Research, vol. 34, no. 11, pp. 2953-2962 (2020).
Discloses the use of garlic for treating rheumatoid arthritis.
Paul D. Leeson and Brian Springthorpe, “The influence of drug-like concepts on decision-making in medicinal chemistry”, Nature Reviews Drug Discovery, vol. 6, pp. 881-890 (2007).
Discloses the relationship between drug ligands and lipophilicity.
Conclusion
No claims are allowed.
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/C.E.R./Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
1 See, e.g., Specification at page 9, paragraph [0056].