DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
The status of the claims are as follows:
Claims 1-12 are pending.
Claims 1-7 are allowed.
Claim 9 is rejected.
Claims 10-12 are objected to.
Priority
Acknowledgement is made that Instant Application 18/843,662, filed on 2024, Sept. 03 is a National Stage entry of PCT/IB2023/000143, filed on 2023, Mar. 02, which claims foreign priority to CN202210200080.X, filed on 2022, Mar. 02. Although the Instant Application appears to have been filed outside of the 30-month deadline, 2024, Sept. 02 was a U.S. federal holiday and the deadline was therefore extended to 2024, Sept. 03. Accordingly, the filing is considered timely despite the apparent delay.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on 2024, Oct. 02 is/are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement(s) is/are being considered by the examiner.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
Claim 9 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treatment of a disease associated with histamine H3 receptors by administering a therapeutically effective amount of a phenyl urea derivative to a subject, does not reasonably provide enablement for prevention of said condition. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims. This is a scope of enablement rejection.
In this regard, the application disclosure and claims have been compared per the factors indicated in the decision In re Wands, 8 USPQ 2nd 1400 (Fed. Cir. 1988) as to undue experimentation. The factors include: (a) The nature of the invention; (b) The breadth of the claims; (c) The relative skill of those in the art; (d) Status of the prior art/predictability or unpredictability of the art (e) the amount of direction or guidance presented; (f) the presence or absence of working examples and (g) the quantity of experimentation necessary. Each factor is addressed below on the basis of comparison of the disclosure, the claims and the state of the art in the assessment of undue experimentation.
The nature of the invention: The invention is directed to a phenyl urea derivative compound and a method for its use in preventing or treating a disease associated with histamine H3 receptors.
The breadth of the claim: The scope of the claim includes a method for preventing or treating a disease associated with histamine H3 receptor in a subject, comprising administration of a therapeutically effective amount of the phenyl urea derivative compound.
The relative skill of those in the art: The level of skill is high comparable to that of an M.D. or Ph.D.
Status of the prior art/predictability or unpredictability of the art: It is known in the art that the histamine 3 receptor (H3R) is highly variable (see Leurs, The histamine H3 receptor: from gene cloning to H3 receptor drugs. Nat. Rev. Drug Discov. 2005, 4, 107-122. doi:10.1038/nrd1631). Leurs teaches the existence of at least 20 different H3R isoforms that have different pharmacological profiles, including agonist potencies, signaling properties, and constitutive activity (page 109, paragraph 2; page 109, Table 1). Moreover, there is evidence of polymorphism within the human H3R. Leurs teaches that one A280V polymorphism was found in a patient with Shy-Drager syndrome (page 109, right column, paragraph 2). Leurs further teaches that activation of H3Rs results in lower hypothalamic histamine release and are therefore associated with other histamine receptor conditions, such as insomnia (page 112, right column, paragraph 4). Additionally, inhibition of the H3R is taught to be associated with wakefulness and may be useful in treating narcolepsy (page 117, left column, paragraph 3). Leurs further teaches that H3R antagonists can effectively regulate acetylcholine release for the treatment of both ADHD and Alzheimer’s disease (page 117, left column, paragraph 4). Accordingly, one can conclude that it is highly unlikely that all H3R isoforms and polymorphs will contribute equally to every indication and/or respond equally to the same therapeutic agent. As such, the etiology and pathophysiology of histamine 3 receptors and associated conditions are highly unpredictable, so one could not accurately predict the correct indication and severity to administer a therapeutically effective dosage for preventative treatment.
The amount of direction or guidance presented: In the instant case, Applicant has not provided guidance as to how one skilled in the art would accomplish the objective of preventing a disease associated with H3R, nor are any references provided that teach the same. Therefore, the instant application is viewed as lacking an adequate enablement of where H3R diseases can be prevented.
The present or absence of working examples: No working examples are provided for preventing H3R diseases by administering a phenylurea derivative compound, for example, in a patient in the specification. The applicant has not provided any competent evidence or disclosed any tests that are highly predictive for the preventative effects of the instant composition. Note that in cases involving physiological activity such as the instant case, "the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved." See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
The quantity of experimentation necessary: The quantity of experimentation would be an undue burden to one of ordinary skill in the art. Thus, factors such as “sufficient working examples,” “the level of skill in the art" and "predictability," etc. have been demonstrated to be sufficiently lacking in the instant case for the instant method claim”. In view of the breadth of the claims, the chemical nature for the instant claims and unpredictability of preventing all meteoropathy, and the lack of working examples regarding the activity as claimed, one skilled in the art would have to undergo an undue amount of experimentation to use the instantly claimed invention commensurate in scope with the claims.
In consideration of the Wands factors, it is apparent that there is undue experimentation because of variability in prediction of outcome that is not addressed by the present application disclosure, examples, teaching and guidance presented. Absent factual data to the contrary, the amount and level of experimentation needed is undue.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 9 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Specifically, the phrase “adverse event associated with” renders the scope of the claim ambiguous.
The phrase “adverse event associated with” does not make clear what adverse events are or are not covered by the scope of the claim (e.g., common side effects, drug-drug interactions, allergic reactions, etc.). Furthermore, a skilled artisan cannot discern to what degree of association is needed to reduce the severity of or prevent toxicity of said adverse event. Accordingly, the above claims are ambiguous.
Claim Objections
Claims 10-12 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Allowable Subject Matter
Claims 1-7 are allowed.
The closest prior art on record to claims 1-7 is Nirogi (US 2014/0135304 A1; published 2014, May 15) in view of Palani (US 2011/0207734 A1; published 2011, Aug. 25) as evidenced by Hohenstein (Effects of heteroatoms on aromatic π-π interactions: benzene-pyridine and pyridine dimer. J Phys Chem A. 2009, 113(5), 878-886. https://doi.org/10.1021/jp809062x).
Claims 1-7 are directed to phenylurea derivative compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof:
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119
344
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.
Nirogi teaches compounds of formula (II), and their pharmaceutically acceptable salts and compositions thereof as histamine H3 receptor ligands (title, abstract).
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167
579
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The compounds taught by Nirogi that are most closely associated with the instant application is N-[4-(1-Cyclobutyl piperidin-4-yloxy)phenyl]-3-(morpholin-4-yl)propionamide as compound 26 (page 10) and N-[4-(1-Cyclobutyl piperidin-4-yloxy)benzyl]-2-(morpholin-4-yl)acetamide as compound 42 (page 11). Both compounds are shown in Table 1, below.
Palani teaches azine derivatives of Formula III (page 9, paragraph 0134), pharmaceutical compositions thereof, and a method of their use in treating disorders implicated with the H3 receptor including allergy, an allergy-induced airway response, congestion, a cardiovascular disease, an inflammatory disease, a gastrointestinal disorder, a neurological disorder, a metabolic disorder, obesity or an obesity-related disorder, diabetes, a diabetic complication, impaired glucose tolerance or impaired fasting glucose (title, abstract).
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151
293
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The compound taught by Palani that is most closely associated with the instant application is compound 24 (page 13, Table 1), which is compared with compounds 26 and 42 of Nirogi and the relevant instant compound BIOS-A-3 in Table 1, below.
Table 1. Prior art compounds most closely associated with instant BIOAS-A-3.
Nirogi Compound 26
Palani Compound 24
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137
263
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139
387
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Nirogi Compound 42
BIOS-A-3
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140
289
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140
323
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A person of ordinary skill in the art would not find it obvious to combine the teachings of Nirogi and Palani in such a way as to arrive at the instantly claimed BIOS-A-3, disclosed derivatives thereof, or the genus therefrom, because the structures of the respective teachings are distinct enough that any necessary combination would be non-obvious and/or lacking in motivation.
Nirogi teaches compound 26 (Table 1) that is comprised of a morpholine ring in the location designated by component ‘A’ in instant Formula I, wherein the morpholine ring is distanced from the carbonyl by two atoms (e.g., –CH2CH2–). Palani teaches compound 24 (Table 1) that is comprised of a morpholine ring in the location designated by component ‘A’ in instant Formula I, wherein the morpholine ring is directly bonded to the carbonyl.
The difference between these combined teachings and that of the instant application is that both Nirogi and Palani fail to teach an embodiment wherein the morpholine ring is distanced from the carbonyl by three atoms.
As stated by MPEP 2144.09, close structural similarity between chemical compounds (homologs, analogues, isomers) may be prima facie obvious. However, Nirogi teaches the component ‘r’ of Formula II as an integer ranging from 0 to 1 (page 1, paragraph 0012). Palani teaches the component Q of Formula III is a morpholine only when it is directly attached to the carbonyl (pages 7-8, paragraphs 0108 – 0115). Even after considering the combination, the combined teachings fail to teach any embodiment wherein the morpholine ring is distanced from the carbonyl by at least three atoms, a skilled artisan would not find it obvious to homologate this chain to the lengths necessary to cover the scope of the instant claims.
Nirogi teaches compound 42 (Table 1) that is comprised of a benzyl amide.
The difference between the compound of Nirogi and the instant application is that Nirogi fails to teach the use of a urea moiety.
However, Palani teaches compound 24 (Table 1) that is comprised of a benzylic urea.
One of ordinary skill in the art would be motivated to combine the teachings of Nirogi and Palani in this regard because both compounds are taught in the same field of endeavor of H3 receptor antagonists. Furthermore, Nirogi teaches the requisite component ‘r’ of Formula II is an integer ranging from 0 to 1 (page 1, paragraph 0012). When Nirogi compound 42 is modified such that ‘r’ = 0, the compound thus formed comprises a benzylic urea, as in Palani compound 24. Therefore, said skilled artisan would find it obvious to try with a reasonable expectation of success because the two species are linked by a common genus that is taught to have similar properties.
However, even after combination, there are differences such that the combined teachings of Nirogi and Palani and the instant application is that the combined teachings fail to teach an embodiment wherein the urea moiety is a phenyl urea.
However, Nirogi further teaches compound 24 (Table 1) that is comprised of a phenyl amide.
A skilled artisan would be motivated to homologate the above-described benzylic urea to the phenyl urea because Nirogi links the benzyl and phenyl amides as having similar properties. Therefore, once a skilled artisan arrives at the benzylic urea as described above, it would be prima facie obvious to homologate the benzyl urea to the phenyl urea because structurally similar compounds are expected to have similar results.
However, the substantial differences between the compounds of Nirogi and Palani would limit a skilled artisan’s motivation to combine their respective teachings.
The teachings of Nirogi and Palani differ by the central aryl ring. For example, while Formula II of Nirogi teaches embodiments wherein the central aryl ring is a pyridinyl ring (page 1, paragraphs 0005- 0009), only 3 of the 51 disclosed species contain a pyridinyl ring (e.g., compounds 34-36, page 10) while the remaining compounds all comprise a phenyl ring. Nirogi measured the binding affinity of phenyl compounds of Formula II (pyridinyl compounds omitted) for human or rat histamine H3 receptors and found the Ki ranged from about 1 nM to about 15 nM (page 11, Example 52). Conversely, while Formula III of Palani teaches embodiments wherein the central aryl ring is a phenyl ring (page 7, paragraph 0098), none of the 64 disclosed species contain a phenyl ring. Palani measured the binding affinity of compounds of Formula III for guinea pig histamine H3 receptors and found the Ki ranged from about 30 nM to about 2 µM (page 35, paragraph 0265). It is known in the art that phenyl rings have different binding affinities than the pyridinyl analogue (see Hohenstein), which may contribute to the observed deleterious effect on H3 receptor binding affinity. Therefore, the motivation for a skilled artisan to combine the teachings of Nirogi and Palani may be limited.
The teachings of Nirogi and Palani differ further by the N-substituent of the piperidine. For example, while Nirogi teaches the component ‘L’ of Formula II is alkyl or C3-C6 cycloalkyl (page 1, paragraphs 0005-0013), only 3 of the 51 disclosed species contain a cyclopropyl, as is present in Palani compound 24 (e.g., Nirogi compounds 23, 38, and 41). Conversely, while Palani teaches component ‘R1’ of Formula III is –(alkylene)n-cycloalkyl (page 9, paragraph 0125), none of the 64 disclosed species is an embodiment wherein the alkylene is absent, as in Nirogi compounds 26 and 42. Therefore, the motivation for a skilled artisan to combine the teachings of Nirogi and Palani is further limited.
The state of the prior art fails to teach phenyl urea compounds that overlap with the scope of instant Formula I. Accordingly, claims 1-7 are allowed.
Conclusions
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/P.A./Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
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