Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Detailed Action
Filing Receipt
The filing receipt mailed 02/28/2025 states that the instant application is a 371 of PCT/US2022/025748, filed 04/21/2022, which claims benefit of provisional applications 63/185,26, filed 05/06/2021, and 63/178,385, filed 04/22/2021.
The instant claims find support in the 63/178,385 application. Therefore the effective filing date is 04/22/2021.
Information Disclosure Statement
The information disclosure statements received 06/05/2024, 08/29/2025, and 01/14/2026 have been considered.
Claim Objections
Claims 58-59 are objected to. Claims 58 and 59 states “wherein the disorder”. Parent claim 57 states “NLRP3-mediated disorder”. Examiner suggests amending claims 58 and 59 to state “NLRP3-mediated disorder” for consistency.
Rejections
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Scope of Enablement
Claims 1, 3, 7, 10, 16, 25-29, 32, 34, 49, 52-54, and 56-59 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for compounds and pharmaceutically acceptable salts, does not reasonably provide enablement for prodrugs. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make/use the invention commensurate in scope with these claims.
“The [eight] factors to be considered [in making an enablement rejection] have been summarized as a) the quantity of experimentation necessary, b) the amount of direction or guidance presented, c) the presence or absence of working examples, d) the nature of the invention, e) the state of the prior art, f) the relative skill of those in that art, g) the predictability or unpredictability of the art, h) and the breadth of the claims”, In re Rainer, 146 USPQ 218 (1965); In re Colianni, 195 USPQ 150, Ex parte Formal, 230 USPQ 546.
a) Finding a prodrug is an empirical exercise. Predicting if a certain ester of a claimed alcohol, for example, is in fact a prodrug, that produces the active compound metabolically, in man, at a therapeutic concentration and at a useful rate is filled with experimental uncertainty. Although attempts have been made to predict drug metabolism de novo, this is still an experimental science. For a compound to be a prodrug, it must meet three tests. It must itself be biologically inactive. It must be metabolized to a second substance in a human at a rate and to an extent to produce that second substance at a physiologically meaningful concentration. Thirdly, that second substance must be clinically effective. Determining whether a particular compound meets these three criteria in a clinical trial setting requires a large quantity of experimentation.
b) The direction concerning the prodrugs is found in paragraph 0141, pages 26-27. No more than a definition of prodrug is disclosed.
c) There is no working example of a prodrug of a compound the formula (I).
d) The nature of the invention is clinical use of compounds and the pharmacokinetic behavior of substances in the human body.
e) Prodrugs are commonly known in the art as drugs which are administered in an inactive (or less active) form, and then metabolized in vivo into an active metabolite. The state of the arts in prodrugs is provided by Stella (J. Pharmaceutical Sciences, 2010, 99(12), pp. 4755-4765), "So while it may appear to be straightforward to try a prodrug approach, making and identifying the best prodrugs that will work in a specific case is less than routine”, see page 4763, left-hand column. Prodrugs are drugs used to overcome some barriers to the utility of the parent drug molecule. Stella addresses the barriers in the form of questions on page 4763. These barriers include, but are not limited to, solubility, permeability, stability, presystemic metabolism, and targeting limitations. Stella also states, “I have seen in both my academic and work capacity as a consultant that what may appear to be straightforward is most often far from predictable”, see page 4763, left-hand column.
f) The artisans making Applicants' prodrugs as a collaborative team of synthetic pharmaceutical chemists and metabolism experts. All would have a Ph. D. degree and several years of industrial experience.
g) It is well established that “the scope of enablement varies inversely with the degree of unpredictability of the factors involved", and physiological activity is generally considered to be an unpredictable factor. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). h) The breadth of the claims includes all of the hundreds of thousands of compounds of formula of claim 1 as well as the presently unknown list potential prodrug derivatives embraced by claim 1.
MPEP 2164.01(a) states, “[a] conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).” That conclusion is clearly justified here. Thus, undue experimentation will be required to determine if any particular derivative is, in fact, a prodrug.
The Examiner suggests deleting the term "prodrug", from the claims.
Enablement – Method Claims
Claims 57-59 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The following Wands factors have been considered if not explicitly discussed: (A) The breadth of the claims, (B) The nature of the invention, (C) The state of the prior art, (D) The level of one of ordinary skill, (E) The level of predictability in the art, (F) The amount of direction provided by the inventor, (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Breadth of the claims
Claim 57 states “A method of treating a NLRP3-mediated disorder, comprising administering a therapeutically effective amount of a compound of claim 1 to a subject in need thereof.
“Treating” includes “obtaining beneficial or desired results with respect to a disease, disorder or medical condition” and “therapeutic effect and/or a prophylactic effect.”
Nature of the Invention
The invention is a clinical method of treating a disorder.
Working examples and guidance provided
The specification discloses examples of a nEK7 assay, a IL-1β release assay, and results of compound tested on those assays in Biological examples 1-3, p. 145-149.
The assays show that compounds of the instant invention have activity in inhibiting NEK7 and in IL-1β release. However, the specification does not discuss how NEK7 inhibitory activity would directly lead to effective treatment or prevention for the number of disorders claimed in claims 58 and 59. There is no information provided in this disclosure that would indicate that the claimed compounds are effective in treating or preventing any of the disorders claimed as well.
State of the prior art
He (Nature, Vol. 530, 2016) discusses the connection between NEK7 and NLRP3 activation. He does not discuss any of the disorders within claims 58 and 59, nor does it suggest how NEK7 inhibition would be effective for methods of treating the claimed disorders. Therefore, the art does not support that NEK7 inhibition would directly result in treating any of the claimed disorders.
Quantity of Experimentation
Considering that the instant specification and the art are silent to a direct connection between the claimed disorders and NEK7 inhibition, there is significant unpredictability should one of ordinary skill in the art attempt to practice the claimed method in efforts to treat or prevent any of NLRP3-mediated diseases or the disorder claimed in claims 58-59.
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.
Claim 57 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.
Claim 57 states “NLRP3-mediated disorder”. This term is not defined within the instant specification. There are no examples of what conditions are considered “NLRP3-mediated disorders” and the instant specification does not provide methods to determine how one of ordinary skill would determine NLRP3-mediated disorders.
Conclusion
No claims allowed.
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/L.G./Examiner, Art Unit 1624
/SUSANNA MOORE/Primary Examiner, Art Unit 1624