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 and Priority
The filing receipt mailed 08/09/2024 states that the instant application is a 371 of PCT/CN2022/119179, filed 09/16/2022.
The filing receipt also states that the application claims foreign benefit of application CHINA 202111098709.6, filed 09/18/2021.
Information Disclosure Statement
The information disclosure statements submitted 08/14/2024, 07/28/2025, and 02/19/2026 have been considered.
Restriction/Species Election
Applicant’s election without traverse of Group I, claims 34-53 is acknowledged. Applicant’s election without traverse of compound 6 (compound only) is also acknowledged.
At examiner’s discretion search has been broadened to include the full scope of ring A, ring B, and wherein L1 is a bond.
Claims 54-57 are hereby withdrawn being drawn to non-elected inventions.
Claims 42-45, 50 and 53 are hereby withdrawn being drawn to non-elected species.
Claim Objections
Claim 34 claims “the structure and atomic number of the azaindazole ring”. Within the chemical arts, “atomic number” refers to the charge number of its atomic nucleus. Applicant appears to be using the term to refer to specific atoms along the azaindazole bicyclic ring structure as a numbering convention. The claim would be in better form if “and atomic number” is removed.
The claims also make use of the phrase “is selected from” and “consisting of” when claiming possible substituents. While applicant is their own lexicographer, the claims would be in better form if instead they stated simply “is”. As an example, “R1 is 1) hydrogen, halogen, cyano…”.
Claim 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.
Polymorphs and Metabolites
Claims 34-41, 46-49, and 51 are rejected under 35 U.S.C. 112, first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter, which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the claimed invention. The specification defines metabolites but not sufficiently that the definition can be considered specified. The mere recitation of “metabolites” is not sufficient to comply with the written description requirement. A metabolite is a compound, which has undergone one or more transformations in vivo from the parent compound, in this case, compounds of formula (I). What are these “metabolites?” What do these look like? Where does Applicant teach how to make these “metabolites?” Did Applicant have possession of these “metabolites?” Do these metabolites still meet the requirements of formula (I) in claim 1? The claim describes the function intended but provides no specific structural guidance to what constitutes a “metabolite.” Attempting to define means by function is not proper when the means can be clearly expressed in terms that are more precise.
Additionally, the term “polymorph” is defined within the specification but not sufficiently that the definition can be considered specified. The specification does not disclose the structure of any polymorphs and the specification lacks any crystallography date that would indicate to one of ordinary skill that crystals and/or polymorphs have been characterized. Additionally, products of synthetic steps taken disclosed within the specification do not mention crystal products.
Prodrugs
Claims 34-41, 46-49, and 51 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 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 the compound of general 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 34 as well as the presently unknown list potential prodrug derivatives embraced by claim 34.
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”.
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 41, 46, and 49 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.
Relative Term – preferably
Claim 49 uses the term “preferably”. The term “preferably” raises indefiniteness issues because it is not clear if the limitation after “preferably” is being claimed or not. “Preferably” should be removed.
Indefinite claim
Claim 41 claims specific substituents for R2 but also claims “m is selected from the group consisting of 0, 1 and 2.”
As claim 41 is specifically drawn to possible substituents of R2, the limitation “m is selected from the group consisting of 0…” raises ambiguity. If m = 0, then R2 is not present and is essentially not required. The claim requires that R2 be present. Within this claim, m must be greater than 0.
Similar issues are found in claim 46.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 34-36, 41, 46, 49, and 51 is/are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Kumar (US20190382402A1).
Kumar discloses compound 55, shown below, which embraces the claims.
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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.
Claim(s) 34-38, 41, 46 49, and 51 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kumar (US20190382402A1) and in view of Silverman (The organic chemistry of drug design and drug action, ACADEMIC PRESS, 1992).
KSR Rationales
The MPEP in section 2143, subsection I gives examples of Rationales for supporting a conclusion of obvious. These rationales are non-exhaustive and include (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) “Obvious to try” – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Discussion of Kumar above is incorporated here.
Kumar’s compound 55 differs from claimed compounds in claims 37 and 38 in that in the instant compound, Ring B is a phenyl.
Silverman in table 2.2 teaches that, within ring systems, a carbon can be replaced with a nitrogen and have the same or similar effects. Silverman states “Bioisosteres are substituents or groups that have chemical or physical similarities, and which produce broadly similar biological properties.”
Therefore, it would have been prima facie obvious at the time of the effective filing date for one of ordinary skill in the art to have modified the compound of Kumar to include a phenyl ring in place of a pyridine ring with a reasonable assumption of success. One of ordinary skill would be motivated to make the modification in research and optimization efforts and also because one of ordinary skill would find the two moieties as alternatives of each other. See KSR B above.
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LUISALBERTO GONZALEZ whose telephone number is (571)272-1154. The examiner can normally be reached M-F 8:30-5:30.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Murray can be reached at (571) 272-9023. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/LUISALBERTO GONZALEZ/Examiner, Art Unit 1624
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