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 12/12/2023 states that the instant application is a 371 of PCT/US21/62755, filed 12/10/2021 which claims benefit of provisional application 63/124,137 filed 12/11/2020.
Information Disclosure Statement
The information disclosure statements submitted 12/12/2023 and 02/11/2026 have been considered.
Restriction/Species Election
Applicant’s election of Group I, claims 1-22 and 24-25 without traverse is acknowledged.
Applicant’s election of the following species without traverse is also acknowledged:
-protecting group: tert-butyloxycarbonyl,
-solvent: a polar aprotic solvent,
-base: alkali metal bicarbonate.
Claims 15, 19, and 23 have been withdrawn being drawn to non-elected inventions and species.
Objections
Claims 7 and 21 are objected to as the structures of compounds VII and VI are slightly overlayed.
Claim 9 is objected to for stating “A process according to any of claim 8”. Only one process is claimed in claim 8.
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 13, 17-18, and 20 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 13 states “A process according to Claim 9, wherein the solvent…”.
Claim 20 states “A process according to Claim 17 wherein the polar aprotic solvent is selected from…”. There is insufficient antecedent basis for these terms.
Claim 17 states “wherein X is chloro or bromo, optionally chloro.” This is improper as it is not clear if “chloro” is include within the PG groups or not.
Claim 18 states “A process according to Claim 17, wherein the reaction is carried in the presence of a polar aprotic solvent, in the presence of a base”. It is not clear from the clam language whether the reaction is claimed to be carried out in the presence of a polar aprotic a solvent exclusively, in the presence of a base exclusively, or both combined. The claim requires a conjunction.
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.
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.
Claim(s) 1-14, 16-18, 20-22, and 24-25 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wang (WO 2018/033853, of the record) in view of Wang (Synthesis, 2017, 49, 4309-4320, herein after Wang 2017), Swiatek (Bioorganic & Medicinal Chemistry, 25, 2017, 316-326) and Gupta (Molecules, 2018, 23, 1719).
Claims 1-6 are drawn to embodiments of the following chemical synthesis:
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.
Dependent claims 2-6 specify protecting groups (claims 2-4), reactions conditions including an acid (claim 5), and required solvents (claims 6-7). Dependent claims 8-14, and 16-18 are drawn to further steps including a deprotection, a chiral resolution, and N-substitution starting from compound VII. Dependent claim 9 specifies the following synthetic step:
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Dependent claims 10-14 specify a base (claims 11-12), a solvent system (claim 13) and reaction conditions (claim 14).
Dependent claim 16-18 and 20 claim an alternative step with similar reactions conditions.
Dependent claim 21 is a combination of claims 1 and 8. Dependent claim 22 claims the salt form of Zanubrutinib.
Dependent claim 24 further comprises making a formulation of Zanubrutinib.
Dependent claim 25 include a deprotection step from claim VII.
Wang on p. 9 teaches a method for synthesizing Zanubrutinib shown below.
Wang Scheme 1
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Note that the critical differences are that the scheme above uses compounds that contain a -CN group as oppose to a -C(O)NH2 group. Wang on p. 19, para. [0096] teaches step 7 of its synthesis which most closely resembles the claimed method of claim 1:
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This step would be identical to the method of claim 1 if not for the fact that the instant method uses a compound with an amide where Wang uses a compound with a nitrile group. In a step that is further along in the synthetic method of Wang, this nitrile group is reduced to an amide group. This step is discussed on p. 22, para. [0103] of Wang and is shown below.
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One of ordinary skill in the art would find it obvious to reduce the nitrile group to the amide before the cyclization step in view of the methods above. This modification amounts to simply modifying the sequence of reactions in the chemical synthesis.
Note that the BOC protecting group is the tert-butyloxycarbonyl protecting group elected.
Chiral resolution is discussed by Wang on p. 40, para. [0147].
Regarding claim 24, Wang on p. 43, para. [0155] discloses dissolving Zanubrutinib in a buffer to create a pharmaceutical formulation.
Regarding the solvent system, Wang teaches toluene as a solvent. Applicant has elected polar aprotic solvents which do not include toluene. This difference is addressed by Wang 2017.
Wang 2017 is drawn to the synthesis of heterocyclic bicyclic ring systems in a one-pot tandem synthesis, shown below (abstract).
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Wang 2017 on p. 4310, Table 1 teaches reaction conditions for the Michael addition of a alkylamine to a 1,4 unsaturated ketone system to give a bicyclic ring system.
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(Table truncated for brevity)
While the compounds in Wang 2017 are not similar to the compounds in the instant method, the reaction conditions can be applied because the first step claimed (claim 1) requires a Michael addition of the pyrazole in compound IX to compound VIII to generate the bicyclic ring system in compound VII. Wang 2017 teaches the solvent of its Michael addition reaction is DMSO. Therefore, one of ordinary skill in the art would find it obvious that a polar aprotic solvent like DMSO could be used in place of the toluene solvent. Additional discussion regarding Michael additions is found in the Examiner’s Comments below.
Regarding claim 9, Swiatek on p. 318, Scheme 2 teaches a similar reaction to that claimed in claim 9.
Swiatek, Scheme 2
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Note that scheme 2 indicates compounds 26a-c can be converted to the alkene via an elimination that occurs in potassium bicarbonate in acetonitrile.
Similar to the reaction claimed in claim 9, the synthetic step in Swiatek involves a secondary nitrogen and a halogenated alkyl-acyl chloride. The elimination occurs in situ with the base potassium bicarbonate and in the solvent acetonitrile.
Wang on p. 23, para. [0105] teaches a synthetic step to afford Zanubrutinib.
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Regarding claim 22, converting pharmaceutical compounds to a salt are well known within the art as discussed in Gupta.
Gupta in sec. Introduction states “The specific salts of active pharmaceutical ingredients (APIs) are often formed to achieve desirable formulation properties. Although addressing poor aqueous solubility is one of the most important reasons to employ a salt formation, pharmaceutical companies also use the formation of unique salt products to commonly address other physiochemical and biological concerns such as stability, toxicity, poor absorption, and issues related to manufacturing processes.” Gupta on p. 2, Table 1 lists a number of ions used for salt formation of pharmaceutical compounds.
The critical differences between the chemical synthesis of Wang and the instant claims are i) the order of reactions, ii) specific reaction conditions, and iii) the alternative synthetic steps claimed in claims 9-14 and 16. Modifying reaction conditions such as solvent, temperature, and reactants are well known within the art and are typically performed to optimize reaction yield. Therefore, modifying the solvent of Wang to instead use DMSO would be obvious. Additionally, the synthetic chemist would find the alternative route in claims 9-14 and 16 obvious in view of Swiatek which teaches acylation of a secondary ring nitrogen followed by an elimination to give an alkene. Modification of synthetic routes that incorporate alternative routes are typically performed to avoid low yielding steps and/or problematic steps. Similarly, the modification of a synthetic route, such as performing a reduction earlier in the synthesis as opposed to later, is something that one of ordinary skill in the art would also find obvious.
The use of analogous reactants in a known process is prima facie obvious unless there is evidence to the contrary, see In re Durden, 226 USPQ 359 (1985). Once the general reaction has been shown to be old, the burden is on Applicants to present reasons or authority for believing that a group on the starting material would take part in or affect the basic reaction and thus alter the nature of the product or the operability of the process. In looking at the instant claimed process as a whole, as stated in In re Ochiai, 37 USPQ 2d 1127 (1995), the claimed process would have been suggested to one skilled in the art.
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 modify the synthesis taught in Wang to include the reaction conditions of Wang 2017 and Swiatek. One of ordinary skill in the art would be motivated to make the modifications in efforts to optimize reaction conditions and yields.
Examiner’s Comments
Michael Addition reactions are a well-known reaction type within chemistry. Exemplary reactions include a Michael donor, a Michael acceptor, and a base as shown below.
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However, Organic Chemistry Portal (Organic Chemistry Portal, Michael Addition, url= https://www.organic-chemistry.org/namedreactions/michael-addition.shtm, accessed 2/11/2026) teaches a number of Michael Additions involving a variety of reactants in a variety of conditions. See the attached webpage for details.
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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/L.G./Examiner, Art Unit 1624
/SUSANNA MOORE/Primary Examiner, Art Unit 1624