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
Claims 1-19 are pending.
Election/Restrictions
Applicant’s election of Group I, claims 1-18, in the reply filed on 10/2/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claim 19 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10/2/2025.
Claims 1-18 are examined herein.
Claim Objections
Claims 1, 11 and 15 are objected to because of the following informalities:
In claim 1, step (b), the second (7) is not bold-typed; and In claim 15, step (b), the (7) is not bold-typed, whereas the numeric designation for all other structures are in bold.
In claim 11 line 2, fluoro diol should be one word rather than two words.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 2-10 and 16-17 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 2 recites “wherein step (b) further comprises contacting with NADP.” It is unclear what is being contacted with NADP: the fluoro hydroxyindanone (6), the ketoreductase, or fluorodiol (7).
Claim 3 recites “wherein the hydroxy indanone (5) of step (a) is prepared by contacting indanone (4) with a FoPip4H enzyme…” Claim 3 is indefinite because it is unclear whether this is a product-by-process limitation or the method further comprises a prior step of preparing hydroxy indanone (5) by the recited steps.
Similarly, claim 5 recites “wherein indanone (4) is prepared by: contacting bromo indanone (3) with a metabisulfite salt in the presence of Ni2+ catalyst and a methylating agent to provide indanone (4).” It is unclear whether this is a product-by-process limitation or whether the method further comprises these additional steps. Applicant may consider amending to “wherein the process further comprises preparing the indanone (4) by contacting bromo indanone (3) with a metabisulfite salt in the presence of Ni2+ catalyst and a methylating agent to provide indanone (4)” or other language that clarifies the claim scope.
Claim 9 is similarly indefinite for the limitation “wherein bromo indanone (3) is prepared by: “cyclizing phenylpropionic acid in thionyl chloride in the presence of a Lewis acid to provide indanone (3),” which can reasonably be interpreted as a product-by-process limitation or as an active method step.
Claim 16 recites “wherein step (b) further comprises NADP.” The claim has more than one reasonable interpretation, rendering it indefinite. It is unclear how step (b) further comprises NADP. Claim 16 may be interpreted as contacting the fluoro hydroxyindanone (6) with both ketoreductase and NADP to provide fluorodiol (7). Alternatively, the claim may be reasonably interpreted as requiring that fluorodiol (7) is subsequently contacted with NADP.
Similarly, claim 17 recites “wherein step (b) further comprises a secondary alcohol.” It is unclear whether the fluoro hydroxyindanone (6) is contacted with a ketoreductase and a secondary alcohol or whether fluorodiol (7) is subsequently contacted with a secondary alcohol.
Claims 4-10 are rejected for depending from a rejected base claim and not rectifying the source of indefiniteness discussed above.
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.
Claims 1-18 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 written description requirement. The claims 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 or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 is drawn to a process for preparing belzutifan comprising (b) contacting the fluoro hydroxyindanone (6) with a ketoreductase comprising an amino acid sequence having at least 90% identity to SEQ ID NO: 2 to provide fluorodiol (7). Fluorodiol (7) has a specific stereochemical configuration in the hydroxyl and fluoro groups (see the structure in claim 1). Claim 2 requires contacting the fluoro hydroxyindanone (6) with the ketoreductase and NADP. Claim 3 recites preparing hydroxy indanone (5) from indanone (4) with a FoPip4H enzyme comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 1.
Claim 15 is drawn to a process for preparing fluorodiol (7) comprising contacting the fluoro hydroxyindanone (6) with a ketoreductase to provide fluorodiol (7). Claim 17 further limits the ketoreductase to an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 2.
SEQ ID NO: 2 is 353 amino acids long, so an amino acid sequence having 90% sequence identity to SEQ ID NO: 2 can differ in 10% of its amino acids from SEQ ID NO: 2, or by 35 amino acids. SEQ ID NO: 1 is 349 amino acids long, so an amino acid sequence having 90% sequence identity to SEQ ID NO: 1 can differ by approximately 35 amino acids as well.
The specification does not disclose any variants of SEQ ID NO: 2 (i.e. sequences with less than 100% identity to SEQ ID NO: 2) that retain the ability to convert fluoro hydroxyindanone (6) to fluorodiol (7). Only the ketoreductase (“KRED”) having SEQ ID NO: 2 successfully converts fluoro hydroxyindanone to fluorodiol (page 21, lines 20-23 Step 5). Likewise, the specification does not disclose any variants of SEQ ID NO: 1. The specification discloses a single species of the enzyme with the ability to catalyze the reaction of indanone (4) to hydroxy indanone (5) (see specification Step 4, lines 20-21 on page 20, Foip4H corresponds to SEQ ID NO; 1, see lines 5-14 on page 14).
An NCBI BLAST protein sequence alignment of SEQ ID NO: 2 indicates that those proteins sharing homology to SEQ ID NO: 2 are primarily uncharacterized or hypothetical proteins (NCBI, pages 6-7, column 3), indicating that the function of these proteins has not been verified and the structure-function relationship between the protein sequence and its function is not established.
A Conserved Domain search (CD Search; 2025 website) classifies SEQ ID NO: 2 as containing a domain corresponding to an aldehyde reductase (also known as a carbonyl reductase) of the extended SDR-type.
Graeff et al. (Proteins: Structure, Function, and Bioinformatics 87.6 (2019): 443-451) teaches several sequence motifs that are used to classify the SDR superfamilies (Table 1). The extended SDR type has an active site motif of YX3K (Table 1). SEQ ID NO: 2 contains this motif at positions 148-152 (YLDEK) as well as at positions 177-181 (YAASK). The active site requires additionally asparagine and serine, located distally from the YX3K motif as part of a catalytic tetrad (page 466, right column, paragraph 1). The glycine-rich motif (Table 1) contributes to the binding of the nicotinamide cofactor (page 466, left column, paragraph 7). SEQ ID NO: 2 also contains the glycine-rich motif (LVTGANGFVG) at positions 16-25. However, the regions of the amino acid sequence responsible for substrate binding and enantioselectivity are not described.
Kavanagh et al. (Cell. Mol. Life Sci. 65 (2008) 3895 – 3906) teaches that differences in the size of the active site pockets of SDR-type epimerases give rise to differences in substrate specificities (page 3900, right column, paragraph 1, SDR-type epimerases, paragraph 1). Thus, the residues responsible for the formation of the active site pocket are key in determining substrate specificity. These residues are unknown in SEQ ID NO: 2.
Kita et al. (Applied and Environmental Microbiology 65.12 (1999): 5207-5211) teaches an aldehyde ketoreductase from Sporobolomyces salmonicolor AKU4429 with GenBank nucleotide accession no. AF160799 (Abstract, page 5208, right column, Nucleotide sequence accession number), which is 82.4% identical to the instant SEQ ID NO: 2 (OA Appendix A). Kita’s aldehyde ketoreductase is capable of catalyzing the selective reduction of ethyl 4-chloro-3-oxobutanoate to ethyl (S)-4-chloro-3-hydroxybutanoate (Title). However, this substrate is structurally and chemically distinct from the claimed substrate fluoro hydroxyindanone (6).
Kamitori et al. (Journal of molecular biology 352.3 (2005): 551-558) also teaches a carbonyl reductase from Sporobolomyces salmonicolor that is capable of stereoselective production of (S) alcohols from ethyl 4-chloro-3-oxobutanoate (Abstract and reaction (a) of Figure 1). Kamitori proposes a mechanism for the catalytic reaction that relies on a hydrophobic channel induced by the binding of NADPH (Figure 5 and Abstract). However, Kamitori’s carbonyl reductase (corresponds to PBD 1Y1P, see Kamitori page 557, right column, Protein Data Bank accession number) is only 82.1% identical to the instant SEQ ID NO: 2 (see OA Appendix B) and it is unknown whether Kamitori’s carbonyl reductase has the presently claimed catalytic activity for the substrate fluoro hydroxyindanone (6).
Nguyen et al. (International Scholarly Research Notices 2014.1 (2014): 124289)
develops a computational model to predict the stereospecificity of Sporobolomyces salmonicolor ketoreductase (PDB 1Y1P) for various substrates (4. Conclusion, paragraph bridging pages 6-7). The substrates are mainly linear, although Nguyen also teaches some fluorinated aryl ketones (Table 1 on page 4), However, none of the substrates are indanones (fused ring structures), let alone indanones with fluoro and methanosulfonyl groups such as structure (6) of the presently claimed invention.
Li et al. (Advanced Synthesis & Catalysis 351.4 (2009): 583-588) teaches that the aldehyde ketoreductase from Sporobolomyces salmonicolor AKU4429 is also capable of catalyzing the enantioselective reduction of diaryl ketones (Scheme 1 and Abstract). Notably, mutation of the enzyme at Q245 resulted in a higher amount of (S)-enantiomer in the products, and for the case of the mutant Q245P the reduction enantio-preference was switched from (R) to (S) (Abstract). Thus, single point mutations in this class of enzymes can result in changes in the enantio-preference of the product.
Zhu et al. (Organic & Biomolecular Chemistry 4.14 (2006): 2690-2695) further studies the activity and enantioselectivity of the aldehyde ketoreductase from Sporobolomyces salmonicolor AKU4429 toward the reduction of a variety of ketones with diverse structures (page 2690, right column, paragraph 1). Although Zhu tests some aryl ketones, including compounds with fused ring structures such as 6-methyl-4-chromanone and 1-tetralone (Table 1), none of the substrates are similar to the claimed fluoro hydroxyindanone (6).
A Clustal Omega multiple sequence alignment (website, 2025) of the two aldehyde reductases from Sporobolomyces salmonicolor (PDB 1Y1P and PDB 1UJM) with SEQ ID NO: 2 indicates that 89% of the amino acids are shared. However, it is unknown whether the two aldehyde reductases from Sporobolomyces salmonicolor also have the ability to catalyze the ketoreduction of the substrate fluoro hydroxyindanone (6) or whether only SEQ ID NO: 2 is capable of catalyzing this reaction. In the latter case, it is unknown which residues are responsible for the claimed function.
In summary, the prior art teaches that Sporobolomyces salmonicolor encodes enantioselective carbonyl reductases that are capable of catalyzing reactions for a variety of substrates. However, the prior art does not teach whether these reductases are capable of catalyzing the reaction of fluoro hydroxyindanone (6) or any structurally similar substrates. The specification discloses the only known species of the claimed genus of ketoreductase variants capable of converting fluoro hydroxyindanone (6) to fluorodiol (7). The specification does not disclose the structure-function relationship between the enzyme and its activity. For example, the residues that form the substrate-binding pocket are unknown.
With respect to the claimed genus of variants of FoPip4H enzyme (claim 3) with at least 90% sequence identity to SEQ ID NO: 1, there are two sequences taught by the prior art with at least 90% identity to SEQ ID NO: 1, but both are hypothetical proteins (see NCBI2, Per. Ident column, page 6). Hibi et al. (Applied and Environmental Microbiology 82.7 (2016): 2070-2077) teaches eight species of proteins homologous to FoPip4H with at least partial L-Pip hydroxylating activity (Table 2 on page 2074). All of the enzymes with greater than 90% identity to FoPip4H retain L-Pip hydroxylating activity. FoPip4H tolerates a wide variety of substrates (Figure 2), including five- and six-membered rings. The stereochemistry of the hydroxyl group varies depending on the substrate. However, none of the substrates include the claimed indanone comprising a fluoro and methanosulfonyl groups as in the presently claimed indanone (4). Furthermore, FoPip4H (protein ID BAU50539.1) is only 87% identical to the instant SEQ ID NO: 1 (OA Appendix C).
Based on the above analysis, the person of ordinary skill in the art would not have recognized that the inventors had possession of the claimed genus of ketoreductases or the claimed genus of variants of SEQ ID NO: 2 capable of catalyzing the enantioselective reduction of fluoro hydroxyindanone (6) to provide fluorodiol (7), or the claimed genus of variants of FoPip4H enzyme capable of converting indanone (4) to hydroxy indanone (5).
Conclusion
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/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/CANDICE LEE SWIFT/Examiner, Art Unit 1657