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 Application
Claims 1-16 are pending and under examination
Claims 17 is withdrawn.
The following Office Action is in response to Applicant's communication dated 06/22/2026.
Applicant’s election without traverse of Group I, which includes Claims 1-16 in the reply filed on 06/22/20266 is acknowledged.
Claim(s) 17 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected method for diversifying a biologically active molecule, there being no allowable generic or linking claim. Election was made in the reply filed on 06/22/2026.
Claim Objections
Claim 16 objected to because of the following informalities: claim 16 recites “ or a combination thereof of from sequence data”, which appear to be a typographical or grammatical error. The second “of” appears to be inadvertent.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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) 1 and 4-14 is/are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Krebber et al. (WO2001012817A1, filed August 11th 2000).
Regarding claim 1, Krebber discloses a method comprising: separately admixing a first reactant and an aqueous solvent with each biocatalyst in a library of biocatalysts to provide a library of product admixtures, wherein the admixing occurs under sustainable reaction conditions, and each product admixture comprises: (i) a first product formed from a chemical reaction between the first reactant and each biocatalyst, (ii) the aqueous solvent, and (iii) the biocatalyst. (e.g. The method involves contacting an organic molecule with one or more members of a library of recombinant derivatizing enzymes and other necessary reactants to form the library of organic molecule derivatives [page 3, lines 24-26]. Biocatalysts (enzymes) are fundamentally sustainable because they drive chemical reactions under mild conditions (ambient temperature and pressure) in aqueous solution.)
Regarding claim 4, Krebber discloses at least one biocatalyst in the library of biocatalysts is a flavin-dependent monooxygenase, a non-heme iron-dependent dioxygenase, a methyltransferase, a trifluoromethyltransferase, an acetyltransferase, a hydroxylase, a halogenase, or cytochrome P450. [page 31, lines 9-12]
Regarding claim 5, Krebber discloses biocatalyst in the library of biocatalysts is a wild-type enzyme or an engineered enzyme. (e.g. libraries of recombinant derivatizing enzymes are variants of a given wild type gene [page 30, lines 13-14]).
Regarding claim 6, Krebber discloses the biocatalysts in the library of biocatalysts performs a site-selection chemical reaction, a stereoselective chemical reaction, a chemoselective chemical reaction, or a combination thereof. (e.g. the recombinant library will contain enzymes that exhibit catalytic properties that differ from one another in features such as catalytic rates and constants, stereo-, regio- and enantiomeric specificity, multiplicity of substrate selectivity [page 10, lines 17-20]).
Regarding claims 7 and 8, Krebber discloses each biocatalyst is admixed with each of the first reactants simultaneously/non-simultaneously. (e.g. The contacting of an organic molecule and other reactants with a recombinant derivatizing enzyme can be done using the entire library of enzymes at once, or with pools of recombinant enzymes from the library, or with a single recombinant enzyme in each reaction. [page 50, lines 24-27]).
Regarding claims 9-11, Krebber discloses the chemical reaction is a functional group transformation, such as hydroxylation, halogenation, epoxidation, a C—H insertion, or a dehydrogenation. (e.g. monooxygenase enzymes suitable for introduction of hydroxyl groups and other modifications of organic molecules include those having activities such as alkane oxidation (e.g., alkyl hydroxylation, formation of ketones, aldehydes, etc.), dehydrogenation, alkene epoxidation, etc. [page 32, lines 1-14]).
Regarding claims 12-14, Krebber discloses chemical reaction is a carbon-carbon bond forming reaction, wherein the carbon-carbon bond forming reaction is an alkylation, such as a methylation (e.g. Fig 12 shows carbon-carbon bond forming reaction catalyzed by S-adenosyl-l-methionine (SAM) dependent methyltransferases, wherein the enzyme transfers the activated methyl group from SAM to the recipient nucleophile [Page 12, lines 20-27]).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Krebber et al. and Cali et al.
Claim(s) 2 and 3 is/are rejected under 35 U.S.C. 103 as being unpatentable over Krebber et al. (WO2001012817A1, filed August 11th 2000) in view of Cali et al. (Expert Opinion on Drug Metabolism & Toxicology, 2(4), 2006, 629–645.).
Regarding claim 2, Krebber discloses admixing a second reactant with one or more product admixtures in the library of product admixtures, wherein the second reactant reacts with the first product in the one or more product admixtures to form a second product. (e.g. the organic molecule derivatives that are synthesized can then be screened to identify those that have a desired property, or can be further modified by one or more additional chemical or enzymatic reactions [page 11, lines 26-30].) However, Krebber does not discloses the second reactant is in situ with product admixtures.
Cali discloses a series of bioluminescent assays that enable the rapid profiling of cytochrome P450 activity against compound collections. The assay uses a coupled reaction where the P450 enzyme metabolizes a luminogenic P450 probe substrates to generate luciferin. Then, the included Luciferin Detection Reagent (containing luciferase, ATP and Mg2+) is added directly into reaction, which quenches the P450 reaction and turns the luciferin into a stable luminescent signal.[“How the technology works” section].
As of the application’ s effective filing date, it would have been prima facie obvious to a person of ordinary skill in the art to modify Krebber’s the enzyme primary screening method by incorporating the in-situ detection strategy taught by Cali because assays offer advantages of speed, improved sensitivity, and decreased interference between optical properties of test compound and cytochrome P450 substrate. The detection assays are sensitive and robust tools for high-throughput cytochrome P450 screening in early drug discovery [abstract]. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (MPEP § 2143).
Regarding claim 3, Krebber discloses subjecting one or more of the first products to one or more biological assays. (e.g. the organic molecule derivatives that are synthesized can then be screened to identify those that have a desired property, or can be further modified by one or more additional chemical or enzymatic reactions [page 11, lines 26-30].) However, Krebber does not discloses without isolating the one or more first products from the one or more product admixtures.
Cali discloses a series of bioluminescent assays that enable the rapid profiling of cytochrome P450 activity against compound collections. The assay uses a coupled reaction where the P450 enzyme metabolizes a luminogenic P450 probe substrates to generate luciferin. Then, the included Luciferin Detection Reagent (containing luciferase, ATP and Mg2+) is added directly into reaction, which quenches the P450 reaction and turns the luciferin into a stable luminescent signal.[“How the technology works” section].
The rationale for combining the Krebber and Cali references with respect to claim 3 is the same as set forth above for claim 2 and is incorporated herein by reference, as claim 3 does not introduce a limitation that would alter the motivation to combine or the predictable resulted achieved by the combination.
Krebber et al. and Mazzaferro et al.
Claim(s) 15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Krebber et al. (WO2001012817A1, filed August 11th 2000) in view of Mazzaferro et al. (J. Am. Chem. Soc. 2015, 137, 38, 12289–12295, disclosed in IDS).
Regarding claim 15, Krebber does not disclose carbon-carbon bond forming reaction is an arylation, such as a methylation biaryl bond forming reaction. However, Krebber disclose screening cytochrome p450 enzyme class for their activity as a monooxygenase.
Mazzaferro discloses that although most members of the cytochrome P450 enzyme superfamily function as monooxygenases, this class of enzyme is also known in the art to also catalyze regio- and stereoselective intermolecular phenol couplings, such as KtnC and DesC. The enzymes KtnC and DesC are eukaryotic phenol-coupling cytochrome P450s catalyze biaryl coupling reactions with high selectivity, irrespective of any additional proteins. [Abstract and Discussion]
As of the application’ s effective filing date, it would have been prima facie obvious to a person of ordinary skill in the art to utilize Mazzaferro’s cytochrome P450 enzymes into Krebber’s biocatalysts screening methods because Krebber seeks to generate structurally diverse libraries of organic molecule derivatives by screening recombinant enzyme libraries for useful catalytic activities. Mazzaferro teaches cytochrome P450 enzymes further capable of biaryl coupling, provide additional valuable catalytic activity. Biaryl bond formation is critical because biaryl axis is the central structural element in a broad variety of biologically active natural products including life-saving pharmaceutical such as well-known antibiotic vancomycin. Hence, one of ordinary skill in the art would have been motivated to include P450 P450 biaryl coupling enzymes among the enzymes classes screened in order to expand the diversity of obtainable products through carbon-carbon forming reactions, with reasonable expectation of success because Mazzaferro’s P450 biaryl coupling enzymes already shown to be able to catalyze the reaction and even display various grades of selectivity [Introduction]. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (MPEP § 2143).
Krebber et al. and Gerlt et al.
Claim(s) 16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Krebber et al. (WO2001012817A1, filed August 11th 2000) in view of Gerlt et al. (Biochim Biophys Acta. 2015;1854(8):1019-1037, disclosed in IDS).
Regarding claim 16, Krebber does not disclose the library of biocatalysts is prepared by constructing one or more phylogenetic trees, one or more sequence similarity networks (SSNs), one or more variational autoencoder (VAE) latent space analyses, or a combination thereof of from sequence data, by assessing a sequence relationship with enzymes of known function, and selecting biocatalysts for inclusion in the curated library based on sequence and sequence-function relationships
Gerlt discloses discloses a protein sequence similarity networks (SSNs), a user-friendly, visually powerful tools for segregating entire protein families into isofunctional groups [abstract].
As of the application’ s effective filing date, it would have been prima facie obvious to a person of ordinary skill in the art to apply SSN to Krebber’s enzyme library construction because Krebber already selecting genetic candidates from the public databases [page 44, lines 21-28], Gerlt’s tool provide organization of data by create SSNs for the “closest neighbors” of a user-supplied protein sequence from public databases, e.g. UniProt. The method is less confusing than trees and dendrograms, while still provide a visually useful alternative that facilitates the design of experiments to experimentally investigate and assign in vitro enzymatic functions [Abstract and Summary]. Accordingly, a skilled artisan would have been motivated to apply this bioinformatic tool to improve the efficiency of selecting biocatalysts while increase the likelihood of identifying enzymes possess desired catalytic activity. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (MPEP § 2143).
Conclusion
No claims are allowed
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Khai Quynh Tien Pham whose telephone number is (571)272-6998. The examiner can normally be reached M-T, 9-4 ET.
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/KHAI QUYNH TIEN PHAM/ Examiner, Art Unit 1684
/JEREMY C FLINDERS/ Primary Examiner, Art Unit 1684
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