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
1. Claims 1-27 are pending and subject to examination on the merits. Claims 4-19 and 24-27 are withdrawn from consideration as being drawn to non-elected subject matter. Claims 1-3 and 20-23 are currently under examination.
Priority
2. Acknowledgment is made for the Applicant’s claim for domestic priority based on the US provisional application PRO 62/491,247 filed 20 March 2023.
Election/Restrictions
3. Restriction to one of the following inventions is required under 35 U.S.C. 121:
I. Claims 1-23, drawn to an engineered cytochrome P450-BM3 variant comprising a polypeptide sequence having at least 85% sequence identity to SEQ ID NO: 36, 4, 66, 72, 198, 226, 244, 286, 358, 410, 534, 734, 748, 828, 968, 984, 1160, or 1266, or a functional fragment thereof, wherein the polypeptide sequence of said engineered cytochrome P450-BM3 variant comprises at least one substitution or substitution set and wherein the amino acid positions of said polypeptide sequence are numbered in reference to the above SEQ ID NOs, classified in C12N 9/0042.
II. Claims 24-26, drawn to a polynucleotide sequence encoding at least one engineered cytochrome P450-BM3 variant of claim 20, said polynucleotide sequence comprises at least 85% or more sequence identity to SEQ ID NOs: 3, 35, 65, 71, 197, 225, 243, 285, 357, 409, 533, 733, 747, 827, 967, 983, 1159, or 1265, and an expression vector and host cell comprising said polynucleotide sequence, classified in C12N 15/52.
III. Claim 27, drawn to a method of producing an engineered cytochrome P450-BM3 variant in a host cell, comprising culturing a host cell of claim 26, under suitable conditions, such that at least one engineered cytochrome P450-BM3 variant Is produced, classified in C12N 15/64.
4. Inventions I and II are related as process of making and product made. The inventions are distinct if either or both of the following can be shown: (1) that the process as claimed can be used to make another and materially different product or (2) that the product as claimed can be made by another and materially different process (MPEP § 806.05(f)). In the instant case, the polypeptide of invention I does not have to be produced by the polynucleotide of invention II. The polypeptide could be produced in a cell-free protein synthesis reaction, utilizing mRNA and cell extracts/machinery.
5. Inventions I and III are related as process of making and product made. The inventions are distinct if either or both of the following can be shown: (1) that the process as claimed can be used to make another and materially different product or (2) that the product as claimed can be made by another and materially different process (MPEP § 806.05(f)). In the instant case, the polypeptide of invention I does not have to be produced by the host cell of invention III. The polypeptide could be produced in a cell-free protein synthesis reaction, utilizing mRNA and cell extracts/machinery.
6. Inventions II and III are related as product and process of use. The inventions can be shown to be distinct if either or both of the following can be shown: (1) the process for using the product as claimed can be practiced with another materially different product or (2) the product as claimed can be used in a materially different process of using that product. See MPEP § 806.05(h). In the instant case, the polynucleotide of invention II does not have to be utilized in the method of producing a polypeptide by expressing an expression cassette encoding said polynucleotide in a host cell. The polynucleotide could be utilized in a study to determine sites of modification rather than the expression of full length protein.
7. Thus, the search for the polypeptide, polynucleotide, and host cells expressing polypeptides would be divergent and thus cause an undue search burden upon the Examiner.
a. the inventions have acquired a separate status in the art in view of their different classification;
b. the inventions have acquired a separate status in the art due to their recognized divergent subject matter;
c. the inventions require a different field of search (for example, searching different classes/subclasses or electronic resources, or employing different search queries);
d. the prior art applicable to one invention would not likely be applicable to another invention;
e. the inventions are likely to raise different non-prior art issues under 35 U.S.C. 101 and/or 35 U.S.C. 112, first paragraph.
Each group is under a unique CPC class and will require a separate and distinct keyword search,
where group I is classified under C12N 9/0042, group II is under C12N 15/52, group III is C12N 15/64.
8. This application contains claims directed to the following patentably distinct species: Species I, directed to the polypeptide sequences of Invention I, SEQ ID NOs: 36, 4, 66, 72, 198, 226, 244, 286, 358, 410, 534, 544, 734, 748, 828, 968, 984, 1160, or 1266; Species II, directed to the substitutions at amino acids of invention I, amino acid positions 52/83/88/105, 32/83/88, 32/83/88/176, 32/83/88/231/574, 32/83/88/574, 52/83/88, 52/83/88/231, 52/83/88/231/433/574, 52/83/88/433, 52/88/349, 83/88/433/574, and 83/88/574; Species III, directed to the polynucleotide sequences of Invention II, SEQ ID NOs: 3, 35, 65, 71, 197, 225, 243, 285, 357, 409, 533, 733, 747, 827, 967, 983, 1159, or 1265. The species are independent or distinct because each sequence encodes for a different protein that are structurally distinct (See MPEP 803.04). In addition, these species are not obvious variants of each other based on the current record.
Applicant is required under 35 U.S.C. 121 to elect a single disclosed species, or a single grouping of patentably indistinct species, for prosecution on the merits to which the claims shall be restricted if no generic claim is finally held to be allowable. Currently, there are NO generic claims.
There is a serious search and/or examination burden for the patentably distinct species as set forth above because at least the following reason(s) apply: each sequence requires its own unique and independent search of the prior art.
Applicant is advised that the reply to this requirement to be complete must include (i) an election of a species to be examined even though the requirement may be traversed (37 CFR 1.143) and (ii) identification of the claims encompassing the elected species or grouping of patentably indistinct species, including any claims subsequently added. An argument that a claim is allowable or that all claims are generic is considered nonresponsive unless accompanied by an election.
The election may be made with or without traverse. To preserve a right to petition, the election must be made with traverse. If the reply does not distinctly and specifically point out supposed errors in the election of species requirement, the election shall be treated as an election without traverse. Traversal must be presented at the time of election in order to be considered timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are added after the election, applicant must indicate which of these claims are readable on the elected species or grouping of patentably indistinct species.
Should applicant traverse on the ground that the species, or groupings of patentably indistinct species from which election is required, are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing them to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the species unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other species.
Upon the allowance of a generic claim, applicant will be entitled to consideration of claims to additional species which depend from or otherwise require all the limitations of an allowable generic claim as provided by 37 CFR 1.141.
Inventorship
9. Applicant is reminded that upon the cancelation of claims to a non-elected invention, the inventorship must be corrected in compliance with 37 CFR 1.48(a) if one or more of the currently named inventors is no longer an inventor of at least one claim remaining in the application. A request to correct inventorship under 37 CFR 1.48(a) must be accompanied by an application data sheet in accordance with 37 CFR 1.76 that identifies each inventor by his or her legal name and by the processing fee required under 37 CFR 1.17(i).
Rejoinder
10. The examiner has required restriction between product or apparatus claims and process claims. Where applicant elects claims directed to the product/apparatus, and all product/apparatus claims are subsequently found allowable, withdrawn process claims that include all the limitations of the allowable product/apparatus claims should be considered for rejoinder. All claims directed to a nonelected process invention must include all the limitations of an allowable product/apparatus claim for that process invention to be rejoined.
In the event of rejoinder, the requirement for restriction between the product/apparatus claims and the rejoined process claims will be withdrawn, and the rejoined process claims will be fully examined for patentability in accordance with 37 CFR 1.104. Thus, to be allowable, the rejoined claims must meet all criteria for patentability including the requirements of 35 U.S.C. 101, 102, 103 and 112. Until all claims to the elected product/apparatus are found allowable, an otherwise proper restriction requirement between product/apparatus claims and process claims may be maintained. Withdrawn process claims that are not commensurate in scope with an allowable product/apparatus claim will not be rejoined. See MPEP § 821.04. Additionally, in order for rejoinder to occur, applicant is advised that the process claims should be amended during prosecution to require the limitations of the product/apparatus claims. Failure to do so may result in no rejoinder. Further, note that the prohibition against double patenting rejections of 35 U.S.C. 121 does not apply where the restriction requirement is withdrawn by the examiner before the patent issues. See MPEP § 804.01.
Oral Election
11. During a telephone conversation with Adelaide Leitzel on 09 February 2026 a provisional election was made without traverse to prosecute the invention of Group I, claims 1-23. Additionally, an election of species was made without traverse of Species 1: SEQ ID NO: 4 and Species 2: SEQ ID NO: 36, comprising the substitutions 52/83/88/105. Affirmation of this election must be made by applicant in replying to this Office action. Claims 24-27 withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention. Additionally, claims 4-19 are withdrawn from further consideration as being drawn to non-elected species.
Claim Objections
12. Claim 2 is objected to because of the following informalities: “one or more positions in…” (claim 2, lines 3-4) should be amended to “one or more amino acid positions in…” to maintain consistency in the claim language, i.e. claim 1, lines 5-6.
13. Claim 20 is objected to because of the following informalities: “(c) a polypeptide sequence forth in” should be amended to “(c) a polypeptide sequence set forth in.” Appropriate correction is required.
Claim Rejections - 35 USC § 102
14. 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.
15. 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.
16. Claims 1-2 and 20-23 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Kumaran et al (Kumaran et al., 2022, US2022/0073955 A1—cited herein). Regarding claims 1-2 and 20 drawn to an engineered cytochrome P450-BM3 variant with at least 85% or more sequence identity to SEQ ID NO: 4 and wherein the polypeptide sequence has at least one substitution at 52/83/88/105, Kumaran et al. teaches SEQ ID NO: 43, which has 94.5% identity to SEQ ID NO: 4 of the instant application, where specifically, the polypeptide SEQ ID NO: 43 comprises amino acid substitutions at amino acid positions: 52/83/88/105 (“SEQ ID NO: 43 vs 4,” downloaded 17 March 2026 as a PDF from <abss.uspto.gov/abss4examiners/>).
Regarding claims 21-23, drawn to the improvement of at least one property, such as improved activity on the substrate (1-tert-Butoxycarbonylamithocyclopentanoic acid), Kumaran et al. does not expressly teach an enzyme derived from B. megaterium cytochrome P450-BM3 comprising substitution mutations at amino acid positions 52/83/88/105 having an improved property, wherein said property is improved activity on a substrate, specifically 1-tert-Butoxycarbonylaminocyclopentanoic acid (claims 21-23). However, according to MPEP 2112, the inherent disclosures of a prior art reference may be relied upon in the rejection of claims under 35 U.S.C. 103. The polypeptide of Kumaran et al. has 96.4% sequence identity to SEQ ID NO: 4 and comprises the amino substitutions at amino acid positions 52/83/88/105, which encompasses the enzyme claimed in claims 1-2 and 20, of which, claims 21-23 are dependent upon. As such, it is the examiner’s position that the polypeptide of Kumaran et al. would necessarily have the characteristics of claims 21-23. Since the Office does not have the facilities for examining and comparing applicant’s enzyme with the enzyme of the prior art, the burden is on the applicant to show a novel or unobvious difference between the recited product and the recited product of the prior art (i.e., that the enzyme of the prior art does not possess the same physicochemical characteristics of the recited enzyme). See In re Best, 562 F.2d 1252, 195 USPQ 430 (CCPA 1977) and In re Fitzgerald et al., 205 USPQ 594.
Claim Rejections - 35 USC § 103
17. 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.
18. Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Kumaran et al (Kumaran et al., 2022, US2022/0073955 A1—cited herein) as applied to claims 1-2 and 20-23 above, and further in view of Whitehouse et al (Whitehouse et al., 2012, Chem. Soc. Rev—cited herein).
The teachings of Kumaran et al. are discussed above and are incorporated into the instant rejection.
Kumaran et al. does not teach an engineered cytochrome P450 BM3 with at least 85% sequence identity to SEQ ID NO: 36 comprising at least one substitution at amino acid 75. Whitehouse et al. teaches that amino acid 75 of the P450 BMC protein is involved in the substrate access channel and active site (p. 1229, Fig. 4). Additionally, Whitehouse et al. teaches multiple amino acid substitutions at amino acid 75, specifically, alanine, arginine, histidine, isoleucine, lysine, proline, serine, threonine, tryptophan, tyrosine, and site saturation (i.e. all amino acids) (p. 1233, Table 3, 14th entry).
Therefore, it 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 combine the teachings of Kumaran et al. and Whitehouse et al. to engineer a P450 BM3 polypeptide with at least 85% sequence identity to SEQ ID NO: 36 with at least one substitution at amino acid 75 to augment the active site and/or substrate channel of the polypeptide as taught by Whitehouse et al. One would be motivated to combine these teachings to arrive at the instant claim to develop P450 variants suitable for biocatalysis, and to specifically continue to develop soluble P450 variants, such as P450-BM3, which are considerably easier isolate than the eukaryotic P450 polypeptides (Whitehouse et al., p. 1232, “4.1 Objectives,” first paragraph). There would be a reasonable expectation of success, yielding no surprising results when combining the teachings of Kumaran et al. and Whitehouse et al. to produce a P450-BM3 polypeptide with 85% or greater sequence identity to SEQ ID NO: 36 with at least one substitution at amino acid 75, since Whitehouse et al. teaches P450-BM3 polypeptides with amino acid 75 substituted for any other natural amino acid.
Double Patenting
19. The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
17. Claims 1 and 20-21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 14 of copending Application No. 18/516,310 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because. Claims 1 and 13-14 of the ‘310 application would anticipate the instant claims.
Claims 1 and 20-21 are drawn to an engineered cytochrome P450-BM3 variant comprising a polypeptide sequence having at least 85% or more sequence identity to SEQ ID NO: 4, wherein the polypeptide sequence of said engineered P450-BM3 variant comprises at least one substitution or substitution set. Additionally, the engineered cytochrome P450-BM3 variant comprises at least one improved property compared to a wild-type B. megaterium cytochrome P450-BM3.
Claims 1 and 13-14 of the ‘310 application are drawn to an engineered cytochrome P450-BM3 variant comprising a polypeptide sequence having at least 85% or more sequence identity to SEQ ID NO: 2, wherein the polypeptide sequence of said engineered P450-BM3 variant comprises at least one substitution or substitution set. Additionally, the engineered cytochrome P450-BM3 variant comprises at least one improved property compared to a wild-type B. megaterium cytochrome P450-BM3.
SEQ ID NO: 2 of the ‘310 application shares 99.3% sequence identity with SEQ ID NO: 4 of the instant claims, where there is at least one amino acid substitution at amino acid positions numbered the same in SEQ ID NO: 4 (“SEQ ID NO: 4 vs 2,” downloaded 17 March 2026 as a PDF from <abss.uspto.gov/abss4examiners/>). Specifically, SEQ ID NO: 2 has substitutions at 105, 256, 433, 453, and 853. Additionally, it is notable that SEQ ID NO: 4 of the instant claims and SEQ ID NO: 92 of the ‘310 application are 100% identical (“SEQ ID NO: 4 vs 92,” downloaded 17 March 2026 as a PDF from <abss.uspto.gov/abss4examiners/>). The only difference between the ‘310 claims and the instant claims are the SEQ ID NOs recited in the claims; however, as demonstrated above, SEQ ID NO: 2 of the ‘310 application will necessarily anticipate claims 1 and 20-21 of the instant application.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
20. All claims are rejected. Claims 2 and 20 are also objected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CIARA A MCKNIGHT whose telephone number is (703)756-4791. The examiner can normally be reached M-F 8:00am-4:30pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Manjunath Rao can be reached on (571) 272-0939. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CIARA A MCKNIGHT/Examiner, Art Unit 1656
/SUZANNE M NOAKES/Primary Examiner, Art Unit 1656
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