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 .
Claims 1-22 are still at issue and are present for examination.
Election/Restrictions
Applicant's election without traverse of the following species:
Species Group 1: MMOH (claim 1).
Species Group 2: MMOHa (A64-L321) of SEQ ID NO:2.
Species Group 3: MMORF (99-348) of SEQ ID NO:5.
Species Group 4: MMOB (retro) of SEQ ID NO:8.
Species Group 5: C-terminus (Claim 14).
in the paper of 1/19/2026, is acknowledged.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609 A(1) states, "the list may not be incorporated into the specification but must be submitted in a separate paper."
Applicants filing of information disclosure statements on 10/26/2023 are acknowledged and have been considered.
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 1-22 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 1 (claims 2-22 dependent on) is indefinite in the recitation “A protein comprising self-assembled ferritin monomers, in which a methane oxidation active domain and an electron transfer domain are fused” in that it is unclear what the specific relationship of each of required components, the methane oxidation active domain and the electron transfer domain, are to each other, and to the self-assembled ferritin monomers. In the interest of advancing prosecution the recitation is interpreted as each of the methane oxidation active domain and the electron transfer domain are fused to a self-assembled ferritin monomer.
Claim 7 is indefinite in that it references “a ferritin monomer fused with the methane oxidation active domain” and “a ferritin monomer fused with the electron transfer domain including a FAD-binding domain” of the protein according to claim 1, however, as discussed above under the rejection of claim 1, there is not necessarily an antecedent basis for the above recitations in claim 7.
Claim 8 (claims 9-12 dependent on) is indefinite in the recitation “the ferritin monomer is further fused with MMOB” in that as discussed above it is not clear if the ferritin monomer of claim 1 is fused and hence this makes “further fused” indefinite.
Claim 14 is indefinite in the recitation “each domain is fused to anyone selected from the group consisting of: inside a-helix of the ferritin monomer; between adjacent a-helices; N-terminus; C-terminus; A-B loop; B-C loop; C-D loop; D-E loop; between N-terminus and A helix; and between E helix and C-terminus” in that it is unclear and confusing as to exactly what each “domain” is fused to. While it is understood what the “a-helix of the ferritin monomer” is in the context of the claim, each of the additional choices “between adjacent a-helices; N-terminus; C-terminus; A-B loop; B-C loop; C-D loop; D-E loop; between N-terminus and A helix; and between E helix and C-terminus” are indefinite in the context of the claim because it is unclear as to what fusion partner each of these choices are referring to.
Appropriate correction and/or comment is required.
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.
Claims 1, 2, 3, 4, 5, 7, 13, 14, 15, 16, 17, 18, 19, 20-22 are rejected under 35 U.S.C. 103 as being unpatentable over the combination of Kim et al., (Nature Catalysis 2.4 (2019): 342-353), Arnold et al. (WO 2006/105082) and Takeshita et al. (WO 03/027301) as evidenced by Gladyshev et al. (J. Biological Chemistry, Vol 271,No. 14, pp 8095-8100, 1996).
Regarding claims 1-4, Kim teaches a protein nanoparticle comprising self-assembled ferritin monomers, comprising a ferritin monomer fused with an active domain having methane oxidation activity (p. 342, 3rd ¶ to p. 343, last ¶; Table 1). The domain(s) having methane oxidation activity comprise domains from particulate methane monooxygenase (pMMO) of M. capsulatus (Bath), comprising residues 33-172 (pmoB1) and 265-414 (pmoB2), which were determined to be the minimal structural units for pMMO catalytic activity (p. 343, 1st and 2nd ¶; p. 350-351, under Biosynthesis of recombinant proteins including pMMO-mimics; Table 1 and Supp. Table 1). Kim teaches that recombinant forms of pMMO are typically inactive due to the membrane-anchored structure of the enzyme, and that expressing pMMO as a fusion construct with ferritin allows for expression of active pMMO by providing a self-assembling particulate scaffold that mimics the native membrane-embedded structure (p. 342, 3rd ¶ to p. 343, last ¶; p. 349, 1st ¶ under Discussion to p. 350, 1st ¶). Kim further teaches that pMMO is of high interest in academia and industry due to its ability to oxidize carbon feedstocks, including the conversion of methane to methanol (p. 342, 1st – 3rd ¶).
Kim teaches that the pmoB1 and pmoB2 domains can each be fused to a single ferritin monomer, and that multiple such monomers can self-assemble to form a catalytically active nanoparticle (Table 1, pMMO-m1; p. 345-347, under Biocatalytic conversion of methane to methanol by pMMO-mimics).
Regarding claim 5, Kim teaches that the pmoB1 and pmoB2 domains can each be fused separately to a ferritin monomer, and that multiple such monomers can self-assemble to form a catalytically active nanoparticle (Table 1, pMMO-m2-pMMO-m4; p. 345-347, under Biocatalytic conversion of methane to methanol by pMMO-mimics).
Regarding claim 10, Kim teaches that the ferritin can be human heavy chain ferritin (p. 343, 1st full ¶; p. 350-351, under Biosynthesis of recombinant proteins including pMMO-mimics; Table 1 and Supp. Table 1, regarding claim 13).
Kim teaches that the pmoB1 and pmoB2 domains are fused to the C-terminus of the ferritin (p. 343, 1st full ¶; p. 350-351, under Biosynthesis of recombinant proteins including pMMO-mimics; Table 1 and Supp. Table 1) and there expression in E. coli.
Kim further teaches compositions for converting methane to methanol comprising the ferritin-pMMO construct and duroquinol as a reducing agent (p. 345-347, under Biocatalytic conversion of methane to methanol by pMMO-mimics). Kim teaches that duroquinol is essential for pMMO activity and binds directly to the catalytic core of the enzyme (p. 346, 1st full ¶).
Arnold et al. (WO 2006/105082) disclose a number of modified hydroxylases, cells expressing such modified hydroxylases and methods of producing hydroxylated alkanes by contacting a suitable substrate with such cells. Arnold et al. teach disclose chimeric polypeptides that include a monooxygenase/hydroxylase catalytic domain derived from a first source and an electron transfer domain derived from a second source (paragraph [00109] -[00111] ). Arnold et al. teach the methods of using these chimeric polypeptides to convert methane to methanol (see claims and supporting text). Arnold et al. teach as an example a converting a heme-containing medium-chain fatty acid hydroxylase to hydroxylating catalysts for small alkanes using an exemplary hydroxylase includes cytochrome P450 BM-3 (CYP102A1) a catalytically self-sufficient fatty acid monooxygenase isolated from Bacillus megaterium. It has a multi-domain structure, composed of three domains: one FAD (electron transfer domain), one FMN and one heme domain fused on the same 119 kDa polypeptide chain (paragraph [00178] regarding claim 5).
Takeshita et al. (WO 03/027301) disclose a methane monooxygenase (MMO) enzyme for the O2 oxidation of methane. Takeshita et al. (WO 03/027301) disclose a methane monooxygenase (MMO) enzyme comprising the amino acid sequence of instant SEQ ID NO:2 (regarding claim 3).
It would have been obvious to one of ordinary skill in the art before the effective filing date to make an enzyme construct capable of converting methane to methanol by fusing a methane oxidizing enzyme to ferritin to make a self-assembled enzyme nanoparticle as taught by Kim wherein the methane oxidizing enzyme is a chimeric polypeptide comprising the MMO catalytic domain and an electron transfer domain as taught by Arnold et al. because it would have been obvious to combine prior art elements according to known methods to yield predictable results. One of skill in the art would have been further motivated to use the monooxygenase enzyme taught by Takeshita et al. in the chimeric polypeptide comprising the MMO catalytic domain and an electron transfer domain as taught by Arnold et al. because it was a known and cloned monooxygenase and its encoding gene was known and available to the ordinary artisan (claims 1-4, 13, 14-22). One of ordinary skill would have been motivated to create these chimeric proteins in E. coli as done by Kim et al. E. coli inherently expresses formate dehydrogenase as evidenced by Gladyshev et al. (J. Biological Chemistry, Vol 271,No. 14, pp 8095-8100, 1996). One of ordinary skill would have been motivated to make an enzyme construct as taught by Kim wherein the enzyme is a monooxygenase/hydroxylase catalytic domain derived from a first source and an electron transfer domain (FAD domain) as taught by Arnold et al. because oxidation of carbon feedstocks, including conversion of methane to methanol, is of great commercial interest (claims 5 and 7). Moreover, making a construct as taught by Kim et al., Arnold et al. and Takeshita et al. would provide an additional source of enzyme (in addition to pMMO) that could expand the range of potential operating conditions, substrates, etc. Making an enzyme construct as taught by Kim wherein the enzyme is AMO would have led to predictable results with a reasonable expectation of success because each of the references Kim et al., Arnold et al. produce similar protein constructs. It would have been obvious to one of skill to use these enzyme constructs, microorganisms and compositions comprising said enzyme constructs in methods of converting methane gas to methanol as taught by Kim et al. and Arnold et al. (claim 21)
Thus, claims 1, 2, 3, 4, 5, 7, 13, 14, 15, 16, 17, 18, 19, 20-22 are rejected under 35 U.S.C. 103 as being unpatentable over the combination of Kim et al., (Nature Catalysis 2.4 (2019): 342-353), Arnold et al. (WO 2006/105082) and Takeshita et al. (WO 03/027301) as evidenced by Gladyshev et al. (J. Biological Chemistry, Vol 271,No. 14, pp 8095-8100, 1996).
Claims 1, 2, 4, 5, 7, 8, 10, 11, 13, 14, 15, 16, 17, 18, 19, 20-22 are rejected under 35 U.S.C. 103 as being unpatentable over the combination of Kim et al., (Nature Catalysis 2.4 (2019): 342-353), Park et al. (Catalysis, 8, 582, Nov 26, 2018) as evidenced by Gladyshev et al. (J. Biological Chemistry, Vol 271,No. 14, pp 8095-8100, 1996).
Regarding claims 1-4, Kim teaches a protein nanoparticle comprising self-assembled ferritin monomers, comprising a ferritin monomer fused with an active domain having methane oxidation activity (p. 342, 3rd ¶ to p. 343, last ¶; Table 1). The domain(s) having methane oxidation activity comprise domains from particulate methane monooxygenase (pMMO) of M. capsulatus (Bath), comprising residues 33-172 (pmoB1) and 265-414 (pmoB2), which were determined to be the minimal structural units for pMMO catalytic activity (p. 343, 1st and 2nd ¶; p. 350-351, under Biosynthesis of recombinant proteins including pMMO-mimics; Table 1 and Supp. Table 1). Kim teaches that recombinant forms of pMMO are typically inactive due to the membrane-anchored structure of the enzyme, and that expressing pMMO as a fusion construct with ferritin allows for expression of active pMMO by providing a self-assembling particulate scaffold that mimics the native membrane-embedded structure (p. 342, 3rd ¶ to p. 343, last ¶; p. 349, 1st ¶ under Discussion to p. 350, 1st ¶). Kim further teaches that pMMO is of high interest in academia and industry due to its ability to oxidize carbon feedstocks, including the conversion of methane to methanol (p. 342, 1st – 3rd ¶).
Kim teaches that the pmoB1 and pmoB2 domains can each be fused to a single ferritin monomer, and that multiple such monomers can self-assemble to form a catalytically active nanoparticle (Table 1, pMMO-m1; p. 345-347, under Biocatalytic conversion of methane to methanol by pMMO-mimics).
Regarding claim 5, Kim teaches that the pmoB1 and pmoB2 domains can each be fused separately to a ferritin monomer, and that multiple such monomers can self-assemble to form a catalytically active nanoparticle (Table 1, pMMO-m2-pMMO-m4; p. 345-347, under Biocatalytic conversion of methane to methanol by pMMO-mimics).
Regarding claim 10, Kim teaches that the ferritin can be human heavy chain ferritin (p. 343, 1st full ¶; p. 350-351, under Biosynthesis of recombinant proteins including pMMO-mimics; Table 1 and Supp. Table 1, regarding claim 13).
Kim teaches that the pmoB1 and pmoB2 domains are fused to the C-terminus of the ferritin (p. 343, 1st full ¶; p. 350-351, under Biosynthesis of recombinant proteins including pMMO-mimics; Table 1 and Supp. Table 1) and there expression in E. coli.
Kim further teaches compositions for converting methane to methanol comprising the ferritin-pMMO construct and duroquinol as a reducing agent (p. 345-347, under Biocatalytic conversion of methane to methanol by pMMO-mimics). Kim teaches that duroquinol is essential for pMMO activity and binds directly to the catalytic core of the enzyme (p. 346, 1st full ¶).
Park et al. (Catalysis, 8, 582, Nov 26, 2018) teach that methane is an important greenhouse gas and teach the mechanisms underlying the extremely stable C-H activation of soluble methane monooxygenase (sMMO). Park et al. teach the expression and purification of the sMMO components including hydroxylase (MMOH), regulatory (MMOB) and reductase (MMOR) from type II methanotroph, Methylosius sporium to characterize its hydroxylation mechanism. Park et al. teach the expression and purification of the hydroxylase (MMOH) from M. sporium and the expression and purification of MMOB and MMOR from E. coli. Park et al. teach that MMOR is an essential component for the catalytic cycle owing for its electron transfer abilities by FAD-containing and [2Fe-2S] cluster ferrodoxin domains to reduce diiron active sites in MMOH. Park et al. further teach that the overall shape and volume of the MMOR-Fd are similar to those of the MMB core region, suggesting that MMOB and MMOR share the binding sites of MMOH.
Park et al. further disclose the activities of the essential MMO components and teach that two molar equivalents of MMOB are necessary to achieve catalytic activities and oxidized a broad range of substrates including alkanes, alkenes, halogens and aromatics. Park et al. further teach that optimal activities of MMO were observed at ph 7.5 for most substrates possibly because of the electron transfer environment in MMOR. Park et al. teach that the substitution of MMOB or MMOR from another type II methanotroph retained specific enzyme activities (see abstract and supporting text).
It would have been obvious to one of ordinary skill in the art before the effective filing date to make an enzyme construct capable of converting methane to methanol by fusing a methane oxidizing enzyme to ferritin to make a self-assembled enzyme nanoparticle as taught by Kim wherein the methane oxidizing enzyme is a chimeric polypeptide comprising the MMO catalytic domain, the MMOB domain and the MMOR domain as taught by Park et al. because it would have been obvious to combine prior art elements according to known methods to yield predictable results. One of skill in the art would have been further motivated to use MMO catalytic domain, the MMOB domain and the MMOR domain as taught by Park et al because it was a known and cloned monooxygenase and its encoding gene was known and available to the ordinary artisan (claims 1, 2, 4,, 13, 14-22). One of ordinary skill would have been motivated to create these chimeric proteins in E. coli as done by Kim et al. E. coli inherently expresses formate dehydrogenase as evidenced by Gladyshev et al. (J. Biological Chemistry, Vol 271,No. 14, pp 8095-8100, 1996). One of ordinary skill would have been motivated to make an enzyme construct as taught by Kim wherein the enzyme is a chimeric polypeptide comprising ferritin monomer, the MMO catalytic domain, the MMOB domain and the MMOR domain as taught by Park et al because oxidation of carbon feedstocks, including conversion of methane to methanol, is of great commercial interest (claims 5 and 7). Moreover, making a construct as taught by Kim et al., Park et al. would provide an additional source of enzyme (in addition to pMMO) that could expand the range of potential operating conditions, substrates, etc. Making an enzyme construct as taught by Kim wherein the enzyme is a chimeric polypeptide comprising the MMO catalytic domain, the MMOB domain and the MMOR domain as taught by Park et al would have led to predictable results with a reasonable expectation of success because each of the references Kim et al., Park et al. produce similar protein constructs. It would have been obvious to one of skill to use these enzyme constructs, microorganisms and compositions comprising said enzyme constructs in methods of converting methane gas to methanol as taught by Kim et al. and Park et al. (claim 21).
Thus claims 1, 2, 4, 5, 7, 8, 10, 11, 13, 14, 15, 16, 17, 18, 19, 20-22 are rejected under 35 U.S.C. 103 as being unpatentable over the combination of Kim et al., (Nature Catalysis 2.4 (2019): 342-353), Park et al. (Catalysis, 8, 582, Nov 26, 2018) as evidenced by Gladyshev et al. (J. Biological Chemistry, Vol 271,No. 14, pp 8095-8100, 1996).
Double Patenting
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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 10, 11 and 15 of copending Application No. 18288728 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because claims 1, 10, 11 and 15 of copending Application No. 18288728 (reference application) are anticipated by instant claims 1-22 drawn to a protein comprising self-assembled ferritin monomers, in which a methane oxidation active domain and an electron transfer domain are fused and compositions and cells comprising said protein and methods of use for converting methane to methanol.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Remarks
No claim is allowed.
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rgh
3/18/2026
/RICHARD G HUTSON/Primary Examiner, Art Unit 1652