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 .
Response to Restriction Requirements
Applicant's election of Group VII, claims 29, 34, 37, 44-47, 58, 59 and 75 in the reply filed on 03/31/2026 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)).
Applicant's election of species of the polypeptide sequence of SEQ ID NO: 21 (claims 34, 37, 47) and the corresponding nucleic acid sequence of SEQ ID NO: 3 (claim 45) in the reply filed on 03/31/2026 is acknowledged.
Claim 75 has been added by applicant as NEW claim which recite modified codeine 3-O-demethylase polypeptide which comprises all the components from sub parts i) and xxvii) showed by recitation of the term “and” at the end of part xxvi. Therefore, the sequence is large sequence comprising all the sequences in the sub parts of the claim from i) to xxvii). Since all the sequence are required in the claim, the species election of SEQ ID NOs would still require other remaining sequences as recited. Therefore, the claim 75 has been further restricted to the subsequent Group XI along with the restriction requirements sent on 02/09/2026.
Claims 1-3, 18-20, 23-25, 28-30, 34, 37, 44-47, 49, 50, 57-62, and 75 are pending.
Claims 1-3, 18-20, 23-25, 28, 30, 49, 50, 57, 60-62 and 75 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 03/31/2026.
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).
Thus claims 29, 34, 37, 44-47, 58 and 59 of elected invention Group VII along with the species of SEQ ID NO: 21 (claims 34, 37, 47) and the corresponding nucleic acid sequence of SEQ ID NO: 3 (claim 45) are examined in this office action.
Specification
The use of the term “gBlock” in page 33 lines 31 and 34, IDT in line 32, NEBuilder in line 33, “Shimadzu” and “LabSolutions” in page 36, line 5 which are trade names or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore, the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM, or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 29, 44 and 59 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter. The claim does not fall within at least one of the four categories of patent eligible subject matter because the claimed invention are directed to judicial exception (i.e., a law of nature, natural phenomenon, or an abstract idea) without significantly more.
Claims 29, 44 and 59 are drawn to any codeine 3-O-demethylase polypeptide or an isolated nucleic acid molecule of it and a cell comprising the molecule.
Isabel et al. (Published: 2012, Journal: Plant Mol Biol 79:295–313
DOI 10.1007/s11103-012-9913-2) discloses a CODM codeine O-demethylase (i.e. codeine 3 O-demethylase) is involved in biosynthesis pathway of converting codeine to morphine in opium poppy plants (i.e. Opium Poppy plant cells). (page 296, Figure 1, page 297, left paragraph 2). Isabel et al. discloses different cultivars 40, Deborah, Marianne, Natasha etc. comprise CODM transcript (page 306, Table 3). Alignment of SEQ ID NO: 21 to the locus ADD85331 of accession GQ500141.1 showed 99% identity single constitutive substitution (see below and enclosed PDF for description of the accession). Therefore, Isabel et al. discloses the CODM is from Genbank accession numbers for opium poppy sequences as GQ500141.
Therefore, the structure of the modified codeine 3-O-demethylase polypeptide would be the same as claim in claim 29 which would be different (i.e. altered) compared to any of a CODM.
Therefore, the recited CODM is naturally occurring protein in puppy cultivars that is involved in biosynthesis pathway of converting codeine to morphine.
The claim is interpreted as “product by process claim” wherein [E]ven though product by process claims are limited by and defined by the process, determination of patentability is based on the product itself. If the product in the product by process claim is the same as or obvious from a product of the prior art, the claim is unpatentable
To withdraw this rejection applicants would need to claim the barley plant or part thereof comprising an isolated DNA molecule operably linked to a heterologous promoter or the gene comprising specific mutation not found in nature.
Thus, the claims do not recite additional elements that amount to significantly more.
Query: ADD85331.1 codeine O-demethylase [Papaver somniferum] Query ID: lcl|Query_5189621 Length: 360
>unnamed protein product
Sequence ID: Query_5189623 Length: 360
Range 1: 1 to 360
Score:732 bits(1889), Expect:0.0,
Method:Compositional matrix adjust.,
Identities:359/360(99%), Positives:360/360(100%), Gaps:0/360(0%)
Query 1 METPILIKLGNGLSIPSVQELAKLTLAEIPSRYTCTGESPLNNIGASVTDDETVPVIDLQ 60
METPILIKLGNGLSIPSVQELAKLTLAEIPSRYTCTGESPLNNIGASVTDDETVPVIDLQ
Sbjct 1 METPILIKLGNGLSIPSVQELAKLTLAEIPSRYTCTGESPLNNIGASVTDDETVPVIDLQ 60
Query 61 NLLSPEPVVGKLELDKLHSACKEWGFFQLVNHGVDALLMDNIKSEIKGFFNLPMNEKTKY 120
NLLSPEPVVGKLELDKLHSACKEWGFFQLVNHGVDALLMDNIKSEIKGFFNLPMNEKTKY
Sbjct 61 NLLSPEPVVGKLELDKLHSACKEWGFFQLVNHGVDALLMDNIKSEIKGFFNLPMNEKTKY 120
Query 121 GQQDGDFEGFGQPYIESEDQRLDWTEVFSMLSLPLHLRKPHLFPELPLPFRETLESYLSK 180
GQQDGDFEGFGQPYIESEDQRLDWTEVFSMLSLPLHLRKPHLFPELPLPFRETLESYLSK
Sbjct 121 GQQDGDFEGFGQPYIESEDQRLDWTEVFSMLSLPLHLRKPHLFPELPLPFRETLESYLSK 180
Query 181 MKKLSTVVFEMLEKSLQLVEIKGMTDLFEDGLQTMRMNYYPPCPRPELVLGLTSHSDFSG 240
MKKLSTVVFEMLEKSLQLVEIKGMTDLFEDGLQTMRMNYYPPCPRPELVLGLTSHSDFSG
Sbjct 181 MKKLSTVVFEMLEKSLQLVEIKGMTDLFEDGLQTMRMNYYPPCPRPELVLGLTSHSDFSG 240
Query 241 LTILLQLNEVEGLQIRKEERWISIKPLPDAFIVNVGDILEIMTNGIYRSVEHRAVVNSTK 300
LTILLQLNEVEGLQIRKE+RWISIKPLPDAFIVNVGDILEIMTNGIYRSVEHRAVVNSTK
Sbjct 241 LTILLQLNEVEGLQIRKEDRWISIKPLPDAFIVNVGDILEIMTNGIYRSVEHRAVVNSTK 300
Query 301 ERLSIATFHDSKLESEIGPISSLVTPETPALFKRGRYEDILKENLSRKLDGKSFLDYMRM 360
ERLSIATFHDSKLESEIGPISSLVTPETPALFKRGRYEDILKENLSRKLDGKSFLDYMRM
Sbjct 301 ERLSIATFHDSKLESEIGPISSLVTPETPALFKRGRYEDILKENLSRKLDGKSFLDYMRM 360
Claim Rejections - 35 USC § 112 - Indefiniteness
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.
Claim 37 is 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 37 recite the term “3-O-demethylase polypeptide is represented by the amino acid sequence set forth in SEQ ID NO: 21” renders claim indefinite since the metes and bound of the term “represented” cannot be determined. For example Merriam Webster dictionary defines the term “represent” as “to point out the chief quality or qualities of an individual or group”, “to present a picture of”, “to serve as a material counterpart of” (accessed at https://www.merriam-webster.com/thesaurus/represented, accessed on 06/24/2026). Therefore, it is not clear what qualities the sequence has to point out? or what it served as counterpart of? to fulfil the claim limitation.
Applicant are advised to specifically recite the recited 3-O-demethylase polypeptide is encoded by SEQ ID NO:21, or clarify in recitation what does “represent” would mean.
Claim Rejections - 35 USC § 112 – lack of written description
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 29, 34, 37, 44-47, 58 and 59 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 claim(s) 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.
Breadth of the Claim
Claims 45-47 recite large genus of nucleotide sequences comprising at least 90% identical to SEQ ID NOs:3 and 8, and amino acid sequences comprising at least 90% identical to SEQ ID NO: 21.
Claim 29 recite any alteration of polypeptides.
What is Described in the Specification
Applicant describes the following:
Seven strains were generated containing mutations at the 259th amino acid residue (E259K, -D, -H, -Q, -A, -Sand -G) of CODM and two strains were generated that contained mutations at the 260th residue (R260T and -K) of CODM (page 36, lines 22-24).
Three double mutant strains were created containing mutations to both the 259th and 260th residues of CODM (E259G + R260T, E259D + R260K and E259G + R260K) (page 36, lines 24-26).
the seven 259 residue mutant strains investigated, only the E259D and E259G mutants demonstrated an improvement in product yield, with morphine yield improved by ~30% and ~24% respectively (page 36, lines 32-34).
Of the six mutant (T3K, P4A, I5K, I7M, Y357S or M360I), (T3K, P4A, I7M or Y357S) led to either a minor improvement in product yield (e.g., T3K or P4A) or a reduction in product yield relative to the WT CODM strain (page 37, lines 29-37).
Difference Between What was Described and What is Claimed
Applicant has not described large genus of nucleotide sequences comprising at least 90% identical to SEQ ID NOs:3 and 8, and amino acid sequences comprising at least 90% identical to SEQ ID NO: 21 (claims 45-47).
Applicant has not described any alternations of codeine 3-O-demethylase polypeptide other than modification in specific position for example E259D that would increase for example the morphine yield relative to a wild type CODM.
Analysis
The purpose of the written description is to ensure that the inventor had possession at the time the invention was made, of the specific subject claimed. For a broad generic claim, the specification must provide adequate written description to identify the genus of the claim.
Applicant has not described large genus of nucleotide sequences comprising at least 90% identical to SEQ ID NOs:3 and 8, and amino acid sequences comprising at least 90% identical to SEQ ID NO: 21. For example the SEQ ID NO: 21 is 360 amino acid long. The amino acid sequences comprising at least 90% identical to SEQ ID NO: 21 would have at least 36 amino acid changes (i.e., substitutions, deletions, insertions, or additions) relative to SEQ ID NO: 21, and this encompasses a genus of amin acids sequence that includes at least ~2036 different molecules. For this reason, the genus of nucleic acid molecules having at least 90% identity to SEQ ID NO: 21 is a very large genus of molecules. Similarly, nucleotide sequences comprising at least 90% identical to SEQ ID NOs:3 and 8 are large genus of molecules. Instead, applicant has not described modification any other sequence other than SEQ ID NO:21 itself at specific positions leading to modifications in the change in yield of morphine productions.
Furthermore, the state of the art at the time of the instant invention was that although the skilled artisan would appreciate the nucleic acid molecule as SEQ ID NO:8; and SEQ ID NO:3 encoding protein of SEQ ID NO: 21, one would not be able to readily predict function of nucleic acid encoding protein having at least 90% identity to SEQ ID NO:21, and it is impossible to predict such a broad sequence variation will have required function. For example, Guo et al. (Published: 2004, Journal: Proceedings of the National Academy of Sciences, 101(25): 9205-9210) describes that while proteins are fairly tolerant to mutations resulting in single amino acid changes, increasing the number of substitutions additively increases the probability that the protein will be inactivated (Right. col., Paragraph 2).
Applicant has not described any alteration or modification of codeine 3-O-demethylase polypeptide other than modification in specific position for example E259D that would increase for example the morphine yield relative to wild type CODM. Any alternation or modification would comprise the alternation or modification in its function or structure. For example, Runguphan et al. (Published: 2012, Journal: Chemistry & Biology 19, 674–678) teaches PsCODM mutant out of 16 PsCODM tested, A1 A2 BC1*C2, contains only four amino acid changes from wild-type PsCODM: E338G, I340L, L341V, and K342E confer substrate or regioselectivity of the dioxygenases in P. somniferum (page 676, left paragraph 2, page 674, Abstract). Therefore, specific mutation would have been important to have specific use of the mutant to have impact on the yield of the downstream products codeine and morphine in subsequent metabolic engineering efforts.
Given the virtually large structural variation associated with these embodiments, the claims read on an extremely broad and highly diverse structures wherein applicant has only showed in specific position for example E259D, E259G that would increase for example the morphine yield relative to wild type CODM.
Given the large size and structural diversity associated with the claimed genus, Applicant’s disclosure is not representative of the claimed genus as a whole. This point is particularly relevant because, as discussed above, the prior art speaks to the disconnection between the structure of the broadly claimed variants in any plants and the recited specific function.
The Federal Circuit has clarified the application of the written description requirement to inventions in the field of biotechnology. The court stated that, “A description of a genus of cDNAs may be achieved by means of a recitation of a representative number of cDNAs, defined by nucleotide sequence, falling within the scope of the genus or of a recitation of structural features common to members of the genus, which features constitute a substantial portion of the genus.” See University of California v. Eli Lilly and Co., 119 F. 3d 1559; 43 USPQ2d 1398, 1406 (Fed. Cir. 1997).
Thus, based on the analysis above, Applicant has not met either of the two elements of the written description requirement as set forth in the court's decision in Eli Lilly. As a result, it is not clear that Applicant was in possession of the claimed genus at the time this application was filed.
Claim Rejections - 35 USC § 102
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.
Anticipated by Isabel et al.
Claims 29, 44 and 59 are rejected under 35 U.S.C. 102 (a) (1) as being anticipated by Isabel et al.
Claims 29, 44 and 59 are drawn to any codeine 3-O-demethylase polypeptide or an isolated nucleic acid molecule of it and a cell comprising the molecule.
Isabel et al. discloses a CODM codeine O-demethylase (i.e. codeine 3 O-demethylase) is involved in biosynthesis pathway of converting codeine to morphine in opium poppy plants (i.e. Opium Poppy plant cells). (page 296, Figure 1, page 297, left paragraph 2). Isabel et al. discloses different cultivars 40, Deborah, Marianne, Natasha etc. comprise CODM transcript (page 306, Table 3). Alignment of SEQ ID NO: 21 to the locus ADD85331 of accession GQ500141.1 showed 99% identity single constitutive substitution (see below and enclosed PDF for description of the accession). Therefore, Isabel et al. discloses the CODM is from Genbank accession numbers for opium poppy sequences as GQ500141.
Therefore Isabel et al. anticipates the claim.
Anticipated by Fechini et al.
Claims 29, 44 and 58-59 are rejected under 35 U.S.C. 102 (a) (1) and/or (a)(2) as being anticipated by Fechini et al. (WIPO International Publication No.: WO 2011/058446 A2, Publication Date: 19 May 2011).
Regarding claim 29, Fechini et al. claim 61 discloses an isolated codeine O-demethylase as SEQ ID NO:3 (i.e. PsCODM) which has 99.8% identity to the applicant’s SEQ ID NO:21 with one conservative substitution (i.e. modified) (see alignment below).
Fechini et al. discloses the sequence of CODM (i.e. DIOX3) has been deposited as GQ500141 in GenBank/EMBL databases (page 62, lines 27-29, page 69, lines 27-29).
Fechini et al. discloses silencing of CODM display metabolic block of codeine (page 73 lines 26-28, Fig 6 A-B).
Regarding claim 58, Fechini et al. claim 71 recite expression cassette comprising a promoter operably linked to the SEQ ID NO:3.
Regarding claim 59, Fechini et al. claims 76 and 81 recite a vector and a recombinant cell comprising SEQ ID NO:3.
Fechini et al. discloses a recombinant protein produced by pDIOX3 (codeine 0-demethylase, CODM) in E. coli (page 14, lines 15-17, Figure 15).
Therefore Fechini et al. anticipates the claims.
Alignment of SEQ ID NO: 21 to geneseqp__le40000 database:
RESULT 3
AZI26750
(NOTE: this sequence has 17 duplicates in the database searched)
ID AZI26750 standard; protein; 360 AA.
XX
AC AZI26750;
XX
DT 04-AUG-2011 (revised)
DT 07-JUL-2011 (first entry)
XX
DE Papaver somniferum codeine O-demethylase (CODM) sequence, SEQ ID 3.
XX
KW CODM; analgesic; cell culture; codeine O-demethylase; medicinal plant;
KW pain; plant; secondary metabolite; seed; therapeutic; transgenic plant.
XX
OS Papaver somniferum.
XX
FH Key Location/Qualifiers
FT Misc-difference 4
FT /note= "Encoded by GCA of AZI26783"
FT Misc-difference 7
FT /note= "Encoded by ATG of AZI26783"
FT Misc-difference 55
FT /note= "Encoded by GCT of AZI26783"
FT Misc-difference 99
FT /note= "Encoded by ATC of AZI26783"
XX
CC PN WO2011058446-A2.
XX
CC PD 19-MAY-2011.
XX
CC PF 12-NOV-2010; 2010WO-IB003137.
XX
PR 12-NOV-2009; 2009US-0260647P.
PR 12-NOV-2009; 2009US-0260659P.
XX
CC PA (UYCO-) UNIV CONCORDIA.
CC PA (UTIU-) UTI LP.
XX
CC PI Ekins A, Facchini P, Farrow S, Fossati E, Hagel J, Lauzon J;
CC PI Martin V;
XX
DR WPI; 2011-F52370/35.
DR N-PSDB; AZI26751, AZI26783.
DR PC:NCBI; gi291264192.
XX
CC PT New isolated thebaine 6-O-demethylase having specific amount of sequence
CC PT homology to specific amino acid sequence useful for producing morphinone,
CC PT thebaine, oripavine, neopinone, opiate and codeinone.
XX
CC PS Claim 61; SEQ ID NO 3; 144pp; English.
XX
CC The present invention relates to a novel thebaine 6-O-demethylase. The
CC invention further relates to: (1) a nucleic acid encoding the thebaine 6-
CC O-demethylase; (2) an expression cassette comprising a promoter operably
CC linked to the nucleic acid encoding a Papaver somniferum thebaine 6-O-
CC demethylase; (3) a vector comprising a promoter operably linked to the
CC nucleic acid encoding a Papaver somniferum thebaine 6-O-demethylase; (4)
CC a recombinant cell comprising the expression cassette; (5) a transgenic
CC Papaver somniferum plant; (6) a seed or a progeny of the plant; (7) a
CC method for producing morphinone, opiate, oripavine, neopinone and
CC codeinone; and (8) a method for producing thebaine by culturing the
CC plant. The method of the invention can be used for producing morphinone,
CC thebaine, oripavine, neopinone and codeinone for treating pain. The
CC present sequence is a Papaver somniferum codeine O-demethylase (CODM)
CC sequence, used in the invention.
CC
CC Revised record issued on 25-JUL-2011 : Enhanced with precomputed
CC information from BOND.
XX
SQ Sequence 360 AA;
Query Match 99.8%; Score 1853; Length 360;
Best Local Similarity 99.7%;
Matches 359; Conservative 1; Mismatches 0; Indels 0; Gaps 0;
Qy 1 METPILIKLGNGLSIPSVQELAKLTLAEIPSRYTCTGESPLNNIGASVTDDETVPVIDLQ 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 METPILIKLGNGLSIPSVQELAKLTLAEIPSRYTCTGESPLNNIGASVTDDETVPVIDLQ 60
Qy 61 NLLSPEPVVGKLELDKLHSACKEWGFFQLVNHGVDALLMDNIKSEIKGFFNLPMNEKTKY 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 NLLSPEPVVGKLELDKLHSACKEWGFFQLVNHGVDALLMDNIKSEIKGFFNLPMNEKTKY 120
Qy 121 GQQDGDFEGFGQPYIESEDQRLDWTEVFSMLSLPLHLRKPHLFPELPLPFRETLESYLSK 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 GQQDGDFEGFGQPYIESEDQRLDWTEVFSMLSLPLHLRKPHLFPELPLPFRETLESYLSK 180
Qy 181 MKKLSTVVFEMLEKSLQLVEIKGMTDLFEDGLQTMRMNYYPPCPRPELVLGLTSHSDFSG 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 MKKLSTVVFEMLEKSLQLVEIKGMTDLFEDGLQTMRMNYYPPCPRPELVLGLTSHSDFSG 240
Qy 241 LTILLQLNEVEGLQIRKEDRWISIKPLPDAFIVNVGDILEIMTNGIYRSVEHRAVVNSTK 300
||||||||||||||||||:|||||||||||||||||||||||||||||||||||||||||
Db 241 LTILLQLNEVEGLQIRKEERWISIKPLPDAFIVNVGDILEIMTNGIYRSVEHRAVVNSTK 300
Qy 301 ERLSIATFHDSKLESEIGPISSLVTPETPALFKRGRYEDILKENLSRKLDGKSFLDYMRM 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 ERLSIATFHDSKLESEIGPISSLVTPETPALFKRGRYEDILKENLSRKLDGKSFLDYMRM 360
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Obvious over Fechini et al. and further in view of Barry et al.
Claims 29, 34 and 37 are rejected under 35 U.S.C. 103 as being unpatentable over Fechini et al. (WIPO International Publication No.: WO 2011/058446 A2, Publication Date: 19 May 2011), and further in view of Barry et al. (WIPO International Pub. Num.: WO 2017 /192560 A1, International Publication Date: 11/09/2017).
Claims are drawn to a modified codeine 3-O-demethylase polypeptide as SEQ ID NO:21.
Regarding claim 29, Fechini et al. claim 61 teaches s an isolated codeine O-demethylase as SEQ ID NO:3 (i.e. PsCODM) which has 99.8% identity to the applicant’s SEQ ID NO:21 with one conservative substitution (i.e. modified) (see alignment above).
Fechini et al. discloses the sequence of CODM (i.e. DIOX3) has been deposited as accession GQ500141 in GenBank/EMBL databases (page 62, lines 27-29, page 69, lines 27-29).
Fechini et al. discloses silencing of CODM display metabolic block of codeine (page 73 lines 26-28, Fig 6 A-B).
Regarding claim 34, The difference between Applicant’s SEQ ID NO:21 and Fechini et al.’s SEQ ID NO:3 or accession GQ500141 is amino acid substitution E259D (i.e. glutamate to aspartate).
Fechini et al. teaches amino acid sequence variants of the polypeptide can be substitutional which comprise the exchange of one amino acid for another at one or more sites within the protein, where such substitutions are designed to modulate one or more properties of the polypeptide, such as stability against proteolytic cleavage, without the loss of other functions or properties (page 22, lines 11-14). Fechini et al. teaches such subsection are conservative which is change of glutamate to aspartate (i.e. E to D) (page 22, lines 14-22).
Fechini et al. teaches amino acids with similar hydropathic index (within ±0.5 are even more preferred) or score can be substituted (e.g. Hydropathic index of glutamate (-3.5) and aspartate (-3.5)) and still results in a protein with similar biological activity, i.e., still obtain a biological functionally equivalent protein (page 23, lines 12-21). Similar close hydrophilicity also are present in aspartate (+3.0 ± 1); glutamate (+3.0 ±1) (page 24, lines 7-11) which would maintain a biologically equivalent and immunologically equivalent protein.
Furthermore, Barry et al. furthermore constructs different libraries of IPD090Aa variants of their Barry’s SEQ ID NOs: 1 and 5 with overlapping homology (Barry et al., Page 131, Table 9) which showed examples of conservative substitution of E to K , E to N, E to S etc. using the QuikChange™ Multi Site-Directed Mutagenesis Kit (Agilent) (Barry et al., page 136-139, Table 12).
Thus it would have been obvious to a skilled in the art before effective date of filling of the invention from teaching, suggestions and motivation of Fechini et al. to make obvious conservative substitution of glutamate to aspartate (i.e. E to D) and it would have been obvious to try from finite number of possible conservative substitution in Fechini et al.’s SEQ ID NO:3, and such substitutions would have predictable result of maintained functions or properties that would lead to the invention of the protein of SEQ ID NO:21 as further taught by Barry et al.
Regarding claim 37, Fechini et al. claim 61 teaches an isolated codeine O-demethylase as SEQ ID NO:3 (i.e. PsCODM).
Obvious over Fechini et al. and further in view of Barry et al. and Puigbo et al.
Claims 29 and 44-47 are rejected under 35 U.S.C. 103 as being unpatentable over Fechini et al. (WIPO International Publication No.: WO 2011/058446 A2, Publication Date: 19 May 2011), and further in view of Barry et al. and further in view of Puigbo et al. (Published: 2007, Journal: Nucleic Acids Research, 35: W126-W131).
Claims are drawn to a modified codeine 3-O-demethylase polypeptide and an isolated nucleic acid encoding the polypeptide. The nuclei acid sequence has 90% identity to SEQ ID NOs:3 or 8.
Regarding claims 29 and 44, Fechini et al. claim 61 teaches s an isolated codeine O-demethylase as SEQ ID NO:3 (i.e. PsCODM) which has 99.8% identity to the applicant’s SEQ ID NO:21 with one conservative substitution (i.e. modified) (see alignment above).
Fechini et al. discloses the sequence of CODM (i.e. DIOX3) has been deposited as accession GQ500141 in GenBank/EMBL databases (page 62, lines 27-29, page 69, lines 27-29).
Fechini et al. discloses silencing of CODM display metabolic block of codeine (page 73 lines 26-28, Fig 6 A-B).
Regarding claim 45, Fechini et al. does not teach SEQ ID NO: 3.
SEQ ID NO: 3 encodes SEQ ID NO: 21 therefore the sequence is a codon optimized version of the nucleotide sequence encoding SEQ ID NO: 3.
Fechini et al. teaches during heterologous protein expression, low expression or the formation of denatured proteins may be attributable to the differences in synonymous codon usage between the heterologous host and the natural host and optimizing codon usage and eliminating mRNA secondary structure can significantly improve the levels of target protein expression in a heterologous host (page 54 and 55 last and first paragraphs).
Furthermore, Puigbo et al. teaches about the web server utility that optimizes a DNA or protein sequence. Puigbo et al. further teaches that "optimizer" software can be used to design any new genes that confer new metabolic capabilities in a given species (Page W130, first paragraph). The codon optimization is a routine procedure to produce the already known protein taught by Fechini et al. as CODM. The claim's patentability hinges on the novelty of the product itself, not the process. The feely available website accessed at http://genomes.urv.es/OPTIMIZER/, accessed at 06/24/2026 as taught by Puigbo et al. showed optimizer is an on-line PHP application that optimizes the codon usage of a DNA sequence to increase its expression level. Furthermore, the codon usage database showed it clearly provides codon usage for example E. coli, for example see the usage table showed below accessed from the linked codon usage database in website.
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Thus it would have been obvious to a skilled in the art before effective date of filling of the invention from teaching, suggestions and motivation of Fechini et al. to make substitution of glutamate to aspartate (i.e. E to D) and it would have been obvious to try from finite number of possible conservative substitution in Fechini et al. SEQ ID NO:3, and such substitutions would have predictable result of maintained functions or properties that would lead to the invention of the protein of SEQ ID NO:21. Furthermore, make a codon optimization to the nucleic acid sequence taught by Fechini et al. for example to optimize to Express in E. coli leading to sequence having at least 90% identity to SEQ ID NO:3 that would encode SEQ ID NO:21.
Regarding claim 46, alignment of applicant’s SEQ ID NO: 3 and 8 (see below) and Specification page 35 last paragraph showed the SEQ ID NO:8 comprise E259G in the CODM sequence.
Fechini et al. teaches amino acids with similar hydropathic index (within ±0.5 are even more preferred) or score can be substituted hydropathic index of glutamate (e.g. (-3.5) and glycine (-0.4)) and still results in a protein with similar biological activity, i.e., still obtain a biological functionally equivalent protein (page 23, lines 12-21). Similar close hydrophilicity also is present in glutamate (+3.0 ±1) and glycine (0) (page 24, lines 7-11) which would maintain a biologically equivalent and immunologically equivalent protein.
Furthermore, Barry et al. furthermore constructs different libraries of IPD090Aa variants of their Barry’s SEQ ID NOs: 1 and 5 with overlapping homology (Barry et al., Page 131, Table 9) which showed examples of conservative substitution of E to K, E to N, E to S etc. using the QuikChange™ Multi Site-Directed Mutagenesis Kit (Agilent) (Barry et al., page 136-139, Table 12).
Furthermore, Puigbo et al. teaches about the web server utility that optimizes a DNA or protein sequence. Puigbo et al. further teaches that "optimizer" software can be used to design any new genes that confer new metabolic capabilities in a given species (Page W130, first paragraph). The codon optimization is a routine procedure to produce the already known protein taught by Fechini et al. as CODM. The claim's patentability hinges on the novelty of the product itself, not the process. The feely available website accessed at http://genomes.urv.es/OPTIMIZER/, accessed at 06/24/2026 as taught by Puigbo et al. showed optimizer is an on-line PHP application that optimizes the codon usage of a DNA sequence to increase its expression level. Furthermore, the codon usage database showed it clearly provides codon usage for example E. coli, for example see the usage table showed above accessed from the linked codon usage database in website.
Thus it would have been obvious to a skilled in the art before effective date of filling of the invention from teaching, suggestions and motivation of Fechini et al. to make substitution of glutamate to aspartate (i.e. E to D) and it would have been obvious to try from finite number of possible conservative substitution in Fechini et al. SEQ ID NO:3, and such substitutions would have predictable result of maintained functions or properties that would lead to the invention of the protein of SEQ ID NO:21. Furthermore, make a codon optimization to the nucleic acid sequence taught by Fechini et al. for example to optimize to express in E. coli leading to sequence having at least 90% identity to SEQ ID NO:8 that would encode modified CODM protein. The sequence would have modification in position 259 or 260 since the Fechini et al. teaches conservative substitution of glutamate (E) to glycine (C) with possible no change in properties or function of the protein.
Alignment of Applicant’s SEQ ID NO: 3 and SEQ ID NO:*.
Query: None Query ID: lcl|Query_2847177 Length: 1083
>
Sequence ID: Query_2847179 Length: 1083
Range 1: 1 to 1083
Score:1989 bits(1077), Expect:0.0,
Identities:1081/1083(99%), Gaps:0/1083(0%), Strand: Plus/Plus
Query 1 ATGGAGACCCCAATCTTGATCAAACTTGGCAACGGGCTCTCGATCCCTAGCGTCCAAGAG 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 1 ATGGAGACCCCAATCTTGATCAAACTTGGCAACGGGCTCTCGATCCCTAGCGTCCAAGAG 60
Query 61 CTCGCCAAGTTGACCCTGGCCGAGATCCCAAGTCGGTATACATGCACAGGTGAGAGCCCA 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 61 CTCGCCAAGTTGACCCTGGCCGAGATCCCAAGTCGGTATACATGCACAGGTGAGAGCCCA 120
Query 121 CTTAACAACATCGGTGCGTCAGTAACAGACGATGAAACGGTGCCGGTCATTGATTTGCAA 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 121 CTTAACAACATCGGTGCGTCAGTAACAGACGATGAAACGGTGCCGGTCATTGATTTGCAA 180
Query 181 AACTTATTAAGTCCAGAGCCAGTAGTGGGGAAATTAGAGTTGGACAAGTTACACTCCGCT 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 181 AACTTATTAAGTCCAGAGCCAGTAGTGGGGAAATTAGAGTTGGACAAGTTACACTCCGCT 240
Query 241 TGCAAAGAGTGGGGCTTCTTTCAGCTTGTCAACCATGGCGTTGATGCCTTGTTAATGGAC 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 241 TGCAAAGAGTGGGGCTTCTTTCAGCTTGTCAACCATGGCGTTGATGCCTTGTTAATGGAC 300
Query 301 AACATTAAGAGCGAAATCAAGGGCTTTTTTAACCTGCCGATGAATGAGAAGACCAAATAC 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 301 AACATTAAGAGCGAAATCAAGGGCTTTTTTAACCTGCCGATGAATGAGAAGACCAAATAC 360
Query 361 GGTCAGCAGGACGGCGACTTTGAAGGGTTCGGTCAGCCTTATATTGAATCTGAGGATCAG 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 361 GGTCAGCAGGACGGCGACTTTGAAGGGTTCGGTCAGCCTTATATTGAATCTGAGGATCAG 420
Query 421 CGCTTGGATTGGACTGAGGTGTTCTCAATGCTCTCGCTGCCACTTCACCTGCGCAAGCCG 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 421 CGCTTGGATTGGACTGAGGTGTTCTCAATGCTCTCGCTGCCACTTCACCTGCGCAAGCCG 480
Query 481 CACCTTTTTCCAGAACTTCCACTTCCGTTTCGCGAGACCCTGGAGTCGTACTTGAGCAAG 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 481 CACCTTTTTCCAGAACTTCCACTTCCGTTTCGCGAGACCCTGGAGTCGTACTTGAGCAAG 540
Query 541 ATGAAAAAACTGTCAACGGTGGTGTTTGAGATGTTAGAAAAGAGTTTGCAACTTGTTGAG 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 541 ATGAAAAAACTGTCAACGGTGGTGTTTGAGATGTTAGAAAAGAGTTTGCAACTTGTTGAG 600
Query 601 ATTAAAGGTATGACTGACTTGTTCGAAGACGGGCTCCAAACGATGCGCATGAATTACTAT 660
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 601 ATTAAAGGTATGACTGACTTGTTCGAAGACGGGCTCCAAACGATGCGCATGAATTACTAT 660
Query 661 CCTCCATGTCCACGGCCTGAGTTGGTATTGGGTCTTACAAGTCATAGTGACTTTTCTGGG 720
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 661 CCTCCATGTCCACGGCCTGAGTTGGTATTGGGTCTTACAAGTCATAGTGACTTTTCTGGG 720
Query 721 TTGACCATTTTACTCCAGTTAAACGAAGTGGAGGGGTTGCAGATTCGGAAGGAAGGTCGG 780
||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||
Sbjct 721 TTGACCATTTTACTCCAGTTAAACGAAGTGGAGGGGTTGCAGATTCGGAAGGAAGACCGG 780
Query 781 TGGATCAGCATCAAACCGCTTCCAGACGCCTTTATTGTCAACGTAGGTGATATTCTCGAA 840
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 781 TGGATCAGCATCAAACCGCTTCCAGACGCCTTTATTGTCAACGTAGGTGATATTCTCGAA 840
Query 841 ATTATGACCAACGGGATCTATCGTAGTGTTGAGCACCGTGCAGTCGTGAATAGTACCAAG 900
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 841 ATTATGACCAACGGGATCTATCGTAGTGTTGAGCACCGTGCAGTCGTGAATAGTACCAAG 900
Query 901 GAGCGGCTTTCCATCGCCACATTCCATGACTCTAAATTGGAATCCGAAATCGGTCCTATC 960
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 901 GAGCGGCTTTCCATCGCCACATTCCATGACTCTAAATTGGAATCCGAAATCGGTCCTATC 960
Query 961 TCTTCGTTGGTTACTCCTGAGACCCCTGCATTATTCAAGCGCGGGCGCTACGAAGACATT 1020
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 961 TCTTCGTTGGTTACTCCTGAGACCCCTGCATTATTCAAGCGCGGGCGCTACGAAGACATT 1020
Query 1021 CTCAAGGAAAACCTTTCGCGCAAACTTGATGGCAAGTCTTTCCTGGATTACATGCGCATG 1080
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Sbjct 1021 CTCAAGGAAAACCTTTCGCGCAAACTTGATGGCAAGTCTTTCCTGGATTACATGCGCATG 1080
Query 1081 TGA 1083
|||
Sbjct 1081 TGA 1083
Regarding claim 47, the isolated nucleic acid molecule would encode at least 90% identical to SEQ ID NO: 21 and would comprises the amino acid substitution E259D.
Conclusion
No claim is allowed.
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/SANTOSH SHARMA/Examiner, Art Unit 1663
/DAVID H KRUSE/Primary Examiner, Art Unit 1663
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