Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
This application is a divisional of 16/326,974, issued as US Patent No. 11,479,758, which is a 371 of PCT/EP2017/071381.
The amendment filed on December 9, 2025 has been entered.
Election/Restrictions
Applicant elected without traverse of Group II with a species election of
(A) S. cerevisiae as the genetically modified Saccharomyces, (B) caffeine synthase 1 (CCS1) from Coffea arabica (UniProKB: Q8H0D3) as the SAM dependent methyltransferase, and (C) deletion of MET17 and MET2 as the downregulated or deleted endogenous genes the reply filed on May 9, 2025.
Claims 20-26, 29-33, and 36-39 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species/invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on September 8, 2020.
Status of Claims
Claims 20-39 are pending.
Claims 20-26, 29-33, and 36-39 are withdrawn.
Claims 27-28 and 34-35 are under examination.
Response to Amendments/Arguments
Claim Rejections - 35 USC § 112
Applicant’s arguments, see page 9 of the Remarks, filed December 9, 2025, with respect to claim 35 have been fully considered and are persuasive. Claim 35 has been amended to delete the indefinite phrase “substrate precursor”. Therefore, the rejection of claim 35 under 35 U.S.C. 112(b) has been withdrawn.
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.
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.
Claims 27-28 and 34-35 is/are rejected under 35 U.S.C. 103 as being unpatentable over Jin (Metabolic engineering of Saccharomyces cerevisiae for caffeine and theobromine production. PLoS One. 2014 Aug 18;9(8):e105368 – form PTO-892), Merkamm (WO 2014/064244 – form PTO-892), and Thomas (Metabolism of sulfur amino acids in Saccharomyces cerevisiae. Microbiol Mol Biol Rev. 1997 Dec;61(4):503-32. – form PTO-892).
Regarding claim 27, Jin discloses a method of producing caffeine in a genetically modified S. cerevisiae comprising a SAM-dependent Coffea arabica methyltransferase, CaXMT1 and TCS1 (abstract, page 1, Figure 1, page 4, right column, and page 7 “Co-expression of CaXMT1 and TCS1 lead to caffeine biosynthesis in yeast”.).
Regarding claim 34, Jin discloses a culture comprising growing yeast, which reads on a composition comprising a plurality of cells (page 7 “Co-expression of CaXMT1 and TCS1 lead to caffeine biosynthesis in yeast”).
Regarding claim 35, Jin discloses a culture medium comprising glucose, a carbon source, and XR, the substrate for CaXMT1 (page 7 “Co-expression of CaXMT1 and TCS1 lead to caffeine biosynthesis in yeast”).
Jin does not disclose deleting MET2 and MET17.
Merkamm discloses a genetically modified S. cerevisiae strain which has an auxotroph phenotype for methionine (page 3, 1st paragraph).
Regarding claims 27 (c) and claim 28, Merkamm discloses that the genetically modified methionine auxotroph Saccharomyces cerevisiae comprises a deletion of MET2 (L-homoserine O-acetyltransferase) and MET25 (homocysteine synthase), wherein methionine production is increased (see page 5, 1st paragraph and page 21, 4th full paragraph). MET25 is also known as MET17 or O-acetyl-homoserine sulfhydrylase, see Thomas, Table 1.
Regarding claim 34, Merkamm discloses a composition comprising cells with high cell density, which reads on a composition comprising a plurality of cells (page 23, 2nd paragraph).
Therefore, in combing the teachings of the above references, it would have been obvious to one having ordinary skill in the art before the time the claimed invention was effectively filed to further modify the genetically modified S. cerevisiae of Jin by deleting MET2 and MET7 resulting in a strain having methionine auxotrophy and culturing said genetically modified S. cerevisiae in a medium comprising glucose, XR, and methionine to produce caffeine. One having ordinary skill in the art would have been motivated to so in order to provide a selection system for the genetically modified S. cerevisiae comprising CaXMT1 and TCS1. One of ordinary skill in the art would have had a reasonable expectation of success Jin discloses a genetically modified S. cerevisiae comprising a SAM-dependent methyltransferase and Merkamm discloses a genetically modified S. cerevisiae comprising deletions of MET2 and MET7 having methionine auxotrophy.
Therefore, the above references render claims 27-28 and 34-35 prima facie obvious.
Applicant has addressed all the 103 rejections together. See below for the response to Applicant’s arguments.
Claims 27-28 and 34 is/are rejected under 35 U.S.C. 103 as being unpatentable over Jin (Metabolic engineering of Saccharomyces cerevisiae for caffeine and theobromine production. PLoS One. 2014 Aug 18;9(8):e105368 – form PTO-892), Merkamm (WO 2014/064244 – form PTO-892), and Thomas (Metabolism of sulfur amino acids in Saccharomyces cerevisiae. Microbiol Mol Biol Rev. 1997 Dec;61(4):503-32. – form PTO-892).
Regarding claim 27, Jin discloses a method of producing caffeine in a genetically modified S. cerevisiae comprising a SAM-dependent Coffea arabica methyltransferase, CaXMT1 and TCS1 (abstract, page 1, Figure 1, page 4, right column, and page 7 “Co-expression of CaXMT1 and TCS1 lead to caffeine biosynthesis in yeast”.).
Regarding claim 34, Jin discloses a culture comprising growing yeast, which reads on a composition comprising a plurality of cells (page 7 “Co-expression of CaXMT1 and TCS1 lead to caffeine biosynthesis in yeast”).
Jin discloses that three SAM are required to produce caffeine (Figure 1). Jin does not disclose deleting MET2 and MET17.
Merkamm discloses a method of improving methionine synthesis in Saccharomyces cerevisiae by converting O-phospho-L-homoserine and methanediol to L-methionine, which allows for better yields of methionine produced from acetylate homoserines (page 2). Merkamm discloses that the genetically modified Saccharomyces cerevisiae can be used to produce SAM from methionine (page 7). Merkamm discloses using S. cerevisiae strain which as an auxotroph phenotype for methionine (page 3, 1st paragraph).
Regarding claims 27 (c) and claim 28, Merkamm discloses that the genetically modified methionine auxotroph Saccharomyces cerevisiae comprises a deletion of MET2 (L-homoserine O-acetyltransferase) and MET25 (homocysteine synthase), wherein methionine production is increased (see page 5, 1st paragraph and page 21, 4th full paragraph). MET25 is also known as MET17 or O-acetyl-homoserine sulfhydrylase, see Thomas, Table 1.
Regarding claim 32, Merkamm discloses a composition comprising cells with high cell density, which reads on a composition comprising a plurality of cells (page 23, 2nd paragraph).
Therefore, in combing the teachings of the above references, it would have been obvious to one having ordinary skill in the art before the time the claimed invention was effectively filed to further modify the genetically modified S. cerevisiae of Jin by deleting MET2 and MET7 and express the enzyme that converts O-phospho-L-homoserine and methanediol to L-methionine. One having ordinary skill in the art would have been motivated to so in order to increase the availability of SAM via methionine because SAM is required by CaXMT1 and TCS1 for their enzymatic activity. One of ordinary skill in the art would have had a reasonable expectation of success Jin discloses a genetically modified S. cerevisiae comprising a SAM-dependent methyltransferase and Merkamm discloses a genetically modified S. cerevisiae comprising deletions of MET2 and MET7 and expression of an enzyme that converts O-phospho-L-homoserine and methanediol to L-methionine, wherein methionine synthesis is increased and thereby increasing SAM.
Therefore, the above references render claims 27-28 and 34-35 prima facie obvious.
Applicant has addressed all the 103 rejections together. See below for the response to Applicant’s arguments.
Claim(s) 27 (regarding the elected species) is/are rejected under 35 U.S.C. 103 as being unpatentable over Jin (Metabolic engineering of Saccharomyces cerevisiae for caffeine and theobromine production. PLoS One. 2014 Aug 18;9(8):e105368 – form PTO-892), Merkamm (WO 2014/064244 – form PTO-892), and Thomas (Metabolism of sulfur amino acids in Saccharomyces cerevisiae. Microbiol Mol Biol Rev. 1997 Dec;61(4):503-32. – form PTO-892) as applied to claims 27-28 and 34-35 above, and further in view of Mizuno (Isolation of a new dual-functional caffeine synthase gene encoding an enzyme for the conversion of 7-methylxanthine to caffeine from coffee (Coffea arabica L.). FEBS Lett. 2003 Jan 16;534(1-3):75-81 – form PTO-892) and Q8H0D3 (Caffeine synthase 1. UnitProKB/Swiss-Prot Database. October 1, 2014 – form PTO-892).
The combined teachings of Jin, Merkamm, and Thomas do not disclose a genetically modified S. cerevisiae comprising a Coffea arabica caffeine synthase having accession Q8H0D3.
However, Jin references Mizuno for the disclosure of a caffeine synthase (CCS1) having accession Q8H0D3 (page 1).
Mizuno discloses that the gene encoding the Coffea arabica methyltransferase (caffeine synthase) has EMBL accession AB08614 and is a SAM-dependent methyltransferase (abstract, page 75, and Figure 1). The encoded methyltransferase has UniProtKB/Swiss-Prot Database accession Q8H0D3, see Q8H0D3. Mizuno discloses that CCS1 has dual methylation activity like tea TCS1 (abstract).
Therefore, in combining the above references, it would have been obvious to one having ordinary skill in the art before the time the claimed invention was effectively filed to replace the TCS1 with the Coffea arabica CCS1 having accession Q8H0D because one of ordinary skill in the art would have been able to carry out such a substitution, and the results were reasonably predictable. The rationale to support a conclusion that the claims would have been obvious is that the substitution of one known element for another yields predictable results (SAM-dependent methylation) to one of ordinary skill in the art since Mizuno discloses that CCS1 has dual methylation activity like TCS1. See MPEP 2143. One of ordinary skill in the art would have had a reasonable expectation of success since Jin discloses a genetically modified S. cerevisiae comprising CaXMT1 and TCS1, Merkamm discloses a genetically modified S. cerevisiae comprising deletions of MET2 and MET7, and Mizuno discloses that CCS1 has dual methylation activity like TCS1.
Therefore, the above references render claims 27-28 and 34-35 prima facie obvious.
Applicant has addressed all the 103 rejections together. See below for the response to Applicant’s arguments.
Claim(s) 27 (regarding the elected species) is/are rejected under 35 U.S.C. 103 as being unpatentable over Jin (Metabolic engineering of Saccharomyces cerevisiae for caffeine and theobromine production. PLoS One. 2014 Aug 18;9(8):e105368 – form PTO-892), Merkamm (WO 2014/064244 – form PTO-892), and Thomas (Metabolism of sulfur amino acids in Saccharomyces cerevisiae. Microbiol Mol Biol Rev. 1997 Dec;61(4):503-32. – form PTO-892) as applied to claims 27-28 and 34 above, and further in view of Mizuno (Isolation of a new dual-functional caffeine synthase gene encoding an enzyme for the conversion of 7-methylxanthine to caffeine from coffee (Coffea arabica L.). FEBS Lett. 2003 Jan 16;534(1-3):75-81 – form PTO-892) and Q8H0D3 (Caffeine synthase 1. UnitProKB/Swiss-Prot Database. October 1, 2014 – form PTO-892).
The combined teachings of Jin, Merkamm, and Thomas do not disclose a genetically modified S. cerevisiae comprising a Coffea arabica caffeine synthase having accession Q8H0D3.
However, Jin references Mizuno for the disclosure of a caffeine synthase (CCS1) having accession Q8H0D3 (page 1).
Mizuno discloses that the gene encoding the Coffea arabica methyltransferase (caffeine synthase) has EMBL accession AB08614 and is a SAM-dependent methyltransferase (abstract, page 75, and Figure 1). The encoded methyltransferase has UniProtKB/Swiss-Prot Database accession Q8H0D3, see Q8H0D3. Mizuno discloses that CCS1 has dual methylation activity like tea TCS1 (abstract).
Therefore, in combining the above references, it would have been obvious to one having ordinary skill in the art before the time the claimed invention was effectively filed to replace the TCS1 with the Coffea arabica CCS1 having accession Q8H0D because one of ordinary skill in the art would have been able to carry out such a substitution, and the results were reasonably predictable. The rationale to support a conclusion that the claims would have been obvious is that the substitution of one known element for another yields predictable results (SAM-dependent methylation) to one of ordinary skill in the art since Mizuno discloses that CCS1 has dual methylation activity like TCS1. See MPEP 2143. One of ordinary skill in the art would have had a reasonable expectation of success since Jin discloses a genetically modified S. cerevisiae comprising CaXMT1 and TCS1, Merkamm discloses a genetically modified S. cerevisiae comprising deletions of MET2 and MET7, and Mizuno discloses that CCS1 has dual methylation activity like TCS1.
Therefore, the above references render claims 27-28 and 34 prima facie obvious.
Applicant has addressed all the 103 rejections together. See below for the response to Applicant’s arguments.
Response to Arguments
Applicant's arguments filed December 9, 2025 have been fully considered but they are not persuasive.
Applicant argues that the claims are not obvious over the cited references because Merkamm’s teaching (S. cerevisiae strain which has an auxotroph phenotype for methionine) is in contrast to Applicant’s invention because Applicant’s invention is directed to a selection system is designed for an assay where selection pressure is implemented by cultivation of a homocysteine auxotroph in a culture medium supplemented with methionine and Applicant’s selection system is not designed for production of methionine.
This is not found persuasive. In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., homocysteine auxotroph in a culture medium supplemented with methionine or not producing methionine) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Applicant argues that for the skilled person seeking to improve the production of caffeine in S. cerevisiae, there is no motivation to modify the production cell of Jin to a methionine auxotroph which then relies on methionine supplementation in the cultivation medium to function.
This is not found persuasive. The first 103 rejection at pages 5-7 does not specify improving the production of caffeine in S. cerevisiae. One having ordinary skill in the art would have been motivated to modify the genetically modified S. cerevisiae of Jin by deleting MET2 and MET7 resulting in a strain having methionine auxotrophy to provide a selection system for the genetically modified S. cerevisiae comprising CaXMT1 and TCS1.
Further, for the second 103 rejection at pages 7-9, one having ordinary skill in the art would have been motivated to modify the S. cerevisiae of Jin by deleting the MET2 and MET7 and express the enzyme that converts O-phospho-L-homoserine and methanediol to L-methionine in order to increase the availability of SAM via methionine because SAM is required by CaXMT1 and TCS1 for their enzymatic activity. The resulting S. cerevisiae, comprising an enzyme that converts O-phospho-L-homoserine and methanediol to L-methionine and deletion of MET2 and MET7, is a methionine auxotroph. In the presence of O-phospho-L-homoserine and methanediol, methionine is produced due to expression of the enzyme that converts O-phospho-L-homoserine.
Hence the rejections have been maintained.
Conclusion
Claims 20-39 are pending.
Claims 20-26, 29-33, and 36-39 are withdrawn.
Claims 27-28 and 34-35 are rejected.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to YONG D PAK whose telephone number is (571)272-0935. The examiner can normally be reached M-Th: 5:30 am - 3:30 pm.
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/YONG D PAK/Primary Examiner, Art Unit 1652