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 .
Application Status
This action is written in response to applicant’s correspondence received February 05, 2026. Claims 1, 5-7, 12-17, 19-23 and 27-30 were amended in the claim set filed February 05, 2026. Claim 18 is cancelled. Claims 5, 28-30 are withdrawn from nonelected invention. Accordingly, claims 1, 7, 12-17,19-23 and 27 are currently pending and under consideration.
Any rejection or objection not reiterated herein has been overcome by amendment. Applicant’s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Election/Restrictions
Claims 5, and 28-30 were withdrawn from prosecution as being drawn to non-elected subject matter in response to Applicant’s correspondence received on May 14, 2025; however, claims 5 and 28-30 do not have the proper status identifier of withdrawn as required by 37 CFR 1.121.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. Claims 1, 6, 7, 12-23, and 27 for foreign priority to EPO 20172078.6, filed on 29 Apr 2020, is acknowledged.
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.
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 1, 6, 7, 12-16, and 18-23 are rejected under 35 U.S.C. 103 as being unpatentable over Vaillancourt (Appl. Environ. Microbiol. (2004), 70, 8, 4596-4603; DOI: 10.1128/AEM.70.8.4596–4603.2004.) in view of de Vin (IDS Received Date: 05/14/2025; Cite No. 1; Appl. Environ. Microbiol. (2005), 71, 7, 3659-3667; DOI:10.1128/AEM.71.7.3659–3667.2005).
For purposes of compact prosecution, the analysis below addresses dependent claims of claim 1 together as they are directed to a method for generating a S. thermophilus strain and recite corresponding subject matter of the strain obtained by this method. The discussion is followed by analysis of dependent claims of claim 13, which are directed to a S. thermophilus strain.
Regarding claim 1, Vaillancourt teaches a method for generating a S. thermophilus strain capable of utilizing galactose for growth via complementation or recombination with galK gene from S. salivarius. Vaillancourt further teaches the process involves transforming plasmid pTRJL2TK carrying the entire S. salivarius galK gene to S. thermophilus SMQ-301 (pg. 4597, under section Construction of a galactose-positive recombinant strain of S. thermophilus). Vaillancourt further teaches that the replacement of a defective galK in SMQ-301 with a functional galK from another Streptococcus species with improved galactokinase activity in SMQ-301 (pg. 4601, left column, first paragraph).
Vaillancourt does not teach introducing a nucleic acid sequence comprising SEQ ID NO:2 or its derivative.
However, de Vin teaches the S. thermophilus EU20 (IMDOST40) strain “did not excrete galactose during growth on lactose and consumed the glucose and galactose moieties of lactose simultaneously” (pg. 3662, right column, second paragraph). de Vin teaches that EU20 carries a 141 bp long galR-galK intergenic region, which is the same as the instant SEQ ID NO: 2, with one key nucleotide substitution (T to G) in its Shine-Dalgarno sequence (pg. 3664, left-column, first paragraph). de Vin further teaches that this nucleotide substitution yielded a frameshift affecting the amino acid sequence of GalR after position 58 (pg. 3664, left-column, second paragraph), and EU20 had 11 amino acid differences in GalK and 13 amino acid differences in GalT (Table 5). Therefore, this nucleotide mutation correlates with the increased galactose-consumption rate and ability to consume the glucose and galactose moieties of lactose simultaneously (pg. 3662, right-column, second paragraph). It is noted that de Vin discloses the advantage of consuming galactose can be useful if applied in dairy products because “galactose accumulation in the milk or curd can cause product defects, such as growth of undesirable heterofermentative lactic acid bacteria and cheese browning during baking” (pg. 3660, left column, second paragraph).
Thus, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have modified Vaillancourt’s S. thermophilus Gal- strain with a functional galR-galK intergenic region (e.g., SEQ ID NO: 2) as taught by de Vin because it would have merely amounted to a simple substitution of prior art elements according to known methods to yield predictable results. One would have been motivated to have done so for the advantage of increasing galactose-consumption rate, especially in applications involving dairy products to prevent undesirable accumulation of galactose in milk. One would have had a reasonable expectation of success in doing so because Vaillancourt teaches a method of generating recombinant S. thermophilus strain by replacement of native and nonfunctional gal operon with functional operon, selection of Gal+ cells, and measurement of galactose consumption.
Regarding claim 6, the obviousness of improving SMQ-301 Gal- cells (VmaxLach less than 50%) to Gal+ (VmaxLach at least 50%) by replacing the defective intergenic galR-galK region with SEQ ID NO: 2 of de Vin is discussed above as applied to claim 1.
Regarding claim 7, an ABSS search indicated that SEQ ID NOs: 3 and 4 align 100% with the EU20 Lelior gene cluster (IDS Received Date: 05/14/2025; Cite No. 6; NCBI Accession Number: AY704367; Version: AY704367.1; Pub Date: 08 Jul 2005). SEQ ID NO: 2 aligns base pairs 1085-1225; SEQ ID NO: 3 aligns to base pairs 891-1225; SEQ ID NO: 4, which encodes for transcriptional activator of the gal operon, aligns to base pairs 90-1225. It is noted that SEQ ID NO: 4 comprises SEQ ID NO:3, which then comprises SEQ ID NO:2. In addition, the gal operon of EU20 is annotated to be immediately downstream from base pairs 1226-4924. Therefore, it evident that SEQ ID NO:4 serves as the gal promoter. Vaillancourt teaches (pg. 4597, under section Construction of a galactose-positive recombinant strain of S. thermophilus) the DNA fragment (1,270 bp) used for recombination comprised of “the entire galK gene with its own ribosome binding site, as well as the promoter region of the gal operon”. Therefore, the obviousness of improving SMQ-301 Gal- cells to Gal+ cells by replacing the defective gal promoter with a functional promoter of de Vin including additional features encoded by SEQ ID NOs 3 and 4 as discussed above in claim 1 also applies here.
Regarding claim 12, it is recited that the strain obtained is not the S. thermophilus DSM32823 strain deposited at DSMZ on May 29th, 2018. The specification teaches that EU20 was originally part of the Rhodia Food Collection and later deposited as DSM32823 by DuPont Nutrition Biosciences ApS (pg. 2, lines 31-36). The recombination technique involves introducing SEQ ID NO:2 (a 141 bp fragment) of the EU20 gal promoter into a different host strain SMQ-301, which would not render the resulting recombinant strain identical to EU20 as a whole. Accordingly, the resulting strain would not inherently be EU20 since the replacement of a promoter fragment does not convert the whole genome of SMQ-301 into EU20.
Regarding claim 19, the obviousness to modify Vaillancourt’s S. thermophilus Gal- strain to incorporate SEQ ID NO: 2 is discussed above as applied to claim 1. Although Vaillancourt and de Vin quantify galactose utilization using different measuring units than percentage of consumed galactose at the end of lactose consumption (VoLach), the difference in measurement units merely reflects a quantitative expression of an inherent characteristic of the recombinant strain resulting from the use of SEQ ID NO:2. The specification disclosed S thermophilus strains “were grown in conditions inspired from de Vin” (pg. 59, lines 33), and de Vin teaches that “during growth on lactose, there was no galactose accumulation detected in the medium for strain IMPOST40” (EU20) (pg. 3666, left-column, first sentence of second paragraph). This positively teaches that galactose in the media was consumed by EU20. Accordingly, one of ordinary skill in the art would have reasonably expected the substitution of the defective gal promoter of SMQ-301 with SEQ ID NO:2 and growing the recombinant cells under the same conditions would inherently yield a strain exhibiting the same known functional characteristics, including a VoLach percentage of at least 70%. Thus, the teachings of Vaillancourt and de Vin meets the claim limitation wherein the galactose utilization profile is further defined by a percentage of VoLach of at least 70%.
Regarding claims 20 and 21, the obviousness of inheriting functional properties VoLach and VmaxLach is discussed above as applied to claim 19. In addition, it would be obvious to one of ordinary skill in the art that a recombinant strain possessing SEQ ID NO: 2, which inherently exhibits each of the individual VmaxLach and VoLach characteristics would likewise exhibit both properties simultaneously.
Regarding claim 22, de Vin teaches additional seven strains besides EU20 displaying high galactose-utilization profiles and consuming all of the excreted galactose within 8.5h of fermentation (pg. 3662, right-column, second paragraph). de Vin further teaches that sequence alignment of these seven intergenic regions with SEQ ID NO: 2 of EU20 showed eight different nucleotide sequences (referred as NS1 to NS8) were found in the intergenic region: five strains contained two different nucleotide sequences (NS2), one strain was NS1, one strain was NS6, and EU20 was NS3 (Fig 2, Fig. 3, Table 4). It would be obvious to one of ordinary skill in the art to improve SMQ301 Gal- strain with one of these seven SEQ ID NO: 2 derivatives. The obviousness as discussed above in claim 1 applies here.
Regarding claim 23, the rationale is discussed above in claim 12 where recombination of a promoter fragment from EU20 into a different host strain SMQ301 would not inherently be EU20, which satisfies with the structural limitation “wherein genome sequence of the strain has an identity which is at most 99.98% to the genome sequence of the DSM32823 strain” (EU20).
Regarding claim 13, the obviousness of a recombinant S. thermophilus strain comprising the recited structural limitations is discussed above as applied to claims 1 and 12.
Regarding claim 14, the obviousness of a recombinant S. thermophilus strain with its gal-lac gene cluster selected from the group consisting of SEQ ID NO:3 and SEQ ID NO: 4 is discusses above as applied to claim 7.
Regarding claim 15 and 16, an ABSS search indicated that SEQ ID NO: 2 is encoded by SEQ ID NOs: 5 and 6 in the EU20 Leloir gene cluster. SEQ ID NO: 5 aligns to base pairs 478-1923 encoding part of the gal operon. SEQ ID NO: 6 aligns to base pairs 90-6040 which encodes for i) the gal operon including the gal promoter genes that code for enzymes of the Leloir pathway, namely, galactokinase (galK), galactose-1-phosphate uridylyltransferase (galT), and UDP-glucose 4-epimerase (galE) and ii) galactose mutarotase (galM). Therefore, it would be obvious to one of ordinary skill in the art to generate a recombinant S. thermophilus strain wherein its gal-lac gene cluster comprises SEQ ID NOs: 5 and 6, and such obviousness is discussed above and as applied to claims 14, 7 and 1.
Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over Vaillancourt (Appl. Environ. Microbiol. (2004), 70, 8, 4596-4603; DOI: 10.1128/AEM.70.8.4596–4603.2004.) in view of de Vin (IDS Received Date: 05/14/2025; Cite No. 1; Appl. Environ. Microbiol. (2005), 71, 7, 3659-3667; DOI:10.1128/AEM.71.7.3659–3667.2005) as applied to claim 1 and 13, and further in view of Alexandraki (Comparative Genomics of Streptococcus thermophilus Support Important Traits Concerning the Evolution, Biology and Technological Properties of the Species, Front. Microbiol. (2019), 10, 1-24; DOI: 10.3389/fmicb.2019.02916).
Regarding claim 17, as previously discussed in claim 1, Vaillancourt teaches a recombinant S. thermophilus Gal+ strain in which its defective lac promoter was replaced a functional heterologous gal promoter.
However, neither Vaillancourt or de Vin teach wherein the gal-lac gene cluster sequence consists of SEQ ID NO: 1 or derivative.
An ABSS search alignment shows that SEQ ID NO: 1 aligns 100% to base pairs 1454790-1465831 of S. thermophilus NCTC12958 strain genomic sequences (NCBI Accession Number: LS483339.1; Pub Date: 17 Jun 2018), which encodes for genes in the lac and gal operon including lacZ, lacS, galM, galE, galT, galK, and galR. In addition, Alexandraki discloses NCTC12958 “seem to be able to catabolize galactose, as they own the relevant G to A mutation in the position -9 of the -10-box related Gal1+ phenotype” (pg. 8, right-column, first paragraph), while noting that experimental verification was anticipated.
de Vin confirms that seven S. thermophilus, including EU20 carrying SEQ ID NO:2, naturally has “only one difference in the -10 region of the gal promoter” (pg. 3663, right-column), and teaches that this nucleotide mutation correlates with the increased galactose-consumption rate and ability to consume the glucose and galactose moieties of lactose simultaneously (pg. 3662, right-column, second paragraph). de Vin further teaches that this nucleotide substitution yielded a frameshift affecting the amino acid sequence of GalR after position 58 (pg. 3664, left-column, second paragraph), and EU20 had 11 amino acid differences in GalK and 13 amino acid differences in GalT (Table 5).
Thus, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have modified Vaillancourt’s S. thermophilus Gal- strain with a functional galR-galK intergenic region (e.g., SEQ ID NO: 1) because it would have merely amounted to a simple substitution of prior art elements according to known methods to yield predictable results. One would have been motivated to have done so for the advantage of increasing galactose-consumption rate, especially in applications involving dairy products to prevent undesirable accumulation of galactose in milk. One would have had a reasonable expectation of success in doing so because i) Vaillancourt teaches a method of generating recombinant S. thermophilus strain by replacement of native and nonfunctional gal operon with functional operon, selection of Gal+ cells, and measurement of galactose consumption, and ii) Alexandrakis teaches relevant mutation in the -10 box of SEQ ID NO: 1, in view of de Vin’s confirmation that single nucleotide substitution confers galactose utilization.
Claim 27 is rejected under 35 U.S.C. 103 as being unpatentable over Vaillancourt in view of van den Bogaard (IDS Received Date: 05/14/2025; Cite No. 4; J. Bacteriol. (2001), 183, 4, 1184-1194; DOI: 10.1128/JB.183.4.1184–1194.2001).
Regarding claim 27, Vaillancourt teaches “recombinant Gal+ strain grew and produced acid more rapidly than the Gal-strain during growth in milk and under time-temperature conditions” (Abstract). Vaillancourt also teaches that derivation of recombinant “food grade equivalent strains may provide an advantage as starter cultures for manufacture of mozzarella cheese and other fermented dairy foods” (pg. 4602, right-column, last paragraph).
Vaillancourt does not teach culturing the recombinant S. thermophilus strain with a bacterial strain from the genus of Lactococcus or Lactobacillus.
However, van den Bogaard teaches that S. thermophilus and Lactobacillus bulgaricus maintain in symbiotic association in co-culture for the production of yogurt (pg. 10, Introduction, first paragraph).
Thus, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have modified Vaillancourt’s Gal+ strain to include a bacterial strain from the genus of Lactococcus or Lactobacillus in culture because it would have merely amounted to a simple combination of prior art elements according to known methods to yield predictable results. One would have been motivated to have done so for the advantage of their complementary metabolic functions. One would have had a reasonable expectation of success in doing so because both microorganisms are known to utilize lactose (S. thermophilus also consumes galactose) and to coexist symbiotically.
Subject Matter Eligibility
Regarding claims 12 and 13, it is noted that the claims require a S. thermophilus strain comprising the sequences as defined in SEQ ID NO:2 or a SEQ ID NO: 2 derivative. The only naturally occurring strain comprising SEQ IS NO:2 is EU20, which is the same DSM32823 strain that is excluded by the claims (see specification pg 2, lines 31-36). Therefore, the current claims are directed to a non-naturally occurring strain comprising SEQ ID NO: 2.
Response to the Arguments
Applicant’s remarks received on February 05, 2026, have been fully considered but they are not persuasive for at least the following reasons.
In response to applicant's arguments on pages 7 and 8 of the remarks that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., “high quantity of galactose in final products is not desired” and “to prevent galactose accumulation during lactose metabolism” 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). Claims recite the limitation of “a high galactose utilization profile” which the specification defines as “a percentage of consumed galactose at the maximum speed of lactose consumption (Vmaxlach) as determined by assay I, by a percentage of consumed galactose at the end of lactose consumption (Volach) as determined by assay I which is at least 70%. As explained in previous Office Action, “under the broadest reasonable interpretation, assay I is a method to calculate consumed galactose and lactose, which does not impart a structural distinction to the method of claim 1. It would have been an obvious routine optimization to employ assay I or its equivalents that inherently measure the same property as such calculation strategies are well known in characterizing metabolic efficiency” (pg. 4), and de Vin teaches IMDOST40 strain, carrying the instantly recited SEQ ID NO: 2 galR-galK intergenic region, did not excrete galactose during growth on lactose (pg. 3662, right-column, second paragraph). Thus, the teachings of the cited references meet the claim limitations.
In response to applicant’s arguments on pages 8 and 9 of the remarks that “high utilization phenotypes never occur in Vaillancourt” and “de Vin does not disclose the introduction of genes into other than IMDOST40”, as well as on page 12 of the remarks that “Alexandraki does not teach or suggest a Streptococcus thermophilus strain…introducing…the sequence set forth by SEQ ID NO: 2…”,
arguing against references individually is discussed in MPEP § 2145(IV). Applicant's reply fails to address the combined teaching of the applied references and instead only argues that each reference individually does not teach all of the claim limitations. One cannot show nonobviousness by attacking reference individually where the rejections are based on combinations of references. All of the limitations of the claim are disclosed in either Vaillancourt or de Vin, and the combination of the references renders the claimed invention obvious. As explained in section 35 U.S.C. 103 above, the only different between claim 1 and the teachings of Vaillancourt is the use of SEQ ID NO: 2. de Vin teaches SEQ ID NO: 2 correlates with increased galactose-consumption rate in S. thermophilus strain. Thus, substituting the defective gal operon in S. thermophilus Gal- strain of Vaillancourt with the functional gal operon taught by de Vin would have been a predictable use of prior art elements according to their established functions to yield predicted results.
In response to applicant’s arguments on pages 8 and 9 of the remarks that “the inventors have surprisingly shown the galactose metabolism of Streptococcus thermophilus can be advantageously changed by modifying specific parts of the gal-lac gene cluster of these strains” and “unexpected results of stains that are capable of preventing galactose accumulation during lactose metabolism are described in detail in Examples 1-7.” MPEP § 716.02(B).II states “[A]ppellants have the burden of explaining the data in any declaration they proffer as evidence of non-obviousness” Ex parte Ishizaka, 24 USPQ2d 1621, 1624 (Bd/ Pat. App. & Inter. 1992). Applicant failed to particularly point out the unexpected results. Examples 1-7, particularly Tables 2-4, teach strain DSM32823, which is IMDOST40 disclosed by de Vin encoding SEQ ID NO: 2, exhibits qualifying characteristics including Vmaxlach and Volach to be considered as a strain with “a high galactose utilization profile”, and recombinant strains of DSM33036 by replacement of gal operon with gal-lac gene cluster comprising SEQ ID NO: 2 exhibited “an improved ability to consume galactose from lactose” (pg. 69, line 17) in comparison to wild-type DSM33036 lacking SEQ ID NO: 2. Such enhancement is consistent with de Vin’s teachings where IMDOST40 “did not excrete galactose during growth on lactose and consumed the glucose and galactose moieties of lactose simultaneously” (pg. 3662, right-column, second paragraph). A person of ordinary skill in the art would have reasonably expected a similar improvement when employing this known functional gal operon.
In response to applicant’s arguments on page 9 that “one of skill in the art would not have taken the teachings of Vaillancourt and sought to modify them with the teachings of de Vin to arrive at a fundamentally different phenotype”, and on pages 9 and 12 that “Vaillancourt teaches away from the possibility of galK complementation to produce simultaneous galactose/glucose utilization”, as discussed above in 35 U.S.C. 103, Vaillancourt teaches galK complementation enabled Gal- SMQ-301 strain “to grow on galactose resulted from the expression of S. salivarius galK (Abstract). Further, de Vin teaches seven strains “consumed all of the excreted galactose” and IMDOST40 “did not excrete galactose during growth on lactose and consumed the glucose and galactose moieties of lactose simultaneously (i.e., a high galactose utilization profile) (pg. 3662, right-column, second paragraph). Thus, one ordinary skill in the art would have taken the teachings of Vaillancourt and sought to modify them with teachings of de Vin because de Vin teaches S. thermophilus strains of fundamentally same phenotype. Further, this modification would have also been obvious because known work in one field of endeavor (de Vin S. thermophilus Gal+ strains comprising functional gal operons) may prompt variations of it for use in the same field (Vaillancourt S. thermophilus strains) based on design incentives if the variations (strains of the same genus and species behaving similarly when introducing genes) are predictable to one of ordinary skill in the art.
Applicant’s response is not sufficient to rebut the prima facie case of obviousness, and the combination of known elements yielded expected results, strengthening the prima facie case of obviousness. Accordingly, Applicant’s arguments have been considered but are not persuasive, and the rejection under 35 U.S.C. 103 is maintained.
Conclusion
No claims are allowed.
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.
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QIWEN SU-TOBON
Examiner
Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636