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 .
Amendments Received
Amendments to the claims were received and entered on 07/31/2025.
Status of Claims
Claims 7-11, 13-15, 17, and 20 are cancelled.
Claims 1-6, 12, 16, 18-19, and 21-22 are currently pending.
Claims 1-6, 18 and 21 are under consideration, as claims 12, 16, 19, and 22 are withdrawn.
Priority
The present application claims status as a 371 (National Stage) of PCT/EP2021/051479 filed on January 22, 2021 and claims priority to Kingdom of Denmark application no. DKPA202000087 filed on January 23, 2020. Acknowledgment is made of applicant’s claim for foreign priority and papers submitted under 35 U.S.C. 119 (a)-(d). The present application and all claims are being examined with an effective filing date of 01/23/2020.
Withdrawn Objections
In view of Applicant’s cancellation of claim 17, the objection to claim 17 is now moot, and is hereby withdrawn.
In view of Applicant’s amendments, wherein references to websites have been limited to the top-level domain name without any prefix, objection to the Specification is hereby withdrawn.
Withdrawn Rejections
In view of Applicant’s cancellation of claims 7, 15, 17, and 20, all rejections of claims 7, 15, 17, and 20 are now moot, and are hereby withdrawn.
In view of Applicant’s amendments, rejections of claims 1, 3-4, 6, and 18 under 35 USC § 102 by Stefan, are hereby withdrawn.
In view of Applicant’s amendments, double patenting rejections of claims 1, 3, 5-6, and 21 over copending Application No. 18561170, are hereby withdrawn.
The provisional non-statutory double patenting rejection over claims 25-26 and 33-41 of copending application 18/177,070 is hereby withdrawn because the ‘070 application issued as U.S. Patent No. 12,188,056 and is no longer copending.
Maintained/Modified Rejections Necessitated by Amendment
Claim Rejections - 35 USC § 112(a)
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 1-6, 18 and 21 are 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.
It is noted that MPEP 2111.01 states that ''[d]uring examination, the claims must be interpreted as broadly as their terms reasonably allow.'' Regarding claims 1, 3-6, 18, and 21, the limitation “a functional homologue thereof which amino acid sequence is more than 97% identical to SEQ ID NO: 1” has been broadly interpreted to encompass a genus of nucleotide sequences that encode a genus of proteins having at least 97% sequence identity with instant SEQ ID NO: 1, and according to the instant specification, “has a function that is beneficial to achieve at least one advantageous effect of the invention” (pg. 7, line 33). Therefore, claim 1 encompasses a genetically modified cell capable of producing a genus of HMOs wherein said cell comprises a heterologous nucleic acid sequence encoding the polypeptide set forth in SEQ ID NO: 1; or a genus of functional homologues thereof with at least 97% sequence identity to instant SEQ ID NO: 1 and having at least one unspecified advantageous beneficial function. Claim 2 recites the genetically modified cell of claim 1, wherein the functional homologue has at least 98% sequence identity to SEQ ID NO:1. Therefore claim 2 encompasses the cell of claim, wherein a genus of functional homologues is at least 98% identical to instant SEQ ID NO: 1 and having at least one unspecified advantageous beneficial function.
MPEP 2163 I. states that to “satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention.
MPEP 2163. II.A.3.(a) states that “Possession may be shown in many ways. For example, possession may be shown by describing an actual reduction to practice of the claimed invention. Possession may also be shown by a clear depiction of the invention in detailed drawings or in structural chemical formulas which permit a person skilled in the art to clearly recognize that inventor had possession of the claimed invention. An adequate written description of the invention may be shown by any description of sufficient, relevant, identifying characteristics so long as a person skilled in the art would recognize that the inventor had possession of the claimed invention.
According to MPEP 2163.II.A.3.(a).ii), “Satisfactory disclosure of a ‘representative number’ depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus…Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are ‘representative of the full variety or scope of the genus,’ or by the establishment of ‘a reasonable structure-function correlation.’"
The recitation of “functional homologue” fails to provide a sufficient description of the genus of proteins as it doesn’t even clearly describe the functional features of the genus without providing any definition of the structural features of the species within the genus. Given that SEQ ID NO: 1 encodes an MFS protein that transports and increases production of HMOs, the genus of functional homologues with at least 97% or 98% sequence identity should at the very least retain those properties, however the specification does not specifically define any of the species that fall within the genus. The specification does not define any structural features commonly possessed by members of the genus that distinguish them from others. One skilled in the art therefore cannot, as one can do with a fully described genus, visualize or recognize the identity of the members of the genus.
Further, with the aid of a computer, one of skill in the art could identify all of the proteins or polypeptides having 97% or more sequence identity with SEQ ID NO: 1. However, there is no teaching regarding which 3% of the amino acids (approximately 12 amino acid residues) can vary from said sequences and result in a functional homologue that has retained the properties of an MFS protein. An important consideration is that structure is not necessarily a reliable indicator of function. In the instant case, there is no disclosure relating similarity of structure to conservation of function. Conservation of structure is not necessarily a surrogate for conservation of function. Since the claimed invention is that of a transporter protein, and there is no disclosure of the domains responsible for required activity, the absence of information may be persuasive that those of skill in the art would not take the disclosure as generic.
Given this lack of description of the representative species encompassed by the genus of the claims, the specification fails to sufficiently describe the claimed invention in such full, clear, concise, and exact terms that a skilled artisan would recognize that applicants were in possession of the inventions of claims 1-6, 18 and 21.
Response to Arguments for Rejections under 35 USC § 112(a)
In the response filed on July 31, 2025, Applicant argues that a stringency of 97%, as currently amended, satisfies the written description requirement, citing Example 10 of the 2008 Written Description Training Materials. However, the instant facts are distinguishable. SEQ ID No: 1 is 393 amino acids in length, and >97% identity still permits variation of up to ~12 amino acids. The specification does not disclose any representative homologues of SEQ ID NO: 1, nor does it identify conserved structural motifs or amino acid residues required to maintain function. Moreover, transporter proteins such as the instant MFS polypeptide are known to be highly sensitive to amino acid substitutions, as even minor changes can alter or abolish substrate specificity. The unpredictability of transporter function is further demonstrated in the instant application (see, e.g., Fig. 7), where some transporters increase HMO production while others decrease it.
In view of the lack of representative species or structural/functional guidance, one of ordinary skill in the art would not have recognized applicant as being in possession of the full scope of the claimed genus of “functional homologues” with >97% identity to SEQ ID NO: 1. Possession of SEQ ID NO: 1 alone does not provide written description support for this broad genus. Applicant’s arguments have been considered in full and have not been found to be persuasive. Accordingly, the §112(a) rejection is maintained.
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 1-2, 6, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Stefan, J. (EP3461890A1, cited in the IDS) and WP_050106571 (NCBI, June 2016, cited in a previous office action), as evidenced by EEQ08298 (GenBank database, June 2009, cited in a previous office action).
Regarding claims 1-2, 6, and 18, Stefan teaches a bacterial host cell, capable to produce oligosaccharides comprising a terminal galactose-(1->4)-glucose disaccharide., comprising at least one recombinant nucleic acid sequence encoding for a protein having a beta-1,4-galactosyltransferase activity…and at least one recombinant nucleic acid sequence encoding a glycosyltransferase that is selected from at least one of the following: a fucosyltransferase, a sialyl-transferase, a glucosamyltransferase, and a galactosyltransferase (Specification, pg. 3, para 0017). With respect to the oligosaccharides that said bacterial cell can produce, Stefan teaches a list of 35 oligosaccharides in Table 1, which include the human milk oligosaccharides 2'-fucosyllactose (2'-FL), 3-fucosyllactose (3-FL), difucosyllactose (DFL), and lacto-N-tetraose (LNT) (Fig. 4). Stefan further teaches said bacterial cell further comprises “a nucleic acid sequence encoding at least one of the following additional proteins: an oligosaccharide exporter protein or a permease exporting the synthesized oligosaccharide from the host cell…” and in an exemplary embodiment, the nucleic acid expressing an exporter protein, is the yberc0001_9420 gene of Yersinia bercovieri ATCC 43970 or variants or homologs or functional fragments thereof (pg. 6, para 0051-0052). As evidenced by EEQ08298, the yberc0001_9420 gene of Yersinia bercovieri ATCC 43970 encodes a major facilitator superfamily protein, having 95.9% sequence identity to instant SEQ ID NO: 1 (Sequence alignment disclosed in Restriction requirement of 02/19/25). Specifically, Stefan discloses an E. coli, 2’-fucosyllactose producing strain, wherein “the gene yberc0001_9420 encoding a sugar efflux transporter of the major facilitator superfamily from Yersinia bercovieri ATCC 43970 (acc no. EEQ08298) was synthesized by GenScript Cooperation (USA) and inserted as EZ-Tn5< Ptet -yberc0001_9420- FRT-cat- FRT> transposon” (pg. 14-15, Example 1, para 0110 and Fig. 5C). Therefore, Stefan teaches a genetically modified cell capable of producing HMOs, including 2’-FL, 3-FL, DFL, and LNT, comprising a heterologous nucleic acid sequence encoding an MFS protein having 95.9% sequence identity to instant SEQ ID NO: 1. While Stefan teaches and suggests “variants or homologs or functional fragments” of the MFS protein yberc0001_9420, Stefan does not expressly teach a functional homolog having at least 97% sequence identity to SEQ ID NO: 1.
WP_050106571 discloses an MFS transporter protein, having 99.6% sequence identity to instant SEQ ID NO: 1 (see sequence alignment in the non-final office action of 05/02/2025).
Pairwise global alignment of the amino-acid sequences of the MFS transporter encoded by the yberc0001_9420 gene (Stefan) and the MFS transporter disclosed in WP_050106571 was performed using EMBOSS needle (Needleman–Wunsch global alignment) with BLOSUM62 scoring, gap open = 10.0, gap extend = 0.5, on Sep 25, 2025. The proteins are both 393 amino acids in length. The alignment shows 376/393 amino acids identical (95.7% identity) and 386/393 similar (98.2% similarity) with 0 gaps (score 1868.0). See sequence alignment below.
An invention would have been obvious to a person of ordinary skill in the art if some teaching in the prior art would have led that person to combine prior art reference teachings to arrive at the claimed invention. Before the effective filing date of the claimed invention, Stefan explicitly teaches use of an MFS oligosaccharide exporter (yberc0001_9420) in a genetically modified cell producing HMOs and expressly contemplates “variants, homologues, and functional fragments” of the disclosed exporter. Given that WP_050106571 is a full-length, gapless MFS protein from the same genus (Yersinia) that is highly conserved relative to Stefan’s MFS protein yberc0001_9420 (95.7% identity; 98.2% similarity), it would have been obvious to substitute WP_050106571 for yberc0001_9420 and expect predictable results (see MPEP 2144.06, “Substituting equivalents known for the same purpose”). A person of ordinary skill in the art would have had a reasonable expectation of functional interchangeability for the purpose of oligosaccharide export, given Stefan’s express teaching to employ homologues/variants of yberc0001_9420, and the near-complete preservation of sequence and key conserved residues across the entire transporter WP_050106571. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Regarding claims 3 and 4, Stefan teaches the recombinant bacterial host cell described above, further comprising “control sequences enabling the controlled overexpression of endogenous or recombinant nucleic acid sequences” such as promoter sequences, and in some embodiments, “the nucleic acid sequence is placed under the control of an inducible promoter” (pg. 7, para 0058 and 0060). Additionally, as indicated in the example disclosed above, the gene encoding the MFS protein is under the control of a promoter (i.e., Ptet).
Claims 5 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Stefan and WP_050106571, as applied to claims 1, 3 and 4 above, further in view of Zhang et al. (Transposon-mediated adaptive and directed mutations and their potential evolutionary benefits. J Mol Microbiol Biotechnol. 2011;21(1-2):59-70, cited in a previous office action).
The teachings of Stefan and WP_050106571, as they apply to claims 1, 3 and 4, have been discussed above. Briefly, Stefan discloses a genetically engineered E. coli host cell, producing the HMO 2’-fucosyllactose, wherein said bacterial host cell comprises the yberc0001_9420 gene, which encodes an MFS protein having 95.9% sequence identity to instant SEQ ID NO: 1. Stefan further teaches the use of variants, homologs, and functional fragments of yberc0001_9420, which would lead a person of ordinary skill in the art to the MFS protein disclosed in WP_050106571. Stefan also teaches the bacterial host cell further comprising “control sequences enabling the controlled overexpression of endogenous or recombinant nucleic acid sequences” such as promoter sequences, including inducible promoters; for example Ptet, as disclosed in the example above.
Regarding claims 5 and 21, Stefan does not expressly teach the promoters PglpF, PglpF_SD4 and PglpF_SD7.
Zhang et al. teaches that the glpFK operon in E. coli, encoding GlpF and GlpK, function to allow entry of glycerol into the cytoplasm and phosphorylation of glycerol, and are under the negative control of GlpR (repressor). Zhang et al. further teaches that glycerol-3-phosphate then binds to GlpR, causing it to dissociate from its operator sites, which are located in the glpFK operator/promoter region (pg. 61, “The E. coli glpFK operon is regulated by Crp and GlpR”). As shown in Fig. 7 (pg. 68), in the presence of glycerol, there is high glpFK promoter activity, whereas in the absence of glycerol (and bound GlpR), there is low promoter activity.
An invention would have been obvious to a person of ordinary skill in the art if some teaching in the prior art would have led that person to combine prior art reference teachings to arrive at the claimed invention. Before the effective filing date of the claimed invention, given that Stefan teaches the yberc0001_9420 gene is under the control of an inducible promoter Ptet, and given the teachings of Zhang et al., that glpFK promoter is mediated by glycerol, it would have been obvious for a person of ordinary skill in the art to substitute the Ptet (promoter) disclosed by Stefan with the glpFK promoter disclosed in Zhang, and expect predictable results (see MPEP 2144.06, “Substituting equivalents known for the same purpose”). There is a reasonable expectation of success because Zhang successfully demonstrates in E. coli that there are repressor binding sites in the promoter region that dissociate in the presence of glycerol, making it an inducible promoter. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Claims 5 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Stefan and WP_050106571, as applied to claims 1, 3 and 4 above, further in view of Pedersen et al. (U.S. Patent No. 11608504B2, EFD 12/19/2018, cited in a previous office action).
The teachings of Stefan and WP_050106571, as they apply to claims 1, 3 and 4, have been discussed above. Briefly, Stefan discloses a genetically engineered E. coli host cell, producing the HMO 2’-fucosyllactose, wherein said bacterial host cell comprises the yberc0001_9420 gene, which encodes an MFS protein having 95.9% sequence identity to instant SEQ ID NO: 1. Stefan further teaches the use of variants, homologs, and functional fragments of yberc0001_9420, which would lead a person of ordinary skill in the art to the MFS protein disclosed in WP_050106571. Stefan also teaches the bacterial host cell further comprising “control sequences enabling the controlled overexpression of endogenous or recombinant nucleic acid sequences” such as promoter sequences, including inducible promoters; for example Ptet, as disclosed in the example above.
Regarding claims 5 and 21, Stefan does not expressly teach the promoters PglpF, PglpF_SD4 and PglpF_SD7.
Pedersen et al. discloses “nucleic acid constructs that allow to modify expression of a desired gene using both in vitro and in vivo gene expression systems. The constructs can advantageously be used to produce a variety of biological molecules recombinantly in industrial scales, e.g. human milk oligosaccharides (HMO)” (Abstract). In preferred embodiments, Pedersen et al. teaches the use of glp promoters in said constructs, including PglpF, PglpF_SD4 and PglpF_SD7, among several others (column 12, lines 6-10 and Table 1, columns 13-26). Pedersen et al. teaches the use of bacterial cells, including E. coli, as the host and the production of several HMOs, using said recombinant system (column 35, line 36 and columns 31-32). Specifically, Pedersen et al. discloses the construction of several strains of E. coli using various glpF promoters for the production of the HMOs LNT, LNFP-I, 3’SL, and 2’FL (columns 61-62 and columns 71-74, Examples 13-17).
An invention would have been obvious to a person of ordinary skill in the art if some teaching in the prior art would have led that person to combine prior art reference teachings to arrive at the claimed invention. Before the effective filing date of the claimed invention, given that Stefan teaches the yberc0001_9420 gene is under the control of an inducible promoter Ptet, and given the teachings of Zhang et al., that glpFK promoter is mediated by glycerol, it would have been obvious for a person of ordinary skill in the art to substitute the Ptet (promoter) disclosed by Stefan with the glp promoters disclosed in Pedersen et al., and expect predictable results (see MPEP 2144.06, “Substituting equivalents known for the same purpose”). There is a reasonable expectation of success because Pedersen et al. successfully demonstrates the construction of several types of glp promoters in a recombinant system for HMO production in E. coli. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Sequence alignment between yberc0001_9420 (Stefan) and WP_050106571 (NCBI)
Program: needle
# Rundate: Thu 25 Sep 2025 19:17:40
# Commandline: needle
# -auto
# -stdout
# -asequence emboss_needle-I20250925-191737-0034-50645972-p1m.asequence
# -bsequence emboss_needle-I20250925-191737-0034-50645972-p1m.bsequence
# -datafile EBLOSUM62
# -gapopen 10.0
# -gapextend 0.5
# -endopen 10.0
# -endextend 0.5
# -aformat3 pair
# -sprotein1
# -sprotein2
# Align_format: pair
# Report_file: stdout
########################################
#=======================================
#
# Aligned_sequences: 2
# 1: EMBOSS_001
# 2: EMBOSS_001
# Matrix: EBLOSUM62
# Gap_penalty: 10.0
# Extend_penalty: 0.5
#
# Length: 393
# Identity: 376/393 (95.7%)
# Similarity: 386/393 (98.2%)
# Gaps: 0/393 ( 0.0%)
# Score: 1868.0
#
#
#=======================================
EMBOSS_001 1 mksaltfsrrinpvflaffvvaflsgiagalqaptlslflstevkvrplw 50
||||||||||||||||||||||||||||||||||||||||||||||||||
EMBOSS_001 1 mksaltfsrrinpvflaffvvaflsgiagalqaptlslflstevkvrplw 50
EMBOSS_001 51 vglfytvnaiagitvsfilakrsdsrgdrrklimvcylmavgncllfafn 100
|||||||||||||||||:||||||.||||||||:||||||||||||||||
EMBOSS_001 51 vglfytvnaiagitvsfvlakrsdlrgdrrklilvcylmavgncllfafn 100
EMBOSS_001 101 rdyltlitagvllasvantampqifalareyadssarevvmfssimraql 150
|||||||||||||||||||||||||||||||||:||||||||||||||||
EMBOSS_001 101 rdyltlitagvllasvantampqifalareyadnsarevvmfssimraql 150
EMBOSS_001 151 slawvigpplsfmlalnygftlmfsiaagifvlsalvvwfilpsvpraep 200
||||||||||||||||||||||||.||||||||||||||||||||.||||
EMBOSS_001 151 slawvigpplsfmlalnygftlmfciaagifvlsalvvwfilpsvqraep 200
EMBOSS_001 201 vvdapvvvqgslfadknvlllfiasmlmwtcntmyiidmplyitaslglp 250
|:|||.|.||||||||:|||||||||||||||||||||||||||||||||
EMBOSS_001 201 vmdapavaqgslfadkdvlllfiasmlmwtcntmyiidmplyitaslglp 250
EMBOSS_001 251 erlagllmgtaagleipimllagysvryfgkrkimlfavlagvlfytglv 300
|||||||||||||||||||||||||||.||||||||||||||||||||||
EMBOSS_001 251 erlagllmgtaagleipimllagysvrrfgkrkimlfavlagvlfytglv 300
EMBOSS_001 301 lfkfktalmllqifnaifigivagigmlyfqdlmpgragaattlftnsis 350
|||||:||||||||||||||||||||||||||||||||||||||||||||
EMBOSS_001 301 lfkfksalmllqifnaifigivagigmlyfqdlmpgragaattlftnsis 350
EMBOSS_001 351 tgvilagvlqggltetwghdsvyvmamvlsilaliicarvrea 393
|||||||||||.|||||||:|||||||:|:||:||||||||||
EMBOSS_001 351 tgvilagvlqgvltetwghnsvyvmamilailsliicarvrea 393
Response to Arguments for Prior Art Rejections
In the response filed on July 31, 2025, Applicant argues that:
1. Stefan addresses a different problem.
2. Exporters in Stefan are optional and not shown to improve HMO yield.
3. Sugar exporter specificity is unpredictable.
4. Substitution of YberC with WP_050106571 is unsupported given the large number of sugar efflux transporters.
5. Unexpected results exist, specifically that Fred increases some HMO production, but decreased LNnT production.
Applicant’s arguments have been considered in full and have been found to be unpersuasive for the following reasons:
Stefan discloses recombinant host cells, e.g., E. coli, engineered to produce 2-FL, 3-FL, DFL, and LNT, wherein said cell may comprise an MFS exporter. Stefan specifically discloses an E. coli 2’-FL producing strain comprising Yberc0001-9420, an MFS exporter. The fact that Stefan also aimed to reduce lactulose byproducts does not change that it explicitly discloses cells producing HMOs with an MFS exporter. Furthermore, Stefan explicitly allows for variants, homologues, or functional fragments of Yberc0001_9420 as exporters. This teaching directly motivates a skilled artisan to consider close functional homologues of YberC for use as exporters. Pairwise alignment shows WP_050106571 is 95.7% identical and 98.2% similar to YberC with zero gaps over 393 amino acids, and >99% identical to SEQ ID NO: 1. WP_050106571 is therefore both a functional homologue of YberC (known at the time of the claimed invention), and satisfies the amended claim’s sequence identity requirement, providing a reasonable basis for substitution. With respect to the optionality of exporters, Stefan’s listing of exporters as optional does not preclude obvious substitution with known functional homologues. The fact that Stefan provides a list of alternative exporters, including YberC, and identifies them as suitable for exporting oligosaccharides, provides motivation for the skilled artisan to consider such proteins. “Optional” features are still teachings of the reference and may form the basis for an obviousness rejection. Both WP_050106571 and yberc0001_9420 are MFS transporters of the same length, highly similar, and from the genus Yersinia. A skilled artisan would reasonably expect WP_050106571 to function as an exporter in Stefan’s engineered cell. The existence of many sugar efflux transporters (>100,000) does not negate this expectation when a closely related, well-characterized homologue is available. The rejection does not rely on random selection among all sugar efflux transporters. Instead, the reasoning is grounded in the specific homology between the MFS proteins, which sharply limits the relevant universe. Given their >95% sequence identity and identical length, a person of ordinary skill in the art would have had a reasonable expectation of similar efflux function upon substitution. With respect to Applicant’s argument that some exporters increase HMO production, while some decrease production, suggesting unpredictability, Applicant’s reliance on Fig. 7 is unpersuasive, as it addresses LNnT production, which is not recited in the claims. Variability in LNnT production does not establish unpredictability for the claimed HMOs, particularly where Stefan already demonstrates that MFS transporters such as yberc0001_9420 are suitable for HMO (e.g., 2’-FL) export. With respect to unexpected results, the claims are not limited to cells exhibiting increased HMO production. The claims merely require a recombinant cell capable of producing the recited HMOs. Moreover, applicant’s alleged results are attributed to the use of Fred (SEQ ID NO: 1), and has not established that such results reflect a unique property of SEQ ID NO: 1, as opposed to close homologs, such as WP_050106571. Accordingly, the alleged results are not commensurate in scope with the claims, which encompass homologous proteins.
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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 1, 3-6 and 21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 8-13 of copending Application No. 18262099 (reference application).
With respect to instant claim 1, claim 1 of ‘099 recites a genetically modified cell capable of producing one of more Human Milk Oligosaccharides (HMO(s)) comprising a sialyl moiety, wherein said cell comprises, inter alia, a heterologous nucleic acid sequence encoding a major facilitator superfamily (MFS) polypeptide of SEQ ID NO: 1, or a functional homologue thereof. It is noted that SEQ ID NO: 1 of ‘099 is 100% identical to instant SEQ ID NO: 1. Therefore, the claimed subject matter of ‘099, specifically disclosed in claim 1, anticipate instant claim 1, which is directed to a genetically modified cell comprising a heterologous nucleic acid sequence encoding a MFS protein set forth in SEQ ID NO: 1, or a functional homologue thereof which amino acid sequence is more than 97% identical to SEQ ID NO: 1, wherein the one or more HMOs is 2’-FL, 3-FL, DFL, LNT, or mixtures thereof. Instant claim 1 is directed to a genetically modified cell comprising a heterologous nucleic acid sequence encoding a MFS protein set forth in SEQ ID NO: 1, or a functional homologue thereof which amino acid sequence is more than 97% identical to SEQ ID NO: 1, wherein the one or more HMOs are selected from 2’FL, 3-FL, DFL, LNT, or mixtures thereof. Although the copending claims requires HMOs comprising a sialyl moiety whereas the instant claim specifies non-sialylated HMOs, the difference is considered an obvious variation. The art recognizes that the biosynthesis of HMOs proceeds through branching pathways to yield neutral, fucosylated, or sialylated structures, and that incorporation of sialyltransferases yields sialylated HMOs from the same core backbones (e.g., LNT). Thus, once a genetically modified cell comprising SEQ ID NO: 1 is disclosed, it would have been an obvious variant to obtain the cell capable of producing either fucosylated or sialylated HMOs by adding or mitting a sialyltransferase. Accordingly, the subject matter of instant claim 1 is not patentably distinct from the subject matter of claim 1 of ‘099. Copending claims 8-10 relate to the genetically modified cell further comprising a regulatory element. Copending claim 11 recites wherein the genetically modified cell is E. coli. Copending claims 12-13 recite a nucleic acid construct comprising the MFS polypeptide of SEQ ID NO: 1 and a regulatory element.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 3-4, 6, and 21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 7, and 9-12 of copending Application No. 18258770 (reference application).
With respect to instant claim 1, claim 1 of ‘770 recites a genetically modified cell capable of producing one or more Human Milk Oligosaccharides (HMOs), wherein said cell comprises a heterologous, recombinant and/or synthetic nucleic acid encoding a. an a-1,2-fucosyltransferase, and b. an a-1,3-fucosyltransferase, and c. a recombinant transporter protein selected from the major facilitator superfamily (MFS). Claim 9 of ‘770 recites the genetically modified cell according to claim 1, wherein the transporter protein is selected from the group consisting of…SEQ ID NO: 42 (fred). It is noted that SEQ ID NO: 42 (fred) is 100% identical to the MFS protein disclosed in SEQ ID NO: 1 of the instant application. Copending claims 2-4 relate to amounts of DFL produced by the cell. Copending claim 7 relates to the amount of 2’FL and 3FL produced by the cell. Copending claim 10 recites wherein the cell is E. coli. Copending claims 11-12 recite the cell further comprises a regulatory element, such as PglpF. Accordingly, the subject matter of application ‘770, namely the subject matter of claim 9, anticipates instant claim 1.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-3, and 6 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 and 11-21 of copending Application No. 18561123 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because ‘123 claims anticipate the instant claims.
With respect to instant claim 1, claim 1 of ‘123 recites a method for the production of a human milk oligosaccharide (HMO) blend with 2'-FL and LNFP-I as the predominant HMO(s), the method comprising the steps of: a. providing a genetically engineered cell capable of producing at least two HMO's, wherein said cell i. comprises a heterologous P-1,3-N-acetyl-glucosaminyltransferase protein as shown in SEQ ID NO: 1, 2 or 3, or a functional homologue thereof having an amino acid sequence which is at least 80 % identical to SEQ ID NO: 12 or 3, ii. comprises a heterologous P-1,3-galactosyltransferase protein as shown in SEQ ID NO: 4 or 5, or a functional homologue thereof having an amino acid sequence which is at least 80 % identical to SEQ ID NO: 4 or 5, and iii. comprises a heterologous a-1,2-fucosyltransferase protein as shown in any one of SEQ ID NO: 6 and 7 and 49, or a functional homologue thereof having an amino acid sequence which is at least 80% identical to any one of SEQ ID NO: 6 or 7 or 49, iv. expresses functionally the colanic acid gene cluster, and v. comprises a native or heterologous regulatory element for controlling the expression of and of i)-iv), b. culturing the cell according to (a) in a suitable cell culture medium to express said proteins and to produce an HMO blend; and c. harvesting the human milk oligosaccharide (HMO) blend produced in step (b). Claim 14 recites the method according to claim 1, wherein the cell further comprises a gene product that upon expression acts as a sugar efflux transporter. Claim 15 recites the method of claim 14, wherein the amino acid sequence of the sugar efflux transporter is selected from the group consisting of…SEQ ID NO: 32, or a functional homologue thereof. It is noted that SEQ ID NO: 32 of ‘123 is 100% identical to instant SEQ ID NO: 1. Therefore, the claimed subject matter of ‘123, specifically disclosed in claim 15, anticipates instant claims 1-3, which is directed to a genetically modified cell comprising a heterologous nucleic acid sequence encoding a MFS protein set forth in SEQ ID NO: 1, or a functional homologue thereof which amino acid sequence is more than 97% or 98% identical to SEQ ID NO: 1, wherein the one or more HMOs are 2’FL, 3FL, DFL and LNT, or mixtures thereof, and wherein the cell further comprises a nucleic acid sequence comprising a regulatory element for the expression of the nucleic acid sequence. Furthermore, copending claim 19 of ‘123 recites a genetically modified cell comprising a recombinant nucleic acid sequence encoding, inter alia, a sugar efflux transporter capable of exporting 2’FL and a heterologous regulatory element, and claim 21 recites that the engineered cell of claim 19 is E. coli. Thus, while instant claim 6 specifies that the genetically modified cell is E. coli, this does not render the claim patentably distinct, as the copending application already contemplates the same cell type with the same relevant functional features.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments for Double Patenting Rejections
In the response filed on July 31, 2025, Applicant’s arguments substantially rely on the assertion that the independent claims of the cited copending applications do not identically recite every element of instant claim 1. However, this argument is incomplete. Both independent and dependent claims of a reference application may be properly relied upon in a double patenting analysis. A dependent claim must be construed to incorporate all of the limitations of its base claim, and thus may anticipate or render obvious the instant claims. In the present case, the cited dependent claims expressly recite limitations applicants allege to be missing, including a nucleic acid encoding an MFS protein set forth in instant SEQ ID NO: 1. Applicant’s arguments are silent as to these dependent claims and therefore fail to overcome the rejections over the recited claims of copending Application No. 18561123, 18258770, and 18262099, which have been maintained and/or modified necessitated by amendment above. For clarity, the present action has provided a more detailed discussion identifying the specific dependent claims and explaining their correspondence to instant claim 1. Arguments regarding rejections over copending claims of Application No. 18561170 and 18177070 have been found to be persuasive. Accordingly, these rejections are hereby withdrawn.
Conclusion
No claim is in condition for allowance.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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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/NAGHMEH NINA MOAZZAMI/Examiner, Art Unit 1652
/ROBERT B MONDESI/Supervisory Patent Examiner, Art Unit 1652