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 .
Status of Claims
Receipt of Arguments/Remarks filed on 6/9/2026 is acknowledged. Claims 46, 55-56, and 67 were amended. Claims 47-51 and 66 were canceled. New claims 68-72 were added. Claims 46, 52-65, and 67-72 are pending. Claims 60-65 are withdrawn as being directed to a non-elected invention.
In view of the prior art search, the species election has been expanded to include SEQ ID NO: 61.
Withdrawn Rejections
The rejection of claims 48-51 under 35 U.S.C. § 112(a) is withdrawn in view of the cancellation of claims 48-51.
The rejection of claims 46-59 and 66-67 under 35 U.S.C. § 102 is withdrawn in view of amendments to claim 46.
New rejections necessitated by amendment
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 46, 52-59, and 67-72 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites “expression of the heterologous porter membrane protein provides one
or more of” options (i)-(x), i.e. only one of options (i)-(x) is required. Option (x) recites,
“(x) enhanced efflux of the oligosaccharide comprising LN3 as a core trisaccharide, and wherein the heterologous membrane protein:”, followed by options (a)-(c) regarding the sequence of the heterologous membrane protein. As the limitation “and wherein the heterologous membrane protein:” begins on the same line as option (x), it is unclear if the heterologous membrane protein with the sequence as set forth in options (a)-(c) is only part of option (x), and therefore not required with any of options (i)-(ix).
Based on applicant remarks filed regarding the amendments, it appears that the membrane protein sequence options (a)-(c) are not meant to be associated only with option (x), but are instead a separate limitation that is required along with any of options (i)-(x). However, as written, this is not clear. It is suggested that the claims be amended to clearly denote that options (a)-(c) are distinct from option (x), for example:
(x) enhanced efflux of the oligosaccharide comprising LN3 as a core trisaccharide;
and wherein the heterologous membrane protein:
For the purposes of examination, it is considered that options (a)-(c) are not associated with only option (x).
Claims 52-59 and 67-72 are included in this rejection because they depend on a rejected claim and do not clarify the issue.
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 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 46, 52-59, and 67-72 are rejected under 35 U.S.C. 103 as being unpatentable over Englert et al., US 2023/0304052 A1 (effective filing date 6/26/2020) in view of Ping et al., Biological and Pharmaceutical Bulletin;30(10):1962-4, as evidenced by NCBI multidrug efflux MFS transporter KdeA [Klebsiella pneumoniae].
Regarding claim 46, Englert teaches a genetically engineered bacterial cell for production of an oligosaccharide of interest (Englert “Abstract”). Englert teaches that a cell for producing lacto-N-triose II (or lacto-N-triose, LN3, LNT-II, see instant specification p. 21 para. 52) expresses a functional β-1,3-N-acetylglucosaminyltransferase (Englert p. 3 para. 40; p. 8 para. 99). Englert teaches that in a first step, the 1,3-N-acetylglucosaminyltransferase is used to convert lactose to lacto-N-triose with the nucleotide sugar donor UDP-N-acetylglucosamine (UDP-GlcNAc), i.e., a GlcNAc residue is transferred from UDP-GlcNAc to a lactose acceptor (Englert p. 8 para. 99). Englert teaches that the genetically engineered cells possess a saccharide transporter in their inner membrane for the translocation of the oligosaccharide of interest from the cells' cytoplasm into the culture medium, wherein the saccharide transporter is expressed from a recombinant gene or a deregulated endogenous gene (Englert p. 2 para. 16). Englert teaches that the bacterial cell may be genetically engineered to express a non-endogenous saccharide transporter (Englert p. 9 para. 103). Englert teaches that when the oligosaccharide of interest is LNT-II, the saccharide transporter is an MdfA multidrug transporter (Englert p. 9 para. 110). Englert teaches an embodiment wherein a cell overexpresses an endogenous membrane protein, MdfA, and exhibits enhanced efflux of LNT (Englert p. 8 para. 100).
Englert does not teach expression of a heterologous membrane protein with a sequence as set forth in claims 46 or 72.
Regarding claim 46, Ping teaches the sequence of a multidrug efflux pump KdeA from Klebsiella pneumoniae, which is similar to the MdfA efflux pump from E. coli (Ping Abstract). The sequence of KdeA is 99.5% identical to instant SEQ ID NO: 61 (see sequence alignment in OA appendix; NCBI KdeA reference). Ping teaches that KdeA has high sequence similarity to MdfA of E. coli (88% identity and 97% similarity), and to other MdfA orthologues from several
pathogenic bacteria such as Shigella flexneri, Salmonella enterica serovar Typhi, and Yersinia pestis (Ping p. 1963 para. 2).
Regarding claim 72, the protein of Ping has (A) an amino acid sequence that is the same length as SEQ ID NO: 61, 410 amino acids, and (B) at least 95% sequence identity over the entire length of the amino acid sequence according to SEQ ID NO: 61 (see sequence alignment in OA appendix; NCBI KdeA reference).
It would have been obvious for a skilled artisan to modify the cell of Englert and express a heterologous transporter as taught by Ping, with a sequence that is 99.5% identical to instant SEQ ID NO: 61. Englert teaches that cells can be engineered to express heterologous transporters for oligosaccharide production, and specifically that expression of MdfA transporters results in increased export of LNT. It would have been obvious that a heterologous transporter, such as that taught by Ping which is highly similar to E. coli MdfA, could be expressed in the cell of Englert instead of overexpressing the endogenous MdfA gene, with a reasonable expectation of success. This would be considered a simple substitution of one known element for another of the same function, as both the Klebsiella transporter taught by Ping and the E. coli MdfA transporter of Englert are expected to have the same function. Particularly in light of the teachings of Englert that the transporters of the genetically engineered cells may be heterologous or endogenous, a skilled artisan would have found it obvious to substitute a heterologous transporter for the overexpressed endogenous transporter exemplified by Englert. A person having ordinary skill in the art could expect that the heterologous transporter would result in the same increase in LNT export as Englert teaches that E. coli MdfA transporters have this function, and Ping teaches that the KdeA transporter is also a multidrug efflux protein belonging to the major facilitator superfamily with high similarity to MdfA from E. coli and other orthologues.
Regarding claims 52-54 and 68-69, Englert teaches that the oligosaccharide comprising a lacto-N-triose as a core trisaccharide is lacto-N-neotetraose, which is a mammalian milk oligosaccharide (Englert p. 3 para. 34). Lacto-N-neotetraose is a neutral oligosaccharide (Englert p. 8 para. 99).
Regarding claim 55, Englert teaches that the cell expresses a gene (i.e. polynucleotide encoding) β-1,4-galactosyltransferase, which converts lacto-N-triose II into lacto-N-neotetraose, i.e. transfers a galactose from a UDP-Gal donor in LN3 (Englert p. 3 para. 38-39; pp. 8-9 para. 101).
Regarding claim 56, the limitation “wherein the cell produces” is a functional limitation of the claimed cell. The structure of the cell of claim 46 (modified host cell expressing β-1,3-N-acetylglucosaminyltransferase and a heterologous transporter with a sequence as claimed) is obvious in view of Englert and Ping, as set forth above. Any cell having the same structure as the cell of claim 46 is capable of performing the function of claim 56.
Regarding claims 57-58, Englert teaches that the cell is a microorganism, E. coli bacterium (Englert p. 12 para. 158).
Regarding claim 59, the limitation “wherein the cell is capable of synthesizing” is a functional limitation of the claimed cell. The structure of the cell of claim 46 (modified host cell expressing β-1,3-N-acetylglucosaminyltransferase and a heterologous transporter with a sequence as claimed) is obvious in view of Englert and Ping, as set forth above. Any cell having the same structure as the cell of claim 46 is capable of performing the function of claim 59.
Regarding claim 67, the limitation “wherein the membrane protein reduces intracellular accumulation” is a functional limitation of the claimed cell. The structure of the cell of claim 46 (modified host cell expressing β-1,3-N-acetylglucosaminyltransferase and a heterologous transporter with a sequence as claimed) is obvious in view of Englert and Ping, as set forth above. Any cell having the same structure as the cell of claim 46 is capable of performing the function of claim 67. Additionally, Englert teaches that expression of a membrane protein, MdfA, increases export of lacto-N-neotetraose into the cell’s surrounding environment (Englert p. 8 para. 100). If the export of the oligosaccharide is increased, the accumulation of the oligosaccharide intracellularly would be reduced.
Regarding claims 70 and 71, the limitation “wherein the cell is capable of synthesizing” in claim 59 is a functional limitation of the claimed cell. The structure of the cell of claim 46 (modified host cell expressing β-1,3-N-acetylglucosaminyltransferase and a heterologous transporter with a sequence as claimed) is obvious in view of Englert and Ping, as set forth above. Any cell having the same structure as the cell of claim 46 is capable of performing the function of claim 59, as well as dependent claims 70 and 71.
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.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 46, 52-59, and 67-72 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 11-12 of U.S. Patent No. 12077788 B2 in view of Englert et al., US 2023/0304052 A1 (effective filing date 6/26/2020) and Ping et al., Biological and Pharmaceutical Bulletin;30(10):1962-4.
Regarding claims 46 and 52-53, claim 1 of ‘788 recites a metabolically engineered cell which expresses an N-acetylglucosaminyltransferase and a galactosyltransferase. Claim 11 of ‘788 recites that the cell comprises i) modified expression of an endogenous membrane protein, ii) modified activity of an endogenous membrane protein, iii) expression of a homologous membrane protein, or iv) expression of a heterologous membrane protein, wherein said membrane protein is involved in secretion of at least one of said at least four different neutral non-fucosylated mammalian milk oligosaccharides. Claim 12 of ‘788 recites that the membrane protein is a porter.
Regarding claims 57-58, claim 20 of ‘788 recites that the cell is a bacterium.
Regarding claims 56, 59, and 67-72, these claims recite functional limitations of the claimed bacterial cell. Any cell comprising the same structural features recited in claim 46 reads on the invention of claims 56, 59, and 67-72.
The claims of ‘788 do not recite a galactoside β-1,3-N-acetylglucosaminyltransferase that transfers an N-acetylglucosamine (GlcNAc) residue from a UDP-GlcNAc donor to a lactose acceptor thereby synthesizing LN3 (claim 46), or that the heterologous membrane protein has a sequence as set forth in claims 46 and 72; lacto-N-neotetraose (claim 54); or N-acetylglucosamine beta-1,4-galactosyltransferase (claim 55).
Regarding claim 46, Englert teaches a genetically engineered bacterial cell for production of an oligosaccharide of interest (Englert “Abstract”). Englert teaches that a cell for producing lacto-N-triose II (or lacto-N-triose, LN3, LNT-II, see instant specification p. 21 para. 52) expresses a functional β-1,3-N-acetylglucosaminyltransferase wherein a GlcNAc residue is transferred from UDP-GlcNAc to a lactose acceptor (Englert p. 3 para. 40; p. 8 para. 99). Englert teaches that the genetically engineered cells possess a saccharide transporter in their inner membrane for the translocation of the oligosaccharide of interest from the cells' cytoplasm into the culture medium, wherein the saccharide transporter is expressed from a recombinant gene or a deregulated endogenous gene (Englert p. 2 para. 16). Englert teaches that the bacterial cell may be genetically engineered to express a non-endogenous saccharide transporter (Englert p. 9 para. 103). Englert teaches that when the oligosaccharide of interest is LNT-II, the saccharide transporter is an MdfA multidrug transporter (Englert p. 9 para. 110). Englert teaches an embodiment wherein a cell overexpresses an endogenous membrane protein, MdfA, and exhibits enhanced export of LNT (Englert p. 8 para. 100).
Regarding claims 46 and 72, Ping teaches the sequence of a multidrug efflux pump KdeA from Klebsiella pneumoniae, which is similar to the MdfA efflux pump from E. coli (Ping Abstract). The sequence of KdeA is 99.5% identical to instant SEQ ID NO: 61 (see sequence alignment in OA appendix; NCBI KdeA reference). Ping teaches that KdeA has high sequence similarity to MdfA of E. coli (88% identity and 97% similarity), and to other MdfA orthologues from several pathogenic bacteria such as Shigella flexneri, Salmonella enterica serovar Typhi, and Yersinia pestis (Ping p. 1963 para. 2).
Regarding claim 54, Englert teaches that the oligosaccharide comprising a lacto-N-triose as a core trisaccharide is lacto-N-neotetraose, which is a mammalian milk oligosaccharide (Englert p. 3 para. 34). Lacto-N-neotetraose is a neutral oligosaccharide (Englert p. 8 para. 99).
Regarding claim 55, Englert teaches that the cell expresses a β-1,4-galactosyltransferase which converts lacto-N-triose II into lacto-N-neotetraose, i.e. transfers a galactose from a UDP-Gal donor in LN3 (Englert pp. 8-9 para. 101).
It would have been obvious for a skilled artisan, based on the teachings of Englert and Ping, to modify the cell of ‘788 and express a heterologous transporter with a sequence that is 99.5% identical to instant SEQ ID NO: 61 and a β-1,3-N-acetylglucosaminyltransferase. Englert teaches a cell for oligosaccharide production which expresses an N-acetylglucosaminyltransferase, a galactosyltransferase, and a transporter protein. Englert teaches that the transporter proteins may be endogenous or heterologous, and that increased expression of MdfA transporters result in enhanced production of LNT. All of these references are directed to HMO production by modified cells, and ‘788 claims a cell which produces neutral HMOs, which includes lacto-N-neotetraose as taught by Englert. Therefore, a skilled artisan would have found it obvious, with a reasonable expectation of success, to modify the cell of ‘788 with the specific enzymes and transporter taught by Englert and Ping, and would have been motivated to do so in order to produce the neutral oligosaccharide lacto-N-neotetraose.
Claims 46, 52-59, and 67-72 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 80, 95, 104, and 112 of copending Application No. 18/041,154 in view of Englert et al., US 2023/0304052 A1 (effective filing date 6/26/2020) and Ping et al., Biological and Pharmaceutical Bulletin;30(10):1962-4.
Regarding claims 46 and 55, claim 80 of ‘154 recites a cell for producing di or oligosaccharides. Claim 104 recites that the cell comprises a β-1,3-N-acetylglucosaminyltransferase and N-acetylglucosamine β-1,4-galactosyltransferase. Claim 95 of ‘154 recites that the cell comprises membrane transporter proteins or polypeptides having transport activity so as to transport compounds across the outer membrane of a cell wall.
Regarding claims 52-54, 56, 59, and 67-72, these claims recite functional limitations of the claimed bacterial cell. Claims 80, 95, and 104 of ‘154 recite a cell having the same structural features of the cell of claim 46. It is thus considered that the cell of ‘154 is capable of producing the oligosaccharides of claims 52-54.
Regarding claims 57 and 58, claim 112 of ‘154 recites that the cell is a bacterium.
The claims of ‘154 do not recite that the heterologous membrane protein has a sequence as set forth in claims 46 and 72.
The teachings of Englert and Ping regarding claims 46 and 72 are set forth above.
It would have been obvious for a skilled artisan, based on the teachings of Englert and Ping, to modify the cell of ‘154 and express a heterologous transporter with a sequence that is 99.5% identical to instant SEQ ID NO: 61 and a β-1,3-N-acetylglucosaminyltransferase. Englert teaches a cell for oligosaccharide production which expresses an N-acetylglucosaminyltransferase, a galactosyltransferase, and a membrane protein. Englert teaches that the transporter proteins may be endogenous or heterologous, and that increased expression of MdfA transporters result in enhanced production of LNT. All of these references are directed to HMO production by modified cells, and ‘154 claims a cell which produces oligosaccharides, which includes lacto-N-neotetraose as taught by Englert. Therefore, a skilled artisan would have found it obvious, with a reasonable expectation of success, to modify the cell of ‘154 with the specific transporter and enzymes taught by Englert and Ping, and would have been motivated to do so in order to produce the specific oligosaccharide lacto-N-neotetraose.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Rejections under 35 U.S.C. § 102
In light of amendments to the claims, the rejection of claims 46-59 and 66-67 under 35 U.S.C. § 102 has been withdrawn. However, upon further consideration, new grounds of rejection of claims 46, 52-59, and 67-72 are made under 35 U.S.C. § 103 in view of Englert and Ping as set forth above. Given these new grounds of rejection, the arguments presented regarding claims rejected under 35 U.S.C. § 102 are moot.
Double patenting rejections
The provisional rejection of claims 46-59 and 66-67 on the grounds of non-statutory double patenting over copending Application No. 18/040,356 are withdrawn.
A modified rejection of claims 46, 52-59, and 67-72 on the grounds of non-statutory double patenting over U.S. Patent No. 12077788 B2; and a modified provisional rejection of claims 46, 52-59, and 67-72 on the grounds of non-statutory double patenting over copending Application No. 18/041,154; are made as set forth above, necessitated by claim amendments.
Conclusion
Claims 46, 52-59, and 67-72 are rejected.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to EMILY F EIX whose telephone number is (571)270-0808. The examiner can normally be reached M-F 8am-5pm ET.
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/EMILY F EIX/
Examiner, Art Unit 1653
/JENNIFER M.H. TICHY/Primary Examiner, Art Unit 1653
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