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
Claims 1-8, 11-21 and 25 are pending following the Reply filed 06/15/2026. Claims 1-8, 11-16 and 18-20 have been amended and new claim 25 has been added without introducing new matter. Claims 1-8, 11-21 and 25 have been examined on the merits.
Information Disclosure Statement
The information disclosure statement (IDS) filed on 06/15/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Withdrawn
The objections to claims 1, 4, 16 and 18-20 are withdrawn in light of the amendments.
The rejection of claims 1-8 and 11-21 under 35 U.S.C. 112(b) are withdrawn in light of the amendments.
The written description rejection of claims 1-8 and 11-21 under 35 U.S.C. 112(a) are withdrawn in light of the amendments and in consideration of Applicant’s arguments. See Response to Arguments below for further discussion.
Claim Rejections - 35 USC § 103
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
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.
Claim(s) 1-3, 5-8, 11, 13-14, 16 and 18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Aesaert, et al. (US 2025/0188504 A1; effectively filed 08/10/2020; cited on Form 892), hereafter “Aesaert”, and further in view of Aesaert, et al. (US 2023/0313253 A1; effectively filed 08/10/2020; cited on Form 892), hereafter, “Aesaert 2023” and Pedersen, et al. (WO 2019/123324 A1; cited in the IDS filed 06/24/2024 at Cite No. 7), hereafter, “Pedersen”.
Regarding claim 1, Aesaert teaches cells metabolically engineered for the production of a mixture of at least three different mammalian milk oligosaccharides (MMOs) (see Abstract). Aesaert teaches that the availability of mixtures of human milk oligosaccharides (HMOs) is limited as production relies on chemical or chemo-enzymatic synthesis or on purification from natural sources (see pg. 1, para. [0004]). Aesaert teaches that chemical synthesis methods are laborious and time-consuming, involve a large number of steps, and are difficult to scale-up (see pg. 1, para. [0004]). Aesaert discloses that it has now been found that it is possible to produce mixtures of MMOs using a metabolically engineered cell (see pg. 1, para. [0007]).
Aesaert claims a metabolically engineered cell producing a mixture of at least three different mammalian milk oligosaccharides, wherein the cell is metabolically engineered for the production of the mixture and expresses at least two glycosyltransferases (see claim 100), wherein one of the glycosyltransferases is an N-acetylglucosaminyl transferase, one of the glycosyltransferases is a galactosyltransferase, and one of the glycosyltransferases is a fucosyltransferase (see claim 105). Aesaert teaches that a particular example of a preferred mixture may be one comprising or consisting essentially of 2’FL, LN3, LNT and LNFP-I (see pg. 28, para. [0230]).
Aesaert’s Examples teach an E.coli K-12 MG1655 strain adapted for the production of an oligosaccharide mixture, comprising (i) a beta-1,3-N-acetylglucosaminyltransferase comprising SEQ ID NO: 27, (ii) a beta-1,3-galactosyltransferase, and (iii) an alpha-1,2-fucosyltransferase comprising SEQ ID NO: 40 to obtain a mixture comprising LN3, LNT and LNFP-I (see pg. 73, para. [0725]).
Regarding limitation (i), as shown in the following alignment, Aesaert’s SEQ ID NO: 27 (bottom) comprises the full-length of instant SEQ ID NO: 1 (top) and is more than 90% identical to the claimed sequence:
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Regarding limitation (iii), as shown in the following alignment, Aesaert’s SEQ ID NO: 40 (bottom) comprises the full-length of instant SEQ ID NO: 49 (top) and is more than 90% identical to the claimed sequence:
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Regarding limitation (ii), while Aesaert teaches one of the glycosyltransferases is a beta-1,3-galactosyltransferase protein, Aesaert does not teach an amino acid sequence that at least 90% identical to SEQ ID NO: 4 or 5.
However, Aesaert teaches that galactosyltransferases are glycosyltransferases that transfer a galactosyl group (Gal) from a UDP-galactose (UDP-Gal) donor onto a glycan acceptor and can be found in GT2 and GT25 CAZy families (see pg. 8, para. [0047]). Aesaert also teaches that the mixture of MMOs comprises at least one MMO of three or more monosaccharide subunits linked to each other via glycosidic bonds, wherein at least one of the monosaccharide residues is a N-acetylglucosamine (GlcNAc) residue, which can be present at the reducing end of the oligosaccharide (see pgs. 20-21, para. [0183]).
Aesaert 2023 teaches a cell metabolically engineered for production of oligosaccharides with an N-acetylglucosamine at the reducing end (see Abstract). Aesaert 2023 also teaches a method for the production of a mixture comprising an oligosaccharide having an N-acetylglucosamine (GlcNAc) unit at the reducing end and one or more lactose-based human milk oligosaccharides (HMOs), produced by a cell capable of expressing a glycosyltransferase to glycosylate the GlcNAc monosaccharide to produce the oligosaccharide, and wherein the cell is further capable of expressing one or more glycosyltransferases to glycosylate lactose to produce the lactose-based HMOs (see pg. 16, para. [0118]-[0119]). Aesaert 2023 teaches that the cell is preferably an Escherichia coli strain, more preferably an Escherichia coli strain
K-12 strain, and even more preferably the Escherichia coli K-12 strain, MG1655, (see pg. 51, para. [0650]). Aesaert 2023 teaches the cell comprises an N-acetylglucosamine beta-1,3-galactosyltransferase (see pg. 18, para. [0138]) wherein the N-acetylglucosamine beta-1,3-galactosyltransferase expressed in the cell comprises a polypeptide sequence according to SEQ ID NO: 8 (see pg. 18, para. [0144]). As shown in the following alignment, Aesaert 2023’s SEQ ID NO: 8 (bottom) is at least 90% identical to the SEQ ID NO: 5 (top):
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It should be noted that the first 4 residues of the claimed sequence are not disclosed in the prior art sequence. However, Aesaert’s SEQ ID NO: 8 comprises 257/262 residues of instant SEQ ID NO: 5, rendering the sequences at least 98% identical.
Aesaert and Aesaert 2023 do not explicitly teach the cell comprising the colanic gene cluster.
Pedersen teaches that the commercial importance of bacterial cells to produce recombinant molecules is increasing (see pg. 1, lines 11-12) and discloses a need for a simple and effective genome-based bacterial expression systems for the industrial production of recombinant polypeptides (see pg. 3, lines 1-2). Pedersen teaches nucleic acid constructs that can advantageously be used to produce a variety of human milk oligosaccharides (HMOs) recombinantly in industrial scales (see pg. 1, lines 5-8). Pedersen further teaches a bacterial recombinant cell comprising the nucleic construct, an expression system comprising the recombinant cell, and a method for the production of the oligosaccharides (see pg. 5, lines 14-22).
Regarding limitation (a), Pedersen discloses the engineering of Escherichia coli for the production of 2’FL and LNFP-I (see pg. 82, lines 8-9; pg. 83, lines 11-12). Pedersen teaches that proteins that are essential for the production of one or more HMOs by a host cell include (see pg. 29, lines 20-21):
(i) β-1,3-N-acetylglucosaminyltransferase (see pg. 29, Table 2);
(ii) β-1,3-galactosyltransferase (see pg. 29, Table 2); and
(iii) α-1,2-fucosyl-transferase (see pg. 30, Table 2).
Pedersen also teaches that the genetically engineered cell:
(iv) comprises the colanic acid gene cluster (see pg. 82, lines 10-19) which includes genes for proteins that are beneficial for the production of one or more HMOs, including, gmd, wcaG, wcaH, wcal, manB and manC (see pg. 29, lines 21-23; Table 3; pg. 82, lines 11-15); and
(v) comprises a regulatory element, such as a PglpF promoter and/or a Plac promoter, to control expression of (i)-(iv) (see pg. 34, lines 6-8; pg. 82, lines 11-15).
Pedersen discloses that the integration of an extra genomic copy of the colanic acid genes under the control of a PglpF promoter resulted in a marked improvement of the LNFP-I titer in an engineered E. coli strain (see pg. 82, lines 11-19).
Regarding limitations (b)-(c), Pedersen teaches the method for producing fucosylated HMOs comprises (b) culturing the bacterium in the presence of a carbon source and (c) retrieving a fucosylated HMO from the bacterium or from the culture supernatant of the bacterium (see pg. 54, lines 13-15).
Therefore, it would have been obvious at the time of filing for a person of ordinary skill in the art to have arrived at the claimed invention by combining the teachings of the aforementioned references for at least the following reasons:
First, one would have recognized that each reference teaches methods for producing HMOs using genetically engineered cells, with both Aesaert and Aesaert 2023 teaching methods of using such cells to produce mixtures of HMOs (i.e., HMO blends). One would have recognized that Aesaert claims a method for producing an MMO mixture using a cell genetically engineered to express an N-acetylglucosaminyl transferase, a galactosyltransferase, and a fucosyltransferase, and that Aesaert teaches the expectation that a genetically engineered cell comprising (i) a beta-1,3-N-acetylglucosaminyltransferase, (ii) a beta-1,3-galactosyltransferase, and (iii) an alpha-1,2-fucosyltransferase could be used to produce an HMO blend. One would have also recognized that Pedersen teaches the expression of enzymes in genetically engineered cells that are homologous to those disclosed by Aesaert to be useful for producing HMOs, and teaches further modifications desirable for their enhanced expression (i.e., expression of colanic acid genes and regulatory elements), which was exemplified to increase production of LNFP-I.
One would have been particularly motivated to combine these teachings, because Aesaert and Pedersen teach the importance of HMOs as an industrial product and the need for more efficient and inexpensive methods to produce said HMOs. Therefore, each reference is not only within the same field of endeavor but are also related to solving a similar problem. One would have also recognized that both Aesaert and Aesaert 2023 teach mixtures comprising a GlcNAc residue at the reducing end of the oligosaccharide, and that the beta-1,3-galactosyltransferase taught by Aesaert 2023 could have been used in the cell taught by Aesaert, because it is taught to have the same function (i.e., a functional homologue). One would have had a reasonable expectation of success when combining these prior art elements to produce HMO mixtures in light of the examples provided by these disclosures, and it was well within the ordinary skill in the art to engineer a cell expressing different glycosyltransferases and regulatory elements to produce oligosaccharides in culture. One would have recognized that the elements taught by each reference (i.e., HMO enzymes, colanic acid gene cluster, regulatory elements, etc.) could be combined by known methods and would have expected these elements to confer an advantage when used in combination. Hence, the combination would have been readily apparent and deemed to be a mere (A) combining of prior art elements according to known methods to yield predictable results (see MPEP 2143(I): Rationales to support rejections under 35 U.S.C. 103).
Regarding claim 2, Pedersen discloses that the integration of an extra genomic copy of the colanic acid genes (i.e., gmd, WcaJ, wcaH, wcal, manC and manB) expressed from the PglpF promoter resulted in a marked improvement of the LNFP-I titer (see pg. 82, lines 10-19). Pedersen teaches that gmd, wcaG, wcaH, cpsB (manC) and cpsG (manB) encode proteins that are beneficial for the production of one or more HMOs (see pg. 29, lines 21-23; Table 3) Hence, it would have been obvious to have overexpressed the colanic acid gene cluster by increasing the copy number of these genes and/or by choosing an appropriate element (i.e., PglpF promoter) in order to improve the production of LNFP-I.
Regarding claim 3, Aesaert teaches a β-1,3-N-acetylglucosaminyltransferase that is at least 90% identical to instant SEQ ID NO: 1, as discussed regarding claim 1.
Regarding claim 5, Pedersen teaches that one approach to overcome the problem of an insufficient level of production is the use of strong inducible promoters for controlling the transcription of integrated recombinant genes (see pg. 3, lines 4-6). Pedersen discloses a strain expressing the heterologous genes IgtA (a β-1,3-N-acetylglucosaminyltransferase), galTK (a β-1,3-galactosyltransferase) and futC (an α-1,2-fucosyl-transferase) from a single genomic copy under the control of the PglpF promoter (see pg. 82, lines 11-13). Pedersen also teaches embodiments wherein the host cell genome preferably comprises two or three copies of a genome-integrated expression cassette (see pg. 34, lines 22-24), wherein the expression cassette comprises genes “essential” for the production of HMOs (see pg. 34, lines 5-8). Hence, it would have been obvious to have overexpressed these proteins by increasing their copy number and/or by choosing an appropriate regulatory element (i.e., a PglpF promoter).
Regarding claim 6, Pederson teaches that in some embodiments “it is preferred that the constructs are integrated in a single copy or a low copy number” (see pg. 34, lines 29-31). In one embodiment, Pedersen teaches the gene encoding a β-1,3-N-acetylglucosaminyltransferase or a galactosyltransferase (which read on the limitations of (i) and (ii), respectively) is under the control of a Plac promoter (see pg. 59, line 31 to pg. 60, line 6). In view of the instant specification, “an activity below 3,000 MU is considered weak” and “an example of a weak promoter is Plac which… has an activity of approximately 2300 MU” (see pg. 33, lines 12-14). Hence, it would have been obvious to have obtained expression from a single copy or by selecting a regulatory element comprising an activity less than 10,000 MU.
Regarding claim 7, Pedersen teaches the host cell preferably comprises two or three copies of the genome integrated expression cassette under the control of a PglpF promoter (see pg. 34, lines 21-24). In view of the instant specification a “regulatory element with an activity above 10,000 MU is considered strong” and “[a]n example of a strong regulatory element is the PglpF promoter with an activity of approximately 14,000 MU” (see pg. 33, lines 10-12). Hence, it would have been obvious to have expressed the proteins from two or more copies of the genes or by selecting a regulatory element comprising an activity greater than 10,000 MU.
Regarding claim 8, Pedersen teaches the genetically engineered cell comprising a regulatory element, such as a PglpF promoter and/or a Plac promoter, to control expression of (i)-(iv), as discussed regarding claim 1(v). Pedersen teaches the PglpF promoter is represented by SEQ ID NO: 12 (see, e.g., pg. 70, line 2). As shown in the following alignment, instant SEQ ID NO: 13 (top) is identical to Pedersen’s SEQ ID NO: 12 (bottom):
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Regarding claim 11, Pedersen discloses a working example wherein the removal of the transcriptional repressor GlpR in an E. coli strain increased expression from the PglpF promoter element (see pg. 78, line 30 to pg. 79, line 3). In view of the instant claims, GlpR meets the limitation of “a gene product that binds to v) or regions upstream of v) and represses the expression of any one of i), ii), iii) or iv)” (see claim 12). Hence, Pedersen teaches a gene product (GlpR) that represses the expression of (i)-(iv), which are under the control of a regulatory element (PglpF promoter), and teaches the deletion of this gene product within the cell to increase expression of said regulatory element. As Pedersen teaches the promoter DNA sequence to comprise binding sites for the GlpR protein (see, e.g., pg. 16, lines 20-24), it is understood that this gene product binds to said regulatory element, “v)”.
Regarding claim 13, Aesaert discloses a mutant strain derived from E. coli K12 MG1655 which was modified to express an alpha-1,2-fucosyltransferase, HpFutC from H. pylori with SEQ ID NO: 4 (see pg. 56, para. [0642]). Aesaert further discloses an E. coli strain modified for GDP-fucose production that was further adapted for LN3 and LNT production by modifying it to express a beta-1,3-N-acetylglucosaminyltransferase (SEQ ID NO: 27, as previously discussed), a beta-1,3-glactosyltransferase and an alpha-1,2-fucosyltransferase from H. pylori with SEQ ID NO: 4 (see pg. 73, para. [0724]). Aesaert discloses that this particular strain produced an oligosaccharide mixture comprising 2’FL, DiFL, LN3, LNT and LNFP-I (see pg. 73, para. [0724]). As shown in the following alignment, Aesaert’s SEQ ID NO: 4 (bottom) is more than 90% identical to instant SEQ ID NO: 6 (top):
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It should be noted that the claimed sequence is 302 amino acids in length, while the prior art sequence is 300 amino acids in length. However, Aesaert’s SEQ ID NO: 4 still comprises 286/302 of the residues in instant SEQ ID NO: 6, rendering the sequences at least 94.7% identical.
Regarding claim 14, Aesaert and Aesaert 2023 teach the method wherein the cell further expresses a membrane transporter belonging to the family of sugar efflux transporters (see Aesaert at pg. 36, para. [0308]; Aesaert 2023 at pg. 24, para. [0181]).
Regarding claim 16, the references above do not explicitly teach the method, “wherein the HMO blend has a molar % of 2’-FL between 25% to 70% and a molar % of LNFP-I between 30% to 60% of the total HMO”. However, the claim only recites an effect of performing the method, and does not imply any further manipulative steps in the claimed process. As the claimed method is obvious over the prior art combination, the effects and properties of said method, as well as the composition used to perform said method, are presumed to be inherent. “[T]he claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable.” In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977). See also MPEP 2112(II) which states:
"Products of identical chemical composition can not have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.
Because the limitations of the claimed method are necessarily present in the prior art combination, the functional limitations of the asserted claim are inherently met by the combination of references. See MPEP 2112. Hence, claim 16 is obvious for the same reasons discussed regarding claim 1.
Regarding claim 18, Pedersen teaches the cultured cells were inoculated into a medium containing 0.5% lactose prior to incubation and harvesting of the HMOs (see pg. 74, lines 1-2), which is equivalent to a level of lactose of 5 g/L. Hence, it would have been obvious for one to have selected this lactose concentration for the fermentation medium. The aforementioned references do not explicitly teach the molar % of 2’-FL to be between 25% to 35% of the produced blend of HMOs. However, this functional limitation does not have any affect on the structure or steps of the claimed process and is directed to an inherent property. Because the limitations of the claimed method are necessarily present in the prior art combination, the functional limitations of the asserted claim are inherently met by the combination of references. See MPEP 2112 and the discussion regarding claim 16 above.
Claim(s) 4 is/are rejected under 35 U.S.C. 103 as being unpatentable over Aesaert, Aesaert 2023 and Pedersen as applied to claims 1-3, 5-8, 11, 13-14, 16 and 18 above, and in further view of NCBI Reference Sequence WP 077641768.1 (cited on Form 892), hereafter, “NCBI ‘768”, and as further evidenced by GenBank BD182026 (cited on Form 892).
Regarding claim 4, Aesaert teaches that galactosyltransferases are glycosyltransferases that transfer a galactosyl group (Gal) from a UDP-galactose (UDP-Gal) donor onto a glycan acceptor and can be found in GT2 and GT25 CAZy families, as discussed above. Aesaert teaches that the galactosyltransferase can be a beta-1,3-galactosyltransferase or a beta-1,4-galactosyltransferase (see pg. 29, para. [0242]) or both (see pg. 31, para. [0253]). Aesaert teaches that to produce lactose-based neutral fucosylated MMOs, the cell can be made to express an N-acetylglucosamine beta-1,3-galactosyltranferase and/or a beta N-acetylglucosamine beta-1,4-galactosyltransferase (see pg. 32, para. [0274]). Aesaert teaches that the cell may also express an N-acetylgalactosaminyltransferase (see pg. 32, para. [0274), and the fucosyltransferases and the N-acetylgalactosaminyltransferases can be derived from Helicobacter species, such as H. pylori (see pg. 30, para. [0244]; pg. 31, para. [0256]).
Pedersen discloses an expression cassette used to transform the cells included a galT gene derived from Helicobacter pylori functioning as a beta-1,4-galactosyltransferase as well as a galTK gene (“homologous to BD182026”) derived from Helicobacter pylori functioning as a beta-1,3-galactosyltransferase (see pg. 67, Table 9).
NCBI ‘768 is identified in GenBank as a glycosyltransferase family 25 lipo-oligosaccharide biosynthesis protein derived from Helicobacter pylori (see DEFINITION and SOURCE). The Genbank entry also identifies three particular regions of the protein, two of which are predicted to be associated with glycosyltransferase family 25, and further discloses this family of proteins to include beta-galactosyltransferases, such as beta-1,4-galactosyltransferases (see “Region”).
As shown in the following alignment, the translated product of BD182026 (bottom), disclosed by Pedersen, comprises three regions that are highly similar to those found in NCBI ‘768 (top):
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Therefore, an ordinary artisan would have recognized that NCBI ‘768 is a glycosyltransferase family 25 protein, which is a group that includes galactosyltransferases, predicted to function in the synthesis of oligosaccharides, and comprises functional domains that share high structural similarity with a known beta-1,3 glycosyltransferase that Pedersen teaches to be useful for producing HMOs.
As shown in the following alignment, NCBI ‘768 (bottom) shares more than 90% sequence similarity with instant SEQ ID NO: 4 (top) across the full-length of the sequences:
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Therefore, it would have been obvious at the time of filing for a person of ordinary skill in the art to have arrived at the claimed invention by substituting the beta-1,3 galactosyl-transferase taught by Aesaert with the beta-1,3 galactosyltransferase of NCBI ‘768, because the functions of these enzymes were known in the art and the results of substituting one known enzyme with another expected to have the same function would have been predictable. One would have expected the protein of NCBI ‘768 to be useful for producing oligosaccharides based on its predicted function and would have further recognized its highly similar structure to other known beta-1,3 galactosyltransferases. One would have also recognized that many glycosyltransferases used to produce HMOs are derived from Helicobacter pylori, and even the use of other galactosyltransferases of family 25 (e.g., beta-1,4-galactosyltransferases) were also within the scope of Aesaert’s methods for producing HMO blends. Here, it was well within the ordinary skill to have modified the cell to express any glycosyltransferase, as it is evidenced by the prior art of record (e.g., Aesaert, Aesaert 2023 and Pedersen) that such cells have been successfully modified to express various combinations of these enzymes to produce HMOs, including HMO blends. Therefore, one would have recognized there to have been a reasonable expectation of success. Hence, the combination would have been readily apparent and deemed to be a mere (B) simple substitution of one known element for another to obtain predictable results (see MPEP 2143(I): Rationales to support rejections under 35 U.S.C. 103).
Claim(s) 12 is/are rejected under 35 U.S.C. 103 as being unpatentable over Aesaert, Aesaert 2023 and Pedersen as applied to claims 1-3, 5-8, 11, 13-14, 16 and 18 above, and in further view of GenBank M96795.1 (previously cited).
Regarding claim 12, Pedersen teaches the GlpR repressor is removed to increase expression of (i)-(iv), as discussed regarding claim 11.
Pedersen does not teach the nucleotide sequence encoding GlpR (SEQ ID NO: 48).
GenBank M96795.1 is identified in GenBank as a region of Escherichia coli comprising “repressor protein (glpR) genes” (see Title and Definition). As shown in the following alignment, instant SEQ ID NO: 1 (top) is nearly identical to GenBank M96795.1 (bottom):
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It should be noted that the only difference between the two sequences is that the GenBank sequence comprises one additional nucleotide (a “C” on line 3 of the alignment). However, the GenBank sequence still comprises all 730 nucleotides of the claimed sequence, and it is identified as being a GlpR repressor in E. coli. Furthermore, the absence of either sequence, due to its deletion, in a particular E. coli strain that normally comprises said sequence would be expected to result in the same remaining structure (i.e., an E. coli strain not having either variation of the sequence).
Therefore, it would have been obvious for a person of ordinary skill in the art to have deleted any sequence identified as a repressor of GlpR, because Pedersen discloses that doing so improves the expression of heterologous enzymes used to produce HMOs. One would have recognized that in order to remove the GlpR repressor gene from the genome of E. coli, the region encoding this gene product must be identified, and that the GlpR repressor gene in E. coli is readily identifiable in public databases. It would have been readily apparent, and well-within the ordinary skill in the art, to have used any known genomic sequence corresponding to the HMO-producing bacterial species/strain in order to identify and remove this gene.
Claim(s) 15, 17 and 19-21 is/are rejected under 35 U.S.C. 103 as being unpatentable over Aesaert, Aesaert 2023 and Pedersen as applied to claims 1-3, 5-8, 11, 13-14, 16 and 18 above, and further in view of Stefan et al. (WO 2018077892 A1; previously cited), hereafter, “Stefan”, and as further evidenced by GenBank EEQ08298 (cited in the IDS filed 06/24/2024 at Cite No. 10).
Regarding claim 15, Aesaert teaches the method wherein the cell expresses a membrane transporter belonging to the family of sugar efflux transporters (see pg. 24, para. [0181]), as discussed regarding claim 14.
Pedersen teaches that the coding DNA of the construct may encode a sugar transporter protein which is normally expressed by the host bacterial cell that naturally comprises in its genome a gene encoding said sugar transporter protein (see pg. 28, lines 24-27).
However, the aforementioned references do not explicitly teach a sugar efflux transporter comprising an amino acid sequence set forth in one of SEQ ID NOs 28-33.
Stefan teaches a method for producing fucosylated oligosaccharides by using a recombinant, genetically modified prokaryotic host cell, and the transport of the produced fucosylated oligosaccharide through the cell membrane is facilitated by an exogenous transport protein (see Abstract). Stefan teaches that numerous beneficial properties of HMOs have been reported, but the occurrence and concentration of these complex oligosaccharides are specific to humans and thus cannot be found in large quantities in the milk of other mammals (see pg. 1, para. [0002]-[0003]). Stefan teaches that the most prominent HMO is 2’-fucosyllactose (2’-FL), and other prominent HMOs in human milk include lacto-N-fucopentaoses (LNFP) (see pg. 2, para. [0004]). Stefan teaches that due to the challenges involved in the chemical synthesis of HMOs, fermentative approaches have been developed using mainly genetically engineered bacterial strains, such as recombinant Escherichia coli, to produce 2’-FL and LNFP-I (see pg. 2, para. [0007]). However, even the most efficient processes based on bacterial fermentation do not hardly achieve HMO titers greater than 20 g/L, while industrial-scale processes must typically exceed titers of 50 g/L, although 100 g/L is more desirable (see pg. 2, para. [0008]).
Stefan teaches the method for the production of HMOs comprises providing a genetically modified host cell comprising an exogenous gene encoding a fucosyltransferase, preferably an alpha-1,2-fucosyltransferase, which is preferably overexpressed in the host cell (see pg. 3, para. [0010]). Stefan teaches the host cell has been further modified to express a gene encoding a protein enabling or facilitating the transport of the desired fucosylated oligosaccharide into the medium the host cell is cultivated in (see pg. 4, para. [0014]). According to a preferred embodiment, the protein that enables or facilitates the export of the desired HMO into the culture medium is the sugar efflux transporter yberc0001_9420 (see pg. 18, para. [0066]). In Stefan’s Examples, the heterologous sugar exporter yberc0001_9420 is disclosed as enhancing 2’-FL production by faster transport of the oligosaccharide outside the cell (see pg. 28, para. [00122]).
Stefan teaches that the gene yberc0001_9420 encodes a sugar efflux transporter of the major facilitator superfamily from Yersinia bercovieri ATCC 43970 and is represented by accession number “EEQ08298” (see pg. 26, para. [00111]). As shown in the following alignment, instant SEQ ID NO: 30 (top) is identical to EEQ08298 found in GenBank (bottom):
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It would have been obvious at the time of filing for a person of ordinary skill in the art to have arrived at the claimed invention by combining the teachings of the aforementioned references, because Stefan teaches that a heterologous sugar efflux transporter can effectively increase the production of HMOs. As Stefan explicitly refers to this accession number as representing the sugar efflux transporter of the disclosure, it would have readily apparent to have selected the same sequence in GenBank. One would have also recognized there to be a reasonable expectation of success when expressing this sequence in an HMO-producing cell, because Stefan provides evidence that E. coli expressing the yberc0001_9420 gene led to a higher production of 2’FL. One would have also recognized that each reference teaches the production of HMOs using genetically engineered E. coli comprising an alpha-1,2-fucosyltransferase. Therefore, one would have recognized that the elements of each reference (i.e., HMO enzymes, colanic acid gene cluster, regulatory elements, sugar efflux transporter, etc.) could be combined by known methods and that the results of the combination would have been predictable. Hence, the combination would have been readily apparent and deemed to be a mere (A) combining of prior art elements according to known methods to yield predictable results (see MPEP 2143(I): Rationales to support rejections under 35 U.S.C. 103).
Regarding claim 17, Stefan discloses that during the production of 2’FL by the strain comprising yberc0001_9420, fermentations were conducted at 30°C (see pg. 29, paras. [00125]-[00126]). Stefan does not explicitly teach the molar % of 2’-FL to be between 30% and 40% of the produced blend of HMOs. However, this limitation is directed to an inherent property that does not affect the structure or steps of the claimed invention. Because the limitations of the claimed method are necessarily present in the prior art combination, the functional limitations of the asserted claim are inherently met by the combination of references. See MPEP 2112 and the discussion regarding claim 16 above.
Regarding claim 19, limitations “i.” through “v.” are obvious for the same reasons discussed regarding claim 1. Regarding the limitation of “vi. a recombinant nucleic acid sequence encoding a sugar efflux transporter capable of exporting 2’FL and/or LNFP-I out of the cell”, Stefan teaches a sugar efflux transporter capable of exporting 2’-FL in E. coli, as discussed regarding claim 15. Hence, claim 19 is obvious for the same reasons discussed regarding claims 1 and 15.
Regarding claim 20, Pedersen discloses that the integration of an extra genomic copy of the colanic acid genes expressed from the PglpF promoter resulted in a marked improvement of the LNFP-I titer, as discussed regarding claim 2.
Regarding claim 21, Aesaert, Aesaert 2023, Pedersen and Stefan all teach the genetically engineered cell is E. coli, as discussed regarding claims 1 and 14.
Claim(s) 25 is/are rejected under 35 U.S.C. 103 as being unpatentable over Aesaert, Aesaert 2023 and Pedersen as applied to claims 1-3, 5-8, 11, 13-14, 16 and 18 above, and in further view of GenBank ARB16053.1.
Regarding claim 25, Aesaert discloses an E. coli strain modified to express a beta-1,3-N-acetylglucosaminyltransferase (SEQ ID NO: 27, as previously discussed), a beta-1,3-glactosyltransferase and an alpha-1,2-fucosyltransferase from H. pylori with SEQ ID NO: 4 (see pg. 73, para. [0724]), as discussed regarding claim 13. As previously discussed, Aesaert’s SEQ ID NO: 4 is 94.7% identical to instant SEQ ID NO: 6.
Aesaert also teaches that fucosyltransferases are glycosyltransferases that transfer a fucose residue (Fuc) from a GDP-fucose (GDP-Fuc) donor onto a glycan acceptor (see pg. 8, para. [0047]).
GenBank ARB16053.1 is identified as an alpha-1,2-fucosyltransferase derived from Helicobacter pylori (see DEFINITION) comprising a GDP-Fucose binding site (see “Site”). As shown in the following alignment, the GenBank sequence (bottom) is more than 95% identical to instant SEQ ID NO: 6 (top):
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It should be noted that the claimed sequence is 302 amino acids in length, while the prior art sequence is 300 amino acids in length. However, the GenBank sequence still comprises 300/302 of the residues in instant SEQ ID NO: 6, rendering the sequences at least 99% identical.
Therefore, it would have been obvious at the time of filing for a person of ordinary skill in the art to have arrived at the claimed invention by substituting the alpha-1,2-fucosyltransferase from H. pylori taught by Aesaert with the alpha-1,2-fucosyltransferase from H. pylori found in GenBank, because the functions of these enzymes were known in the art and the results of substituting one known enzyme with another having the same function would have been predictable. One would have expected the protein of the GenBank to be useful for producing oligosaccharides based on its predicted function and would have further recognized its highly similar structure to the alpha-1,2-fucosyltransferase taught by Aesaert. One would have also recognized that many glycosyltransferases used to produce HMOs are derived from Helicobacter pylori. Here, it was well within the ordinary skill to have modified the cell to express any glycosyltransferase, as it is evidenced by the prior art of record (e.g., Aesaert, Aesaert 2023 and Pedersen) that such cells have been successfully modified to express various combinations of these enzymes to produce HMOs, including HMO blends. Therefore, one would have recognized there to have been a reasonable expectation of success. Hence, the combination would have been readily apparent and deemed to be a mere (B) simple substitution of one known element for another to obtain predictable results (see MPEP 2143(I): Rationales to support rejections under 35 U.S.C. 103).
Response to Arguments
Regarding the written description rejection under 35 U.S.C. 112(a), Applicant makes the following arguments:
(1) Applicant presently amends claims 1 and 19 to require at least 90% sequence identity to the recited sequences for the functional homologues, which represents a modest subset of these classes of compounds.
(2) Applicant argues that alpha-1,2-fucosyltransferase, beta-1,3-galactosyltransferase, and beta-1,3-N-acetyl-glucosaminyltransferase proteins are well characterized in the literature and a skilled artisan would have significant knowledge regarding the structure and function of these proteins. A simple NCBI search shows that there are thousands of compounds with these classifications, and these enzyme classifications are associated with each of their recited functions.
(3) Applicant argues that a skilled artisan would readily appreciate that the data disclosed in the present specification supports that sequence identity is not critical to the claimed invention. For example, MP1 contains FutC (SEQ ID NO: 6) and MP4 contains Mtun (SEQ ID NO: 7) as the alpha-1,2-fucosyltransferase protein, and while these sequences share only 29% identity, both were found to produce the claimed blend. This evidence suggests that the function (i.e., transferring a fucose moiety from GDP-fucose to a lactose) is more important than the structure provided by the sequence as it pertains to the claimed alpha-1,2-fucosyltransferase protein or a functional homologue thereof.
(3) Applicant further argues that a skilled artisan could have derived from techniques in Izidoro et al., Bioinformatics 31: 864-870 (2015) and Jumper et al., Nature. 596:583-589 (2021), that substitutions in an alpha-1,2-fucosyltransferase at positions 13, 45, 114, 166, 168, 171, 205, 234, and 250 should be avoided to maintain protein activity as described in WO2025/190861, pp. 8-9 and Figure 8A and 8B (explaining the rationale derived from protein structure available at the time of filing of the instant application).
(4) Applicant further argues that there are more than 190 natural alpha-fucosyltransferase homologues from Helicobacter pylori in the UniProt database which have a sequence identity between 85% and 98%, so the skilled person has an ample source to identify conserved positions in the enzyme and would be aware of what changes may affect functionality. Applicant further cites prior art references teaching mutation sites for increasing 2’-FL production and prior art teaching other mutation sites in FutC.
(5) Applicant further argues that the present inventors demonstrated that a beta-1,3-galactosyltransferase (GalTK; SEQ ID NO: 4) and a beta-1,3-N-acetyl-glucosaminyltransferase (IgtA; SEQ ID NO: 1) could be used to produce a blend of 2’FL and LNFP-I, and Applicant submits that a skilled artisan would appreciate that these enzymes are known to produce the same precursors (LNT and LNT-II, respectively) as their functional homologues, e.g., CvbGalT (SEQ ID NO: 5), HD0466 (SEQ ID NO: 3) and PmnagT (SEQ ID NO: 2), and the desired result of a specific HMO blend is achievable by having these shared functions.
Applicant’s arguments have been fully considered and are found to be persuasive.
Upon further consideration, the examiner agrees that the recited enzymes are defined by their respective functions, and their structures are well known and characterized in the prior art of record. Further, the limitation of “at least 90%” sequence identity reasonably limits the enzyme structure to substitutions which would include conservative amino acids. Therefore, a person having ordinary skill in the art would be able to recognize enzymes having the same function and may know where to modify such enzymes to maintain functional equivalency. In review of the prior art of record, there appears to be numerous structures associated with and characterized by the respective functions of the three genera of glycosyltransferases recited in the claims, which is sufficient to show possession of the claimed genus. Accordingly, the rejection has been withdrawn.
Regarding the rejection of claims 1-8, 11, 13, 16 and 18 under 35 U.S.C. 103, Applicant argues that, as indicated in the above interview summary, the Office erred in providing an accurate reference to the relied-upon sequence. The error was not a mere typographical error. Thus, Applicant respectfully requests withdrawal of the pending obviousness rejection for failing to establish a prima facie case of obviousness, which the Office has implicitly acknowledged by recognizing the error. Alternatively, Applicant respectfully requests that the finality of any subsequent rejection over Pedersen in view of McCoy be withdrawn if the rejection is maintained.
In the interview summary on page 7, Applicant states that the examiner clarified that a mistake was made in the obviousness rejection and that Genbank ID BD 182026 was intended instead of GenBank ID AB050723 identified in the Office Action on page 18. The examiner clarified that the sequence alignment listed on page 19 is correct and refers to Genbank ID BD 182026, not GenBank ID AB050723 as indicated on page 18 of the Office Action.
Applicant’s arguments with respect to the rejection(s) of claim(s) 1-8, 11, 13, 16 and 18 under 35 U.S.C. 103 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, new ground(s) of rejections are made in view of Aesaert, Aesaert 2023 and Pedersen, and further in view of NCBI Reference Sequence WP 077641768.1 in the case of claim 4, which have been necessitated by Applicant’s amendments to the claims.
Examiner acknowledges the error of referring to the GenBank accession AB050723, disclosed in Table 2 of Pedersen’s disclosure, when the GenBank accession BD182026, disclosed in Table 9 of Pedersen’s disclosure, was intended and used in the sequence alignment regarding limitation “ii” of claim 1.
However, the finality of the present office action is still deemed proper, because the amendments to the claims necessitated a new grounds of rejection requiring new prior art. It should be noted that no rejection in the present office action relies upon the prior art of McCoy, and further, the amendments to the claims necessitated a further search of the prior art leading to a new grounds of rejection which could not have been using the previous prior art combination.
Per MPEP 706.07(a), second or any subsequent actions on the merits shall be final, except where the examiner introduces a new ground of rejection that is neither necessitated by applicant’s amendment of the claims, nor based on information submitted in an information disclosure statement filed during the period set forth in 37 CFR 1.97(c) with the fee set forth in 37 CFR 1.17(p). Further, a dependent claim is treated as amended if the independent claim or any claim it references is amended because a dependent claim incorporates all the subject matter of the referenced claim(s). In the instant case, the amendments to at least claims 1 and 4, as well as any depending claim, necessitated a new grounds of rejection relying on new prior art.
In particular, the claim 1 limitation of “a functional homologue” of a “heterologous β-1,3-galactosyltransferase protein” has been amended to require an amino acid sequence at least 90% identical to SEQ ID NO: 4 or 5, which necessitated a new grounds of rejection, because even the correct sequence of GenBank BD182026 does not share this percent identity. This required a further search of the prior art leading to the present rejection in view of Aesaert, Aesaert 2023 and Pedersen.
Similarly, the claim 4 limitation of “wherein the heterologous β-1,3-galactosyltransferase protein comprises… a functional homologue thereof with an amino acid sequence at least 90% identical to SEQ ID NO: 4” necessitated a new grounds of rejection in view of the prior art above, and in further view of NCBI Reference Sequence WP 077641768.1. The examiner notes that while BD182026, as disclosed by Pedersen, is used as evidence to support the rejection, additional prior art was still required to meet the claimed limitation of “at least 90%” sequence identity.
In the spirit of compact prosecution, Applicant addresses the intended rejection of
Pedersen in view of McCoy where Genbank ID BD 182026 is substituted for GenBank ID
AB050723. Applicant argues that the protein associated with GenBank ID BD182026 only has 82.6% sequence identity with instant SEQ ID NO: 4.
Applicant’s arguments with respect to the limitation of instant SEQ ID NO: 4 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
In the instant case, the present rejection further relies upon Aesaert, Aesaert 2023 and the NCBI Reference Sequence, WP 077641768.1, and does not rely upon the prior art of McCoy.
Applicant further argues that one skilled in the art would not combine Pedersen and McCoy in the manner suggested by the Office Action, because the alpha-1,2-fucosylases relied upon in the Office Action were characterized as inferior to the novel alpha-1,2-fucosylases disclosed by McCoy. A skilled artisan upon reading McCoy would observe that McCoy teaches improved alpha-1,2-fucosyltransferases with minimal sequence identity to the originally-known sequence. McCoy also fails to disclose any production of HMOs using SEQ ID NO: 1.
Applicant’s arguments have been fully considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument. In the instant case, the McCoy reference is not relied upon in the rejection.
Applicant further argues that as discussed in the present application and in Pedersen and McCoy, the field was motivated to produce a single HMO by fermentative methods with the highest yield and lowest amount of impurities. Consequently, a skilled artisan would not be motivated to alter Pedersen in any manner that might increase the level of impurities, such as modifying the enzymes included in Pedersen' s genetically modified cells.
Applicant's arguments have been fully considered but they are not persuasive.
Applicant’s argument is also, at least in part, moot, because the McCoy reference is not relied upon in the present rejection.
Applicant has not submitted any objective evidence to demonstrate that there was a lack of motivation in “the field” that would necessarily discourage one from combining the prior art teachings of Pedersen with other prior art teachings related to the fermentative production of HMOs. Furthermore, there does not appear to be any mention of “impurities” in the Pedersen reference. Furthermore, Pedersen recites methods to produce “one or more” HMOs throughout the disclosure (see, e.g., pg. 29, lines 20-23) and does not appear to teach away from producing more than a “single HMO”.
Applicant is reminded that “[t]he use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain." In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)). Further, “[a] reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989). See MPEP 2123. As the methods of Aesaert necessarily require the expression of multiple glycosyltransferases to produce HMO mixtures, and these same enzymes are already known for the production of single HMOs, an ordinary artisan would have considered Pedersen’s teachings, particularly as they relate to the improved expression of these enzymes.
Applicant further argues that the genus of known alpha-1,2-fucosyltransferases is vast. A Genbank search of "alpha-1,2-fucosyltransferase" returns 10,744 protein entries. Despite Pedersen and McCoy disclosing α-1,2-fucosyltransferases, one skilled in the art would appreciate that not all a-1,2-fucosyltransferases are equivalent. Indeed, McCoy's novel alpha-1,2-fucosyltransferases are allegedly superior to the known alpha-1,2-fucosyltransferases. In re Ruff, 256 F.2d 590, 599 (CCPA 1958) ("The
equivalence must be disclosed in the prior art").
Applicant's arguments have been fully considered but they are not persuasive.
Applicant’s argument is also, at least in part, moot, because the McCoy reference is not relied upon in the present rejection.
As discussed in the present rejection, Aesaert explicitly discloses producing a mixture of HMOs using a cell comprising glycosyltransferases that are within the scope of claim 1, which includes at least two different alpha-1,2-fucosyltransferases that are within the scope of the claims (i.e., at least 90% identical to SEQ ID NOs 6 and 49). Therefore, there was no need for one to have blindly selected any enzyme having this classification from a long list of protein entries in order to have arrived at the claimed invention.
While it is unclear how Applicant’s citing of In re Ruff pertains to the rejection, this argument is moot, because it appears to be disparaging the examiner’s previous use of the McCoy reference. It should be noted that a patent reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. See the present rejection for further discussion.
Applicant further argues that Pedersen does not disclose the production of a blend of 2'-FL and LNFP-I by the cell of Example 14. Instead, Figure 14 only shows the production of LNFP-1. Example 17 of Pedersen separately discloses production of 2'FL
with a different genetically modified E. coli. Specific genetic modifications to E. coli are also disclosed in Pedersen to produce LNnT (Example 12, Figs. 12A & 12B), LNT (Example 13, Figs. 13A & 13B), 3'-SL (Example 15, Fig. 15), and 6'-SL (Example 16, Fig. 16). In each instance, Pedersen discloses the production of a single HMO.
Applicant's arguments have been fully considered but they are not persuasive.
In response to applicant's argument that Pedersen only discloses the production of a single HMO, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
In the instant case, the present rejection relies upon the teachings of Aesaert and Aesaert 2023 who explicitly teach the production of HMO mixtures. Furthermore, an ordinary artisan would have recognized from Pedersen the advantage of overexpressing the colanic acid gene cluster when producing one or more HMOs. It should be noted that the same types of glycosyltransferases are involved in the production of HMOs in each disclosure (i.e., glucosaminyl transferases, galactosyltransferases, fucosyltransferases), whether or not a “blend” was an express objective of every disclosure used in the rejection. Furthermore, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). See the present rejection for further discussion.
Applicant further argues that like Pedersen, McCoy teaches production of a single HMO. McCoy references production of a "purified fucosylated oligosaccharide" and that the "purified fucosylated oligosaccharide" could be "2'-FL, LDFT, LNF I or LDFH I." However, McCoy only exemplifies the production of 2' -FL.
Applicant’s arguments have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
In light of the above, Applicant argues that Pedersen and McCoy fail to add to the "nonexistent" literature surrounding the production of an HMO blend. Specification, p. 1, 1.36 - p. 2, 1.2. As producing an HMO blend has not been described to Applicant's knowledge, the technology is inherently unpredictable. Therefore, a person of ordinary skill would not enjoy a reasonable expectation of success.
Applicant's arguments have been fully considered but they are not persuasive.
Applicant’s argument is also, at least in part, moot, because the McCoy reference is not relied upon in the present rejection.
As discussed in the present rejection, Aesaert and Aesaert 2023 explicitly teach the production of HMO mixtures by engineering cells to express glycosyltransferases. See the present rejection for further discussion.
Regarding the rejection of claim 12 under 35 U.S.C. 103, Applicant argues that the deficiencies noted above with respect to Pedersen and McCoy, which are incorporated here, are not remedied by Genbank M96795.1.
Applicant's arguments have been fully considered but they are not persuasive.
Applicant’s argument is also, at least in part, moot, because the McCoy reference is not relied upon in the present rejection.
The alleged deficiencies with respect to Pedersen have been fully addressed above. See the present rejection for further discussion.
Regarding the rejections under 35 U.S.C. 103 in further view of Stefan, Applicant argues that Stefan is yet another example where the inventors sought to produce a single HMO. Therefore, the deficiencies noted above with respect to Pedersen and McCoy are not remedied by Stefan.
Applicant's arguments have been fully considered but they are not persuasive.
In response to applicant's argument that Stefan only discloses the production of a single HMO, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
In the instant case, the present rejection relies upon the teachings of Aesaert and Aesaert 2023 who explicitly teach the production of HMO mixtures. Furthermore, an ordinary artisan would have recognized from Stefan the advantage of using a sugar efflux transporter to increase HMO production. Applicant’s argument fails to specifically point out any other deficiencies with respect to the Stefan reference.
Regarding the rejections under 35 U.S.C. 103 in further view of Stefan as further evidenced by GenBank EEQ08298, Applicant argues that the Office Action acknowledges that none of the cited art discloses SEQ ID NO: 30 and advances Genbank EEQ8298 for the limited purpose of allegedly teaching SEQ ID NO: 30. Applicant respectfully submits that the deficiencies noted above with respect to Pedersen and McCoy, which are incorporated here, are not remedied by Stefan as evidenced by Genbank EEQ.
Applicant's arguments have been fully considered but they are not persuasive.
Applicant's arguments fail to comply with 37 CFR 1.111(b) because they amount to a general allegation that the claims define a patentable invention without specifically pointing out how the language of the claims patentably distinguishes them from the references.
In the instant case, GenBank EEQ8298 is also cited prior art, as it is expressly relied upon by the examiner in the rejection. Therefore, the statement “the Office Action acknowledges that none of the cited art discloses SEQ ID NO: 30” is incorrect. Moreover, Applicant appears to disparage this reference as being advanced for a “limited purpose” without specifically pointing out how it fails to teach the limitation at issue.
Furthermore, the alleged deficiencies of Pedersen and Stefan have been fully addressed above.
Applicant further contests the inherency findings in the Office Action with respect to claims 16-18. Notably, the inventors found that protein selection allows for modification of the ratio between 2'-FL and LNFP-1. Specification, p. 15, 11. 21-24. Still further, the specification makes clear that fermentative conditions can influence the composition of the HMO blend. See, e.g., Specification, p. 47, 11. 22-28. "The fact that a certain result or characteristic may occur or be present in the prior art is not sufficient to establish the inherency of that result or characteristic." MPEP 2112 (emphasis in original). The Office Action fails to establish that the claimed characteristics must occur or be present in the cited art in order to rely on the inherency doctrine.
Applicant's arguments have been fully considered but they are not persuasive.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., fermentation conditions which can influence the composition of the HMO blend) 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). While claims 17-18 recite temperature and a level of lactose, respectively, claim 16 does not recite any such condition. Furthermore, the recited conditions are taught by the prior art used in the rejection. Hence, it is unclear whether Applicant means to imply that there are further conditions required by the claims in order to achieve the recited effects.
Regarding inherency, a functional limitation is inherently present in a prior art combination if the explicitly taught structural and manipulative elements necessarily result in that specific function. Per MPEP 2112(IV), the examiner may provide rationale or evidence to show inherency, and the examiner’s rationale is in line with this section of the MPEP:
"[I]n order to rely on inherency to establish the existence of a claim limitation in the prior art in an obviousness analysis – the limitation at issue necessarily must be present, or the natural result of the combination of elements explicitly disclosed by the prior art." Ex parte Levy, at 1195-96, 112 USPQ2d at 1952 (Emphasis added). But see, Persion Pharms. LLC v. Alvogen Malta perations LTD., 945 F.3d 1184, 1191, 2019 USPQ2d 494084 (Fed. Cir. 2019), where the court stated that a proper finding of inherency does not require that all limitations are taught in a single reference, and that inherency may meet a missing claim limitation when the limitation is "the natural result of the combination of prior art elements." (emphasis in original). The court found that pharmacokinetic limitations of the asserted claims were inherently met by combining prior art references because the limitations were necessarily present in the prior art combination. Id. See also Hospira, Inc. v. Fresenius Kabi USA, LLC, 946 F.3d 1322, 1329-32, 2020 USPQ2d 6227 (Fed. Cir. 2020).
See also MPEP 2112(II) which states, “[t]here is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003).”
In the instant case, claim 16 does not recite any further step or require any further structure in order to produce the effects resulting from the method of claim 1. Therefore, these results are necessarily present when performing the claimed method. As the combination of prior art elements, each of which are explicitly disclosed in the prior art, lies entirely within the scope of the claim, the functional limitations of the claim are properly presumed to be the natural result of combining these elements, regardless of whether these effects were known at the time of filing. Similarly, claims 17-18 recite further functional limitations that must necessarily flow from performing the method of each claim. As each of the required manipulative steps and recited structures are explicitly disclosed in the prior art combination, the examiner’s rationale in determining inherency regarding the recited functional limitations is still deemed proper, absent evidence to the contrary.
Conclusion
No claims are allowed.
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 DENNIS ARMATO whose telephone number is (703)756-5348. The examiner can normally be reached Mon-Fri 11:00am-7:30pm EST.
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/DENNIS IGNATIUS ARMATO JR/Examiner, Art Unit 1651
/MELENIE L GORDON/Supervisory Patent Examiner, Art Unit 1651
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