DETAILED ACTION
Status of the Application
Claims 1, 3-7, 9-11, 15-28, 30-31, 33, 35-38, 40-41, 91 are pending.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s amendment of claims 1, 3-7, 9, 11, 15-16, 19-20, 22, 25-27, 30, 33, 35-37, addition of claim 91 and cancellation of claim 90 as submitted in a communication filed on 8/12/2025.
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 8/12/2025 has been entered.
New claim 91 is directed to the elected invention. Claims 1, 3-7, 9-11, 15-28, 30-31, 33, 35-38, 40-41 and 91 are at issue and will be examined only to the extent they encompass the elected invention.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 8/12/2025 and 1/12/2026 are acknowledged. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Claim Objections
Claims 1, 3-7, 9-11, 15-28, 30-31, 33, 35-38, 40-41 remain objected for being directed in part to non-elected inventions. Applicant argues that it would be unfair to remove sequences other than SEQ ID NO: 3 from the claims because that would fragment an invention that is best understood and most efficiently examined as a unified whole. Applicant’s arguments have been fully considered. However, Applicant is reminded that as result of an election, the remaining inventions encompassed by the claims are ”non-elected”, which is the basis of the objection. Appropriate correction is required.
Claim 1 is objected to due to the recitation of “…polypeptide having 72.50% or more sequence identity to the full-length of SEQ ID NO: …”. To enhance clarity and to be consistent with commonly used claim language, the term should be amended to recite “…polypeptide having 72.50% or more sequence identity to the full-length of the polypeptide of SEQ ID NO: …”. Appropriate correction is required.
Claim 9 is objected to due to the recitation of “(ii) is a polypeptide having 50.50% or more sequence identity to the full-length of any one of SEQ ID NO: …”. To enhance clarity and to be consistent with commonly used claim language, the term should be amended to recite “(ii) is a polypeptide having 50.50% or more sequence identity to the full-length of any one of the polypeptides of SEQ ID NO: …”. Appropriate correction is required.
Claim 11 is objected to due to the recitation of “iv)…….in culture medium under conditions permissive to express…”. To enhance clarity and to be consistent with commonly used claim language, the term should be amended to recite “iv)…….in a culture medium under conditions permissive to express…”. Appropriate correction is required.
Claim 35 is objected to due to the recitation of …concentration, such, that….”. To enhance clarity, the comma between “such” and “that” should be deleted to recite “….concentration, such that…..”. Appropriate correction is required.
Claim 91 is objected to due to the recitation of “wbO gene”. It is believed the correct term is “wbgO gene”. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b) or Second Paragraph (pre-AIA )
Claims 1, 3-7, 9-11, 15-28, 30-31, 33, 35-38, 40-41 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 pre-AIA the applicant regards as the invention. New grounds of rejection are necessitated by amendment.
Claim 1 (claims 3-7, 9-11, 15-28, 30-31, 33, 35-38, 40-41 dependent thereon) is indefinite in the recitation of “means for catalyzing the transfer of….and wherein the means comprises the polypeptide of SEQ ID NO: …” for the following reasons. The term “means” is equivalent to something that is useful or helpful to a desired end. Because “something” can be anything, it is unclear as to what is encompassed by the term so that the metes and bounds of the claims can be determined. Does the method require anything that can catalyze the reaction beyond the presence of the recited polypeptide? For examination purposes, it will be assumed that the claimed method requires anything that can catalyze the transfer of a fucose residue from the GDP-fucose to the glucose residue of Gal-β1, 3-GlcNAc-β1, 3-Gal-β1, 4-Glc in an α-1,3-linkage. Correction is required.
Claim 3 is indefinite in the recitation of “wherein said fucosylated compound comprises an oligosaccharide comprising the pentasaccharide Gal-β1, 3-GlcNAc-β1, 3-Gal-β1, 4-[Fuc-α1,3]-Glc, wherein said pentasaccharide is modified with at least one additional monosaccharide” for the following reasons. If the pentasaccharide is modified with an additional monosaccharide, the fucosylated compound may no longer comprise the pentasaccharide Gal-β1, 3-GlcNAc-β1, 3-Gal-β1, 4-[Fuc-α1,3]-Glc. If, for example, the pentasaccharide is modified to replace one of the saccharides with monosaccharide X within the structure of the pentasaccharide, such that the pentasaccharide’s structure after the modification has the structure Gal-β1, 3-GlcNAc-β1, 3-X-β1, 4-[Fuc-α1,3]-Glc, the fucosylated compound will no longer have the structure Gal-β1, 3-GlcNAc-β1, 3-Gal-β1, 4-[Fuc-α1,3]-Glc. If this is the case, the scope of claim 3 would not be encompassed by claim 1 because claim 1 requires the fucosylated compound to have the pentasaccharide Gal-β1, 3-GlcNAc-β1, 3-Gal-β1, 4-[Fuc-α1,3]-Glc. Claim 3 is broader in scope and does not further limit claim 1. Correction is required.
Claim 5 is indefinite in the recitation of “…saccharide substrate: comprises an oligosaccharide comprising the tetrasaccharide Gal-β1, 3-GlcNAc-β1, 3-Gal-β1, 4-Glc, wherein the tetrasaccharide is modified with at least one additional monosaccharide …” for the following reasons. If the tetrasaccharide is modified with an additional monosaccharide, the saccharide substrate may no longer comprise the tetrasaccharide Gal-β1, 3-GlcNAc-β1, 3-Gal-β1, 4-Glc. If, for example, the tetrasaccharide is modified to replace one of the saccharides with monosaccharide X within the structure of the tetrasaccharide, such that the tetrasaccharide ‘s structure after the modification has the structure Gal-β1, 3-GlcNAc-β1, 3-X-β1, 4-Glc, the saccharide substrate will no longer have the structure Gal-β1, 3-GlcNAc-β1, 3-Gal-β1, 4-Glc. If this is the case, the scope of claim 5 would not be encompassed by claim 1 because claim 1 requires the saccharide substrate to have the tetrasaccharide Gal-β1, 3-GlcNAc-β1, 3-Gal-β1, 4-Glc. Claim 5 is broader in scope and does not further limit claim 1. Correction is required.
Claim 6 is indefinite in the recitation of “wherein said means has additional alpha-1,3-fucosyltransferase activity on a monosaccharide …” for the following reasons. There is no mention of alpha-1,3-fucosyltransferase activity in claim 1. In addition, as indicated above, the term “means” is equivalent to something that is useful or helpful to a desired end. Because “something” can be anything, it is unclear as to what is encompassed by the term so that the metes and bounds of the claims can be determined. For examination purposes, it will be assumed that claim 6 is a duplicate of claim 1 as interpreted above. Correction is required.
Claim 7 is indefinite in the recitation of “wherein said means has alpha-1,4-fucosyltransferase activity on (i) said saccharide substrate, (ii) a monosaccharide, (iii) a disaccharide and/or (iv) an oligosaccharide, optionally wherein said monosaccharide, disaccharide …is linked to a peptide, a protein and/or a lipid” for the following reasons. As indicated above, the term “means” is equivalent to something that is useful or helpful to a desired end. Because “something” can be anything, it is unclear as to what is encompassed by the term so that the metes and bounds of the claims can be determined. For examination purposes, it will be assumed that claim 6 is a duplicate of claim 1 as interpreted above, wherein the method also requires anything that has alpha-1,4-fucosyltransferase activity Correction is required.
Claim 9 is indefinite in the recitation of “wherein said means has α-1,3-fucosyltransferase activity on the GLC residue of LNT and comprises any one of the polypeptides of SEQ ID NO: …3, or is a polypeptide having 50.50% or more sequence identity to the full length of…SEQ ID NO: …3…” for the following reasons. Claim 1 requires the means to be a polypeptide having at least 72.5% sequence identity to, for example, the protein of SEQ ID NO: 3. Claim 9 requires the means to be a polypeptide having at least 50.50% sequence identity to, for example, the polypeptide of SEQ ID NO: 3. Therefore, the scope of claim 9 is broader than the scope of claim 1. Claim 9 does not further limit claim 1. Correction is required.
Claim 25 is indefinite in the recitation of “….or polypeptide having transport activity…(a) provides improved production and/or (b) enabled and/or enhanced flow across the outer membrane of the cell wall of said fucosylated compound compared to a method wherein the cell used does not have modified or increased expression or activity of an endogenous…. and/or compared to a method wherein the cell does not express a heterologous membrane transport protein” for the following reasons.
The method requires a comparison with a genus of methods that require a genus of cells that do not have modified or increased expression of a genus of endogenous membrane transporters or a genus of cells that do not express a genus of heterologous membrane transporter proteins. The basis for comparison is variable, thus making the determination as to what is encompassed and what is excluded impossible. For example, the same method having the recited limitations can be encompassed by the claim if the method used for comparison is one that uses cell X that has an endogenous membrane transporter Y, and not encompassed by the claim if the method used for comparison is one that uses cell Y that has an endogenous membrane transporter Z. For examination purposes, it will be assumed that claim 25 is a duplicate of claim 22. Correction is required.
Claim 27 is indefinite in the recitation of “wherein said cell produces 90 g/L or more of said fucosylated compound in whole broth and/or supernatant of the cultivation, wherein the supernatant is the cultivation medium obtained after cell culturing and cell removal” for the following reasons. It is unclear as to what whole broth of the cultivation is. Does the term refer to the cultivation medium after the cultivation step that includes the cells? If this is the case, the claim should be amended accordingly. Correction is required.
Claim 31 is indefinite in the recitation of “…the method comprising at least one of the following:….ii) adding to the culture medium in a reactor at least one precursor feed for producing…wherein a total reactor volume ranges….” for the following reasons. There is no mention in claim 31 or claim 11 of a reactor, or any mention in claim 31 that the cultivation of step iv) is carried out in a reactor. Please note that while Applicant states that the “reactor” has been mentioned in the specification, the issue is not whether the term has been defined in the specification or that one of skill in the art would not know what a reactor is. Instead, the issue is whether the term as recited in the claim is clear. In addition, the term “a total reactor volume” is unclear because one cannot determine if the volume refers to the reactor where the culture medium is present. For examination purposes, no patentable weight will be given to the term “ii) adding to the culture medium in a reactor at least one precursor feed for producing…wherein a total reactor volume ranges….”. Correction is required.
Claim 31 is indefinite in the recitation of “…the method comprising at least one of the following…iii) adding to the culture medium in a reactor at least one precursor feed for producing…wherein the total reactor volume ranges from …., optionally in a continuous manner, and optionally so that a final volume of the culture medium is not more than three-fold the volume of the initial culture medium” for the following reasons. There is no mention in claim 31 or claim 11 of a reactor, or any mention in claim 31 that the cultivation of step iv) is carried out in a reactor. Please note that while Applicant states that the “reactor” has been mentioned in the specification, the issue is not whether the term has been defined in the specification or that one of skill in the art would not know what a reactor is. Instead, the issue is whether the term as recited in the claim is clear. In addition, the term “optionally in a continuous manner” is unclear because one cannot determine what is carried out in a continuous manner. Moreover, the term “optionally so that a final volume of the culture medium is not more than three-fold the volume of the initial culture medium” is unclear because one cannot determine how the limitations regarding an initial and final volume relate to the step of adding the precursor feed. It should be noted that even if one assumes that the limitation in part iii) refers to adding a precursor feed continuously, a limitation defining the final volume based on an initial volume is unclear because if one adds something continuously, there is no initial volume. For examination purposes, no patentable weight will be given to the term “iii) adding to the culture medium in a reactor at least one precursor feed for producing…wherein the total reactor volume ranges from …., optionally in a continuous manner, and optionally so that a final volume of the culture medium is not more than three-fold the volume of the initial culture medium”. Correction is required.
Claim 33 is indefinite in the recitation of “the method comprising at least one of the following: i) utilizing a culture medium comprising at least 50 grams of lactose per liter of initial culture medium in a reactor wherein the volume of the reactor ranges from….; ii) adding to culture medium a lactose feed comprising at least 50 grams of lactose per liter of initial culture medium in a reactor wherein the volume of the reactor ranges…..” for the following reasons. There is no mention in claim 11 of a reactor, or any mention in claim 33 that the cultivation of step iv) is carried out in a reactor. Moreover, it is unclear as to which is the “initial” culture medium and whether the components of the initial culture medium and those of the culture medium referred to in parts i) and ii) are the same except for the presence of lactose at the recited concentration. With regard to part ii), it is unclear as to which is the culture medium to which the lactose feed is added since there is no “a” or “the” prior to the term “culture medium”. If the intended feed is a lactose feed that comprises at least 50 grams of lactose per liter of lactose feed, the claim should be amended accordingly. For examination purposes, no patentable weight will be given to parts i) and ii). Correction is required.
Claim 36 is indefinite in the recitation of “wherein said cell is cultivated….in a culture medium comprising a carbon source comprising a monosaccharide…..pyruvate and a complex medium comprising molasses, corn steep liquor….and yeast extract; optionally the culture medium…” for the following reasons. As written, it is unclear if the cell should be cultivated in two different culture media, one that comprises the recited carbon sources and another one that is a complex medium comprising molasses, corn steep liquor , peptone, tryptone, and yeast extract. For examination purposes, no patentable weight will be given to the term “in a culture medium comprising a carbon source…(LacNAc)”. Correction is required.
When amending the claims, applicant is advised to carefully review all examined claims and make the necessary changes to ensure proper antecedent basis and dependency.
Claim Rejections - 35 USC § 112(a) or First Paragraph (pre-AIA )
Claims 1, 3-7, 9-11, 15-28, 30-31, 33, 35-38, 40-41 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This rejection is necessitated due to the introduction of new matter.
As set forth in MPEP 2163 (I)(B), new or amended claims which introduce elements or limitations that are not supported by the as-filed disclosure violate the written description requirement. See, e.g., In re Lukach, 442 F.2d 967, 169 USPQ 795 (CCPA 1971) (subgenus range was not supported by generic disclosure and specific example within the subgenus range); In re Smith, 458 F.2d 1389, 1395, 173 USPQ 679, 683 (CCPA 1972) (an adequate description of a genus may not support claims to a subgenus or species within the genus).
Amended claims 1, 3-7, 9-11, 15-28, 30-31, 33, 35-38, 40-41 are now directed in part to a method that requires any means for catalyzing the transfer of a fucose residue from GDP-fucose to the Glc residue of a saccharide substrate that comprises Gal-β1, 3-GlcNAc-β1, 3-Gal-β1, 4-Glc, wherein said means comprises the polypeptide of SEQ ID NO: 3. As indicated above, the term “means” encompass anything that is useful or helpful to a desired end. While the Examiner has been able to find support for an enzyme that has α-1,3 fucosyltransferase activity and can catalyze the transfer of a fucose residue in GDP-fucose to the Glc residue of a saccharide substrate that comprises Gal-β1, 3-GlcNAc-β1, 3-Gal-β1, 4-Glc, the Examiner has not been able to find any mention of any means able to catalyze the recited transfer or any means that is able to catalyze the recited transfer and comprises the recited polypeptide. Also, amended claim 37 now requires a method that comprises culturing a cell, wherein said culturing requires two phases of exponential growth. While the Examiner has found support for culturing a cell, wherein said culturing comprises two phases, wherein exponential growth occurs in one of the phases, the Examiner has found no mention of culturing a cell in a process that requires two phases of exponential growth. There is no indication that a method that requires any means of catalyzing the recited transfer of a fucose residue from GDP-fucose or a method that requires culturing a cell in a process that comprises two phases of exponential growth were within the scope of the invention as conceived by Applicant at the time of the invention. Accordingly, Applicant is required to cancel the new matter in the response to this Office Action.
Claims 1, 3-7, 9-11, 15-28, 30-31, 33, 35-38, 40-41 remain 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
This rejection has been discussed at length in the prior Office action. It is maintained for the reasons of record and those set forth below.
Applicant argues that the claims have been amended to recite “means for catalyzing” , which is allegedly fully supported. Applicant states that the specification demonstrates possession of the claimed invention by disclosing the structure of the polypeptides of SEQ ID NO: 1-51 and polypeptides having at least 72.50% sequence identity to the polypeptides of SEQ ID NO: 1-51. Applicant states that the specification provides a functional definition of a fucosyltransferase having α-1,3-fucosyltransferase activity on the GlcNAc and/or Glc residue of Gal-β1, 3-GlcNAc-β1, 3-Gal-β1, 4-Glc and cites specific Examples and Tables of the specification as describing specific embodiments tied to some of the proteins disclosed. Applicant states that a global sequence alignment of the proteins of SEQ ID NO: 1-51 reveals substantial sequence divergence. Applicant states that Table 1 provides the % sequence identity between two polypeptides that is at least 72.5%, thus providing support to the claims. Applicant states that the polypeptide of SEQ ID NO: 3 has two functional domains that are used for its fucosyltransferase activity on substrates like lactose. Applicant submits that an alignment of the pfam domain PF18025 extracted from all the proteins of the present specification reveals conserved amino acids as well as positions within the pfam domain with high variability, and that a similar result was found when only certain enzymes of the invention are aligned. Applicant submits that an alignment of the pfam domain PF00825 extracted from the enzymes of the instant application and FucT shows conserved amino acids and regions with higher flexibility. Applicant states that both pfam domains PF18025 and PF00825 have been described over 20 years ago and are well known in the art. According to Applicant, based on the knowledge of the art, one can analyze the fucosyltransferases of the present application and easily derive which amino acids are conserved in these PFAM domains and which positions have more flexibility to select homologs having the recited % sequence identity and the recited α-1,3-fucosyltransferase activity.
Applicant’s arguments have been fully considered but not deemed persuasive to overcome the instant rejection. The Examiner acknowledges the amendments made to the claims, the alignments presented, and the teachings of the specification. However, the Examiner strongly disagrees with Applicant’s contention that the claims as amended are adequately described.
For the reasons extensively discussed above, a genus of means able to catalyze the recited transfer has not been mentioned or suggested at all in the specification. As explained in Claim Rejections - 35 USC § 112(b) or Second Paragraph (pre-AIA ), the term “means” is equivalent to something that is useful or helpful to a desired end. In the instant case, the claims require anything that can catalyze the transfer of a fucose residue in GDP-fucose to the Glc residue of a saccharide substrate that comprises Gal-β1, 3-GlcNAc-β1, 3-Gal-β1, 4-Glc. Please note that as indicated above, this “means” is not limited to the polypeptide of SEQ ID NO: 3 in view of the fact that the claims recite “means comprises”. Thus, the required means can be anything that can catalyze the recited transfer and also comprises the polypeptide of SEQ ID NO: 3.
The Examiner acknowledges that the specification discloses a few species of the genus of enzymes that can catalyze the recited fucose transfer. The Examiner also acknowledges that one of skill in the art have the tools to make an alignment of protein sequences and determine conserved regions. However, it is noted that conserved regions in a protein sequence alignment are not necessarily associated with function and can be variable depending on the sequences used in the alignment. In some instances, conserved regions are associated with how closely related the organisms from which the proteins originate are.
With regard to the pfam domains PF18025 and PF00825 in the protein of SEQ ID NO: 3 and the argument that, based on the knowledge of the art, one can analyze the fucosyltransferases of the present application and easily derive which amino acids are conserved in these PFAM domains and which positions have more flexibility to select homologs having the recited % sequence identity and the recited α-1,3-fucosyltransferase activity, it is noted that there is absolutely no teaching in the specification and/or the prior art suggesting that any conserved amino acids found in these two domains are associated with the required fucosyltransferase specificity, or which of the fucosyltransferases of the specification should be included in an alignment so that the conserved regions found in those two domains among those fucosyltransferases are those which provide the desired specificity. As indicated above, conserved regions are also dependent upon the sequences used in the alignment. As admitted by Applicant, there is variability among the two domains in the enzymes disclosed. Therefore, it is abundantly clear that the mere presence of these two domains is not an indication that the protein comprising them would have the desired fucosyltransferase specificity. Moreover, there is nothing in the specification and/or the prior art indicating that other regions of the protein of SEQ ID NO: 3 which are not these two domains, are unrelated to the required specificity or enzymatic activity.
As explained in the prior Office action, the UniProt entry A0A1I0RR58_9BACT provides the structure of the protein of SEQ ID NO: 3 and also indicates which fragments of the polypeptide of SEQ ID NO: 3 are identified as an alpha-(1,3)-fucosyltransferase FucT N-terminal domain and a C-terminal domain of a family of fucosyltransferases. However, neither the specification nor the prior art disclose that every alpha 1,3-fucosyltransferase having the specificity recited in the claims would comprise (a) amino acids 33-129 of the polypeptide of SEQ ID NO: 3 (fragment identified as comprising an alpha-(1,3)-fucosyltransferase FucT N-terminal domain PF18025) and (b) amino acids 163-303 of the polypeptide of SEQ ID NO: 3 (fragment identified as comprising a C-terminal domain of a family of fucosyltransferases PF00852). There is no information as to how much structural variability can be present in the fragment that comprises amino acids 33-129 of the polypeptide of SEQ ID NO: 3 and the fragment that comprises amino acids 163-303 of the polypeptide of SEQ ID NO: 3 without altering enzymatic activity and/or specificity. The pfam ID numbers provided represent domains obtained by sequence alignments of known proteins to annotate proteins of unknown function. These domains are not experimentally validated such that one could reasonably conclude that every protein that comprises these domains would display the recited enzymatic activity. Therefore, the presence of conserved regions in these two domains obtained from an alignment of fucosyltransferases cannot necessarily be associated with the required specificity without some additional structure/function information.
Even if the argument is made that the “means” is limited to a variant of the polypeptide of SEQ ID NO: 3 having at least 72.5% or 50.5% sequence identity to the polypeptide of SEQ ID NO: 3, wherein said variant catalyzes the transfer of a fucose residue from GDP-fucose to a substrate that comprises Gal-β1, 3-GlcNAc-β1, 3-Gal-β1, 4-Glc, there is a significant amount of structural variability with respect to the members of the genus of fucosyltransferases required by the claimed method. It is reiterated herein the total number of variants having at least 72.5% sequence identity to the polypeptide of SEQ ID NO: 3 that result from amino acid substitutions is 335!x1993/(335-93)!/93! or 3.53x10203 variants. See calculations provided in the prior Office action. This number is even higher for variants of the polypeptide of SEQ ID NO: 3 having at least 50.5% sequence identity to the polypeptide of SEQ ID NO: 3. In the instant case, there is absolutely no indication as to which modifications can be made within the polypeptide of SEQ ID NO: 3 such that the required enzymatic activity and specificity is maintained. Even if the argument is made that the claims require the structural variants of the polypeptide of SEQ ID NO: 3 to comprise amino acids 33-129 and 163-303 of the polypeptide of SEQ ID NO: 3, which correspond to the two domains referred to by Applicant, there is absolutely no information as to which modifications can be made in the remainder of the structure (approximately 30%) such that the desired enzymatic activity is maintained. There is no indication that any modification made to the remainder of the structure would not have any impact on enzymatic activity and/or specificity. There is no structure/function correlation or some guidance as to which variants of the polypeptide of SEQ ID NO: 3 having the recited % sequence identity are more likely to have fucosyltransferase activity and the recited specificity. As previously indicated, while one could argue that the species disclosed is representative of the structure of all the members of the genus, it is noted that the art teaches several examples of how even highly structurally homologous polypeptides can have different enzymatic activities. See the teachings of Witkowski et al., Seffernick et al. and Tang et al. previously discussed.
Therefore, for the reasons of record and those set forth above, one cannot reasonably conclude that the specification and/or the prior art adequately describes the genus of variants of the polypeptide of SEQ ID NO: 3 required by the claims and the genus of cells and modifications encompassed by the claimed method.
Claims 1, 3-7, 9-11, 15-28, 30-31, 33, 35-38, 40-41 remain rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method for producing lacto-N-fucopentaose V (LNFP V), wherein said method comprises culturing an E. coli cell that has been genetically modified to (a) constitutively express the fucosyltransferase of SEQ ID NO: 3, the sucrose transporter encoded by the E. coli cscB gene, a fructokinase encoded by the Z. mobilis frk gene, a sucrose phosphorylase encoded by the B. adolescentis sucP gene, a mannose-6-phosphate isomerase encoded by the E. coli manA gene, a phosphomannomutase encoded by the E. coli manB, a mannose-1-phosphate guanyltransferase encoded by the E. coli manC gene, a GDP-mannose dehydratase encoded by the E. coli gmd gene, a GDP-fucose synthase encoded by the E. coli fcl gene, the lactose permease encoded by the E. coli lacY gene, a galactoside beta-1,3-N-acetylglucosaminyltransferase encoded by the N. meningitidis lgtA gene, and an N-acetylglucosamine β-1,3-galactosyltransferase encoded by the E. coli wbgO gene, and (b) disrupt the endogenous wcaJ, thyA, lacZ, lacY, lacA, and nagB genes, does not reasonably provide enablement for (I) a method for producing any fucosylated compound that comprises Gal-β1, 3-GlcNAc-β1, 3-Gal-β1, 4-[Fuc-α1,3]-Glc from GDP-fucose and a saccharide substrate comprising Gal-β1,3-GlcNAc-β1,3-Gal-β1,4-Glc (LNT), wherein said method comprises contacting GDP-fucose and LNT with any fucosyltransferase having α-1,3-fucosyltransferase activity that is a variant of the polypeptide of SEQ ID NO: 3 having the recited % sequence identity, (II) the method of (I) wherein said fucosylated compound is produced by a cell modified by any means to produce said fucosylated compound and/or said saccharide substrate, (III) a method for producing LNFP V, wherein said method comprises culturing a cell modified by any means to produce GDP-fucose and LNT, wherein said cell expresses the polypeptide of SEQ ID NO: 3, or (IV) any means to catalyze the transfer of a fucose residue in GDP-fucose to the Glc residue of a saccharide substrate that comprises Gal-β1, 3-GlcNAc-β1, 3-Gal-β1, 4-Glc. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
This rejection has been discussed at length in the prior Office action. It is maintained for the reasons of record and those set forth below.
Applicant argues that under 35 USC § 112(f), a means plus function element is construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof. Applicant states that § 112(f) does not require enablement of all possible ways to perform the function, only the disclosed structure and known equivalents at the time of filing. Applicant states that the amended “means” recited in the claims is expressly tied to the corresponding structure of SEQ ID NO: 1-51 and to variants having at least 72.5% sequence identity. Applicant states that the disclosure of sequences in full provides a clear linkage between their structure and the claimed catalytic function. Applicant states that because the amino acid sequences are disclosed, one of ordinary skill in the art could make and use the claimed polypeptides without undue experimentation. Applicant cites different sections of the specification in support of the argument that there is support for the disclosed structure and function. Applicant states that the specification discloses other cells or modifications that could be made to a cell for the required production of the fucosylated compound, GDP-fucose and/or LNT, referring to different sections of the specification. Applicant also asserts that the specification discloses how LNT can be produced by a cell and how LNT production can be obtained and/or optimized in different host cells. Applicant states that the structural variants of the polypeptide of SEQ ID NO: 3 having the recited % sequence identity would not be essentially infinite to one of ordinary skill in the art.
Applicant’s arguments have been fully considered but not deemed persuasive to overcome the instant rejection. The Examiner acknowledges the amendments made to the claims. However, the Examiner strongly disagrees with Applicant’s contention that the full scope of the claims as amended is enabled by the teachings of the specification and/or the prior art.
It is reiterated herein that a genus of means able to catalyze the recited transfer has not been mentioned or suggested at all in the specification. As explained in Claim Rejections - 35 USC § 112(b) or Second Paragraph (pre-AIA ), the term “means” is equivalent to something that is useful or helpful to a desired end. In the instant case, the claims require anything that can catalyze the transfer of a fucose residue in GDP-fucose to the Glc residue of a saccharide substrate that comprises Gal-β1, 3-GlcNAc-β1, 3-Gal-β1, 4-Glc. Please note that as indicated above, this “means” is not limited to the polypeptide of SEQ ID NO: 3 in view of the fact that the claims recite “means comprises”. Thus, the required means can be anything that can catalyze the recited transfer and also comprises the polypeptide of SEQ ID NO: 3.
With regard to the argument that 35 USC § 112(f) does not require enablement of all possible ways to perform the function, only the disclosed structure and known equivalents at the time of filing, it is noted that the only “means” disclosed as being able to catalyze the transfer of a fucose residue from GDP-fucose to the Glc residue of a saccharide substrate that comprises Gal-β1, 3-GlcNAc-β1, 3-Gal-β1, 4-Glc is the polypeptide of SEQ ID NO: 3 as well as the polypeptides of SEQ ID NO: 1-2, 4-51. With regard to “means” that are limited to variants of the polypeptide of SEQ ID NO: 3 that have the recited % sequence identity, it is noted that the invocation of 35 USC § 112(f) does not exempt an Applicant from compliance with 35 USC § 112(a). See MPEP § 2181(II)(A) and MPEP § 2181(IV).
While Applicant argues that the disclosure of sequences in full provides a clear linkage between their structure and the claimed catalytic function, it is reiterated herein that the specification and the prior art are completely silent as to the structural features required in the recited variants of the polypeptide of SEQ ID NO: 3 such that the variants would have the desired enzymatic activity and specificity, or a structure/function correlation that would allow one of skill in the art to determine which variants of the polypeptide of SEQ ID NO: 3 having the recited sequence identity are more likely to have the desired function and specificity. There is no indication in the specification or the prior art as to which structural features in the polypeptide of SEQ ID NO: 3 are essential for the desired enzymatic activity and specificity. Therefore, contrary to Applicant’s assertions, there is no clear linkage between the structure of the polypeptide of SEQ ID NO: 3 and the claimed catalytic function. As indicated above, the number of structural variants of the polypeptide of SEQ ID NO: 3 having the recited % sequence identity is essentially infinite. While applicant argues that the number of structural variants of the polypeptide of SEQ ID NO: 3 is not essentially infinite, it is noted that just the number of variants of the polypeptide of SEQ ID NO: 3 having at least 72.5% sequence identity to the polypeptide of SEQ ID NO: 3 alone amounts to 3.53x10203 variants. This number is even higher for variants of the polypeptide of SEQ ID NO: 3 having at least 50.5% sequence identity to the polypeptide of SEQ ID NO: 3 (335!x19166/(335-166)!/166! or 5.64x10311 variants). In the instant case, there is absolutely no indication as to which modifications can be made within the polypeptide of SEQ ID NO: 3 to obtain a variant having the recited % sequence identity such that the required enzymatic activity and specificity is maintained.
It is reiterated herein that the art is silent with regard to the structural features required in an α-1,3-fucosyltransferase that can catalyze the transfer of fucose from GDP-fucose to Glc or GlcNAc in the recited substrate. Moreover, the art clearly teaches that (i) there is a high level of unpredictability associated with accurate functional annotation of proteins based solely on structural homology, and (ii) modification of a protein’s amino acid sequence to obtain the desired activity without any guidance/knowledge as to which amino acids in a protein are tolerant of modification and which ones are conserved is highly unpredictable. See the teachings of Singh et al. and Sadowski et al. previously discussed. While Applicant argues that because the amino acid sequences are disclosed, one of ordinary skill in the art could make and use the claimed polypeptides without undue experimentation, it is noted that the issue in the instant case is not whether one of skill in the art could make a structural variant of the polypeptide of SEQ ID NO: 3 having the recited % sequence identity. Instead the issue is that one of skill in the art would have to test an essentially infinite number of variants to find those that have the desired enzymatic activity and specificity in view of the lack of knowledge or guidance as to which are the structural features required in a variant as recited for such variant to have the recited function. This is not deemed routine experimentation.
With regard to the argument that the specification discloses other cells or modifications that could be made to a cell for the required production of the fucosylated compound, GDP-fucose and/or LNT, as well as how LNT can be produced by a cell and how LNT production can be obtained and/or optimized in different host cells, the Examiner acknowledges what is disclosed in the specification. However, it is reiterated herein that the modifications/cells encompassed by the claims are not limited to what is disclosed in the specification and include disruption of an unknown number of endogenous genes as well as the expression of unknown enzymes that would lead to the synthesis of precursors of the desired fucosylated compounds, such as GDP-glucose and LNT. Moreover, these modifications also encompass unknown methods to increase the expression of genes encoding biosynthetic enzymes, as well as unknown methods to inactive biosynthetic pathways of unknown metabolites that could reduce the synthesis of the desired compounds. It was not routine in the art at the time of the invention to screen by a trial and error process for any number of modifications in any cell so that the cell can synthesize a particular fucosylated compound, or it can produce GDP-fucose and/or LNT. In the absence of (i) a rational and predictable scheme for selecting those proteins most likely to have the desired functional features, (ii) a correlation between structure and α-1,3-fucosyltransferases activity with the desired specificity, and (iii) a rational and predictable scheme for determining those modifications that can be made to any cell to produce the desired compound, such as those biosynthetic enzymes that should be expressed and those endogenous genes that should be disrupted, one of skill in the art would have to test an essentially infinite number of proteins and modifications to determine which proteins have the desired functional characteristics, and which modifications could be made to achieve the desired synthesis. This is not considered routine experimentation. Therefore, contrary to Applicant’s assertions, one cannot reasonably conclude that the teachings of the specification and/or the prior art enable the entire scope of the claimed invention.
Allowable Subject Matter
A method for producing lacto-N-fucopentaose V (LNFP V), wherein said method comprises culturing an E. coli cell that has been genetically modified to (a) constitutively express the fucosyltransferase of SEQ ID NO: 3, the sucrose transporter encoded by the E. coli cscB gene, a fructokinase encoded by the Z. mobilis frk gene, a sucrose phosphorylase encoded by the B. adolescentis sucP gene, a mannose-6-phosphate isomerase encoded by the E. coli manA gene, a phosphomannomutase encoded by the E. coli manB, a mannose-1-phosphate guanyltransferase encoded by the E. coli manC gene, a GDP-mannose dehydratase encoded by the E. coli gmd gene, a GDP-fucose synthase encoded by the E. coli fcl gene, the lactose permease encoded by the E. coli lacY gene, a galactoside beta-1,3-N-acetylglucosaminyltransferase encoded by the N. meningitidis igtA gene, and an N-acetylglucosamine β-1,3-galactosyltransferase encoded by the E. coli wbgO gene, and (b) disrupt the endogenous wcaJ, thyA, lacZ, lacY, lacA, and nagB genes, appears to be allowable over the prior art of record.
Conclusion
No claim is in condition for allowance.
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Any inquiry concerning this communication or earlier communications from the examiner should be directed to DELIA M RAMIREZ, Ph.D., whose telephone number is (571) 272-0938. The examiner can normally be reached on Monday-Friday from 8:30 AM to 5:00 PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert B. Mondesi, can be reached at (408) 918-7584. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
/DELIA M RAMIREZ/Primary Examiner, Art Unit 1652
DR
January 24, 2026