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 .
Priority
This application is a National-Stage entry of PCT/US2022/075915, filed 9/2/2022, which claims benefit to US Provisional Application 63/240,245, filed 9/2/2021. Acknowledgment is made of applicant’s claim for priority under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-3, 7, 10, 20, 24, 28, 29, 32,
35, and 37, in the reply filed on 5/21/2026 is acknowledged.
Claims 88, 93, 98, 173, 179, and 180-182 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 5/21/2026.
Claims 1-3, 7, 10, 20, 24, 28, 29, 32, 35, and 37 have been examined on the merits.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 10/15/2024 and 5/21/2026 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 Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-3, 7, 10, 20, 24, 28-29, 32, 35, and 37 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites: “the yeast host cell is:
(a) deficient in expression of one or more genes encoding an endogenous oxidoreductase;
(b) deficient in activity of one or more endogenous oxidoreductase proteins; and/or
(c) deficient in a level of a reduced form of a reducing sugar.”
The term “deficient” as used here in claim 1 is a relative term which renders the claim indefinite. The phrases “deficient in expression”, “deficient in activity”, and “deficient in a level of” are not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree required for a cell to be considered deficient, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. These limitations refer to the relative amount of the mRNA or protein of the endogenous enzyme, the protein activity level, and/or the amount of a reduced form of any reducing sugar. Because there is no recited control or a normal cell to which to compare the claimed level of deficiency to, the metes and bounds of the claimed comparisons are impossible to determine. Further, even if the claim recited a wild-type control cell to compare it to, one would not have any indication of the amount of the deficiency required to fulfill the claim limitation. Does a deficiency of 10% less than normal meet this limitation? The claim is indefinite because there is no manner to determine if any given cell is considered deficient in one of the alternatives as recited.
Claims 3, 20, and 28 also recite the term “deficient”. These claims do not further clarify the amount of deficiency that is required of the claimed yeast cell, and the resulting claims are also indefinite, as described above.
Claim 10 does not overcome these issues of indefiniteness. Although claim 10 recites alternatives that limit how the cell is made “deficient”, the term is still a relative term, and the ambiguity regarding the extent of the deficiency (i.e. the expression level of the gene, the activity of the enzyme, or the amount of the reducing sugar) required to satisfy the limitation remains.
All other claims depend directly or indirectly from the rejected claims and are, therefore, also rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, for the reasons set forth above.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-3, 7, 10, 20, 24, 28, 32, and 35 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 claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 recites:
A yeast host cell capable of producing a human milk oligosaccharide (HMO), wherein the yeast host cell is:
(a) deficient in expression of one or more genes encoding an endogenous oxidoreductase;
(b) deficient in activity of one or more endogenous oxidoreductase proteins; and/or
(c) deficient in a level of a reduced form of a reducing sugar.”
There is no recitation in the claim of what condition or manipulation renders a yeast host cell “capable of producing a human milk oligosaccharide (HMO)”. This element has been recited in the preamble, but it is considered limiting because it imparts a structural and/or functional element to the yeast host cells (i.e. there must be a genetic manipulation to yield such yeast capable of making HMOs). Herein, the cell has been described only in a functional requirement, without any particular structure recited that satisfies the claim limitation.
Claim 1 thus encompasses any and all possible modifications which may result in a yeast host cell capable of producing a human milk oligosaccharide (HMO). The cells must also have at least one of the limitations of (a), (b), and (c), however there are no limitations in claim 1 regarding the synthetic pathways for making the HMO, nor limits on the structure of the HMO.
The dependent claims 2-3, 7, 10, 20, 24, 28, 32, and 35 do not practically limit the encompassed yeast cells by reciting a specific modification or particular genotype/strain of yeast that would provide any structure that performs the claimed HMO synthesis activity.
According to the B.R.I. of the claim, when viewed in light of the specification, there exists a very broad number of structures and variants of engineered yeast that may fall within the claimed scope. Comparatively, the specification only recites a small number of species of the broad genus that meet the recited limitations.
MPEP § 2163.(II)(A)(3)(a) states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
The specification fails to reasonably describe the full genus of the claimed invention.
The instant specification does not disclose relevant identifying characteristics, such as key structural or other physical properties, or functional characteristics coupled with a known or disclosed correlation between function and structure, such that the entirety of the claimed genus is encompassed by the description in the disclosure. The broad descriptions in the specification amount to prophetic embodiments but are not evidence of possession of the full claim scope.
The specification states that there are over 200 different species of HMOs (page 1, lines 10-12 of the specification. The disclosure describes in detail pathways for producing two species of HMO, lacto-n-neotetraose (LNnT) and 2’-fucosyllactose (2’-FL). The disclosure states that production of LNnT in yeast requires the expression of three genes (“a lactose permease (e.g., LAC12 from K. lactis) to import fed lactose, an LgtA (β-1,3-N- acetylglucosaminyltransferase) to convert lactose to LNT2, and an LgtB (β-1,4-galactosyltransferase) to convert LNT2 to LNnT (see page 1, lines 20-24; page 4, line 6 – page 5, line 17). For 2’-FL, four genes must be expressed in the yeast host cell: lactose permease (e.g., Lac12 from K. lactis) to import fed lactose, a GDP-mannose 4,6-dehydratase, a GDP-L-fucose synthase, and an α-1,2-fucosyltransferase (page 1, lines 25-28; page 5, lines 18-41).
Pages 38- 46 of the specification describe various possible host cells and genetic modifications that amount to cells capable of producing HMOs. However, from these descriptions, it is evident that the pathways to produce the HMOs in yeast are complex and require the consideration of multiple metabolites and the incorporation of various exogenous enzymes in the host cells.
When considering that multiple species of yeast, different genetic backgrounds and strains, and multitudes of biosynthetic pathways could be involved, it is evident that the modified host cells encompass a nearly limitless number of combinations.
There are no recitations of specific HMO pathways nor practical limitations for the host cells in claims 1-3, 7, 10, 20, 24, 28, 32, and 35.
The two examples in the specification include Example 1, which describes the heterologous production of LNnT with the three non-native enzymes: lactose permease (LAC12 from K. lactis), LgtA (β-1,3-N-acetylglucosaminyltransferase), and LgtB, using the LNnT-producing strain S. cerevisiae Y67002 (see FIG. 2A; page 72, line 12-page 76, line 19). The specification states that “two reductases found to have significant activity toward lactose and LNnT were GCY1 and GRE3” (see page 76, lines 13-15).
Example 2 pertains to the production of 2’-FL, in a S. cerevisiae strain Y71081, and demonstrates that combination of this strain with a deletion in gcy1 (page 76, lines 21-41; “the reductase knockout strain in 0.25-L fermentation tanks resulted in a decrease in peak area for 2′-fucosyllactitol and slight increase in 2′-FL peak area from the parent Y71081”; FIGs. 20-23).
Thus, the specification provides only two working examples of the claimed genus, using specific defined parental strains for producing LNnT or 2′-FL. This cannot be considered a sufficient description of a representative number of species by actual reduction to practice of the full breadth of the vast genus. There is no evidence that, at the time of filing, the Applicant possessed additional representative species of the full genus of all yeast cells capable of producing HMOs, in combinations with any of the modifications described in (a), (b), or (c), as recited in the claims, beyond those provided in the working examples.
For these reasons, the disclosure fails to provide adequate written description to support the entirety of the broad genus claim to using any and all yeast host cells capable of producing a human milk oligosaccharide (HMO).
Claim 1 is thus rejected under 35 U.S.C. § 112(a) because the claimed subject matter is not described in the specification in such a way as to reasonably convey to a skilled artisan that the inventor, or a joint inventor, had possession of the claimed invention.
The dependent claims 2-3, 7, 10, 20, 24, 28, 32, and 35 are also rejected under 35 U.S.C. § 112(a), because these claims require the yeast host cells according to claim 1, and fail to practically further limit the claimed invention to those adequately described in the disclosure.
Claim 29 and claim 37, dependent thereof, recite structural modifications of the host yeast cells that amount to specific genetic modifications. These are adequately described in the specification to satisfy the written description requirement, as indicated above.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-3, 10, 20, 28-29, 32, and 35 are rejected under 35 U.S.C. 103 as being unpatentable over Maertens et al. (US PGPub No. 20130122553, herein termed “Maertens”).
Maertens discloses genetically engineered organisms, including yeast cells, for the production of added value bio-products such as specialty saccharides and activated saccharides (Abstract, Claim 1). Maertens teaches cells and methods for producing the human milk oligosaccharide 2-fucosyllactose ([0011]). Maertens teaches that the engineered ‘organism’ may be a bacterium, a yeast or a fungus cell, latter yeast preferably belonging to species Saccharomyces cerevisiae ([0061]; claim 8).
Maertens teaches engineered organisms that can be used to produce fucosylated sugar derivates such as fucosyllactose, and more specifically α-1,2-fucosyllactose (i.e. 2-Fucosyllactose (2'-FL)), α-1,3-fucosyllactose, α-1,4-fucosyllactose, α-1,6-fucosyllactose as specialty products with specific fucosyltransferases originating from for example but not limited to Helicobacter pylori, Bacteroides sp., Homo sapiens, Mus musculus, Bos taurus and, Dictyostelium discoideum ([0085]). Regarding claim 35, Maertens teaches that the specialty product may also be Lacto-N-tetraose ([0087]).
Maertens teaches that genes coding for mannose-6-phosphate isomerase, phosphomannomutase, mannose-1-phosphate guanylyltransferase, GDP-mannose 4,6-dehydratase and GDP-fucose synthase may also be expressed or enhanced in expression in order to increase the flux towards GDP-fucose ([0175]). Maertens teaches that this GDP-fucose is linked to lactose by the α-1,2-fucosyltransferase ([0175]). Maertens also teaches that “The strain is modified to force the cell to produce frucose-6-phosphate which is an intermediate in the synthesis of GDP-fucose” ([0021]).
In one embodiment Maertens teaches yeast cells (Saccharomyces cerevisiae), having a deletion in the aldose reductase gene GRE3, which is an exemplary oxidoreductase of the instant invention (Example 32, [0200]), and is one of the endogenous oxidoreductases recited in dependent claims 3 and 20. Maertens teaches that deleting the aldose reductase GRE3 along with GAL7 (an UDP-glucose-hexose-1-phosphate uridylyltransferase) will increase the supply of galactose-1-phosphate in the biosynthetic pathways of a specialty carbohydrate, as described therein ([0200]). Maertens also teaches that one goal for maximizing the production of a specialty product is to increase the supply of saccharides to a biosynthetic pathway of a specialty carbohydrate, avoiding the use of the saccharides for growth (see Figure 1, [0009], [0012]). Maertens teaches that cells which accumulate more galactose-1-phosphate are useful when producing the HMO Lacto-N-biose (see [0211]).
Therefore, to one of ordinary skill in the art, prior to the effective filing date of the instant invention, it would have been obvious over all of the teachings of Maertens to produce a yeast host cell expressing genes necessary for producing the human milk oligosaccharide 2-fucosyllactose, wherein the cells further comprise a deletion in the gene gre3, an aldose reductase, for the predicted benefit of manipulating the metabolism of the host cell to improve the amount of carbohydrates available for producing a desired product.
Maertens teaches both the deletion of the aldose reductase GRE3 will increase the supply of galactose-1-phosphate in the biosynthetic pathways of a specialty carbohydrate. Maertens also teaches cells having all of the components necessary to produce human milk oligosaccharides, including 2-fucosyllactose or Lacto-N-biose. One of ordinary skill would recognize that deletion of the aldose reductase GRE3 would have been useful to accumulate basic carbohydrates and one would have sought to increase the amount of such carbohydrate building blocks when seeking to produce high yields of complex human milk oligosaccharides. Because the reference teaches cells for producing human milk oligosaccharides and teaches deletion of GRE3, it would have been a matter of optimization for one having ordinary skill in the art to arrive at the instantly recited yeast cells. One would have predicted, with a reasonable expectation of success, that the combination of biosynthetic pathway with a deletion of the aldose reductase GRE3 (i.e. or reduction in its activity) would lead to more galactose-1-phosphate,and such a mutation is taught explicitly for increased production of the HMO Lacto-N-biose in Maertens.
Regarding claims 2-3, 10, and 20, the gre3 deletion taught in Maertens satisfies at least one of the alternative limitations required of these claims.
Regarding claim 28, if one of ordinary skill following the teachings of Maertens produces a yeast cell wherein there is a deletion in gre3 and said cell is used for the production of an HMO such as Lacto-N-biose or 2-fucosyllactose, then the reduction in the level of lactitol and/or 2-fucosyllactitol would necessarily have followed from this. In this case, because the claims are directed to a product, i.e. the yeast cell, then the properties such as levels of these metabolites would likely be found in the cells of the prior art, also having a knockout of gre3. Also, it is noted that the motivation to combine teachings in the art does not necessarily have to explicitly be the same as the Applicant’s. "Newly discovered results of known processes directed to the same purpose are not patentable because such results are inherent." Bristol-Myers Squibb Co. v. Ben Venue Labs. Inc., 246 F.3d 1368, 1376 (Fed.Cir.2001) (citing In re May, 574 F.2d 1082, 1090 (Cust. & Pat. App.1978)).
Regarding claim 29, the selection and providing of the genes described in Maertens to generate 2-fucosyllactose in such a background would have been a matter of routine substitution and optimization to one having ordinary skill in the art. These include all of the genes recited in option (b) of the instant claim.
Regarding claims 32 and 35, Maertens explicitly teaches means for the production of 2-fucosyllactose, which is a reducing sugar (e.g. it has free aldehyde groups) that also comprises a terminal lactose residue.
From the teachings of Maertens, it is apparent that there would have been a reasonable expectation of success in combining the teachings therein to arrive at the claimed invention because Maertens teaches both the deletion of gre3 in yeast cells that are used to produce HMOs, and the reference also teaches expressing heterologous genes for the production of the HMOs, including lacto-N-biose or 2-fucosyllactose.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date, as evidenced by the cited references, especially in the absence of evidence to the contrary.
Claims 1-3, 10, 20, 28-29, 32, 35, and 37 are rejected under 35 U.S.C. 103 as being unpatentable over Maertens et al. (US PGPub No. 20130122553) as applied to claims 1-3, 10, 20, 28-29, 32, and 35 above, and further in view of Q9X3N7 (UniProt Entry Q9X3N7_HELPX for alpha-1,2-fucosyltransferase, fucT2, from Helicobacter pylori)), to include the rejection of claim 37.
Maertens et al. makes obvious a yeast host cell having a deletion in at least gre3 and the recombinant pathway for producing 2-fucosyllactose, required for claims 1 and 29, for all of the reasons described above. The relevant teachings of Maertens include all those set forth previously. Maertens teaches that for producing 2-fucosyllactose, an α-1,2-fucosyltransferase originating from Helicobacter pylori may be provided ([0085]).
However, Maertens does not explicitly teach that the sequence of the α-1,2-fucosyltransferase originating from Helicobacter pylori is at least 85% identical to that of the instantly recited SEQ ID NO: 20, as recited in alternative (e) of claim 37.
Q9X3N7 (UniProt Entry Q9X3N7_HELPX) discloses a protein sequence that is 100% identical to that of the instantly recited SEQ ID NO: 20. This is an α-1,2-fucosyltransferase from Helicobacter pylori.
Therefore, to one having ordinary skill in the art, prior to the effective filing date of the instant application, it would have been prima facie obvious in view of Maertens and Q9X3N7 to select and provide the particular sequence of Q9X3N7, encoding an α-1,2-fucosyltransferase from Helicobacter pylori, when producing a yeast cell having a biosynthetic 2-fucosyllactose pathway and a knockout in one or more oxidoreductases, as taught in Maertens.
One would have been motivated to do so because Maertens teaches that the α-1,2-fucosyltransferase for producing 2-fucosyllactose can come from Helicobacter pylori. Thus, when seeking to express such an enzyme one would have turned to a known amino acid sequence in the art, including the one so instantly claimed, which is the same as the wild-type protein the H. pylori α-1,2-fucosyltransferase according to Q9X3N7.
There would have been a reasonable expectation of success because Maertens teaches using such enzymes, including those from Helicobacter pylori and one of ordinary skill in the art would be skilled in the selection and expression of enzymes known to this art.
Therefore, the invention of claim 37 as a whole would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date, as evidenced by the cited references, especially in the absence of evidence to the contrary.
Citation of Pertinent Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Chomvong et al. (US PGPub No. 20200165621) discloses genetically modified microorganisms and related methods for enhanced utilization of oligosaccharides and improved productivity of compounds derived from the metabolism of the oligosaccharides, and the genetic modifications taught therein provide the microorganisms an increased ability to utilize an oligosaccharide to produce a compound of interest, including the HMOs 2′-fucosyllactose and lacto-N-tetraose (LNT) (Abstract, [0040]).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ANDREW TERRY MOEHLMAN whose telephone number is (571)270-0990. The examiner can normally be reached M-F 9am-5pm EST.
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/A.T.M./Examiner, Art Unit 1655
/ANAND U DESAI/Supervisory Patent Examiner, Art Unit 1655
APPENDIX A: Alignment of SEQ ID NO: 20 and Q9X3N7 from Helicobacter pylori
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