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
Acknowledgment is made of the instant application being a 371 of PCT/EP2022/055763 filed on 03/07/2022 as well as applicant's claim for foreign priority (EPO application EP21305277.2 filed on 03/08/2021) under 35 U.S.C. 119 (a)-(d).
Status of Claims/Application
Claims 1-15, filed on 09/05/2023, are currently pending and are examined on the
merits herein. Preliminary amendment was submitted to remove multiple dependencies from the claims.
Information Disclosure Statement
The information disclosure statement (IDS) submitted in the instant application on 09/05/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 3, 5, 7, 11, and 15 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.
In claims 3, 11, and 15 the phrase "such as" renders the claims indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 3 recites the broad recitation “W is a polylysine”, and the claim also recites “in particular a poly-L-lysine, such as ε-poly-L-lysine” which is the narrower statement of the range/limitation. The claim is considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claim.
Claim 11 recites the broad recitation “for use in treating or preventing F18+ E. coli infections in mammals”, and the claim also recites “in particular in treating or preventing of a post weaning diarrhea and/or edema disease in pigs” which is the narrower statement of the range/limitation. The claim is considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claim.
Claim 15 recites the broad recitation “wherein the linear protein has pendant primary amino groups”, and the claim also recites “in particular is polylysine” which is the narrower statement of the range/limitation. There are two instances of this in the same claim. The claim is considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claim.
Claim 5 recites the broad recitation “n is in the range from 8 to 240”, and the claim also recites “particularly from 8 to 40, and in particular in the range from 10 to 35, more specifically in the range from 12 to 35” which is the narrower statement of the range/limitation. The claim is considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claim.
Claim 7 recites the limitation "the polylysine" in the preamble of the claim, “Conjugates (I) according to claim 1, wherein the polylysine”. There is insufficient antecedent basis for this limitation in the claim.
Claim 7 recites the broad recitation “the polylysine”, and the claim also recites “in particular, the ε-poly-L-lysine” which is the narrower statement of the range/limitation. In addition, claim 7 recites the broad recitation “the polylysine, and in particular, the ε-poly-L-lysine, has a weight average molecular weight Mw in the range from 2000 to 33000 g/moL”, and the claim also recites “in particular in the range from 3200 to 6850 g/moL “ which is the narrower statement of the range/limitation. Claim 7 also recites the broad recitation “an average degree of polymerization (DP) in the range from 15 to 240”, and the claim also recites “in particular in the range from 20 to 50” which is the narrower statement of the range/limitation. The claim is considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1 – 3, 5, 6, and 8 – 12 are rejected under 35 U.S.C. 103 as being obvious over US 2011/0306574 (IDS 09/05/2023), and Liang et al (Structure and antimicrobial mechanism of ε-polylysine-chitosan conjugates through Maillard reaction, International Journal of Biological Macromolecules 70, (2014), 427-434 (PTO-892)).
US’574 teaches blood group A/B/H determinant on Type 1 Core glycosphingolipids chains as recognition point for the FedF protein of F18-fimbriated Enterotoxigenic and verotoxinogenic Escherichia coli and the use of compounds comprising such determinants for the treatment of F18+ E. coli infections in pigs and in screening methods (pg. 1, col. 1, [0001]).
US’574 teaches the use of a compound for binding to F18+ E. coli, F18 fimbriae, F18 adhesin, FedF or the receptor binding domain of FedF wherein said compound is a compound of formula (I)
[X(Fucα2)Galβ3(Y)TV]n-W (I)
X is absent, Galα3 or GalNAcα3 and when X is absent, then Y is absent;
Y is absent or Fucα4;
T is absent or ZNAcε3; and wherein Z is Glc or Gal; and ε is α or β;
V is absent or a mono-or polysaccharide;
n is 1 or more; and
W is absent or a carrier capable of binding n (one or more) polysaccharide chains (pg. 3, col. 2, ([0036] – [0045]). Further, W is a mono- or polysaccharide, a protein, a lipid, a glycolipid, a glycoprotein, a glycosphingolipid or a ceramide (pg. 3, col. 2, [0047]).
US’574 teaches the use of a compound wherein said compound is a compound of formula (Ia)
[X(Fucα2)Galβ3(Y)ZNAcε3UGalβ4Glcβ1]n-W (Ia)
wherein U is absent, Galα4, Galβ3GlcNAcβ3, or (Fucα2)Galβ3GlcNAcβ3 (pg. 3, col. 2, [([0051] – [0052]).
US’574 teaches the use of a compound, wherein said compound is
[Fucα2Galβ3]n-W;
[Fucα2Galβ3GlcNAcβ3Galβ4Glcβ1]n-W;
[Galα3(Fucα2)Galβ3GlcNAcβ3Galβ4Glcβ1]n-W;
[GalNAcα3(Fucα2)Galβ3GlcNAcβ3Galβ4Glcβ1]n-W;
[GalNAcα3(Fucα2)Galβ3(Fucα4)GlcNAcβ3Galβ4Glcβ1]n-W;
[Galα3(Fucα2)Galβ3(Fucα4)GlcNAcβ3Galβ4Glcβ1]n-W;
[GalNAcα3(Fucα2)Galβ3GlcNAcβ3Galβ3GlcNAcβ3Galβ4Glcβ1]n-W;
[GalNAcα3(Fucα2)Galβ3GalNAcβ3Galα4Galβ4Glcβ1]n-W; or
[GalNAcα3(Fucα2)Galβ3GalNAcα3(Fucα2)Galβ3GlcNAcβ3Galβ4Glcβ1]n-W (pg. 3, col. 2, [0054]).
US’574 teaches the above described compounds for use as a medicine, for use in the treatment of F18+ E. coli infections in pigs in particular in the treatment of post weaning diarrhea and edema disease in pigs or for the manufacture of a medicament for the treatment of F18+ E. coli infections in pigs in particular in the treatment of post weaning diarrhea and edema disease in pigs (pg. 4, col. 1, [0056]).
US’574 teaches a pharmaceutical composition comprising pharmaceutically acceptable carriers and as an active ingredient a therapeutically effective amount of a compound as described above. US’574 teaches a process of preparing such a pharmaceutical composition wherein the pharmaceutically acceptable carriers and a compound as described above are intimately mixed (pg. 4, col. 2, [0068]).
US’574 teaches a food or drink additive comprising a compound or a molecule as described above. It further teaches a pig feed supplemented with a compound, a molecule, a pharmaceutical composition or a food additive as described above (pg. 4, col. 2, [0069]).
US’574 teaches that when W is a multivalent carrier of the polysaccharide chain it can carry more than one, more than 1000 exemplars of the polysaccharide chain, between 2 and 1000 exemplars of the polysaccharide chain, between 500 to 1000 exemplars of the polysaccharide chain, between 2 and 500 exemplars of the polysaccharide chain, between 2 and 300 exemplars of the polysaccharide chain, between 2 and 100 exemplars of the polysaccharide chain, between 2 and 50 exemplars of the polysaccharide chain, preferably 30; 29; 28; 27; 26; 25; 24; 23; 22; 21; 20;19; 18; 17; 16; 15; 14; 13; 12; 11; 10; 9; 8; 7; 6; 5; 4; 3 or 2 exemplars of the polysaccharide chain (pg. 6, col. 1, [0115]). US’547 teaches that when bound to the carrier W, the oligosaccharide sequence is preferably conjugated from the reducing end of the oligosaccharide sequence, as a conjugate, in particular a polyvalent conjugate from the reducing end of the oligosaccharide residue (pg. 6, col. 1, [0117]).
US’574 teaches oligosaccharides conjugated to HSA (Human Serum Albumin), FIG. 8: Effect of pre-incubation of F18+ E. coli with multivalent blood group sugars. F18+ E. coli strain 107/86 was incubated with different concentrations of blood group H type 1 pentasaccharide conjugated to HSA (H5-1/HSA) or blood group A type 1 hexasaccharide conjugated to HSA (A6-1/HSA) in PBS for 1 h at room temperature (pg. 5, col. 1, [0080]).
US’574 does not teach the carrier W to be a linear protein.
Liang teaches the formation, and antimicrobial activity of ε-polylysine–chitosan conjugate through Maillard reaction, and that the conjugate showed strong antibacterial activity against Escherichia coli, Staphylococcus aureus, Bacillus subtilis and beer yeast (Abstract). Liang teaches that a novel conjugate formed by the ε-polylysine and chitosan was prepared for food preservation. Browning and fluorescence reaction of heated ε-polylysine and chitosan indicated the presence of Maillard reaction products. The shift of amide/amino bands and the DSC (Differential scanning calorimetric measurement) peak shift of the conjugate further testified the formation and structural characteristics of the conjugate. The antimicrobial and antifungal activities of the conjugate were stronger than chitosan alone. Ultra-structural analysis by TEM (transmission electron microscopy) provided an intuitionistic evidence that the cytoplasmic membrane disruption and lysis were generated by conjugates in E. coli and S.aureus. The integrity, OM (outer membrane) and IM (inner membrane) permeability of cell membranes in E. coli and S. aureus implied that the conjugates killed bacteria by disrupting their OM and IM, which led to the damage of structure, function and permeability, leakage of intracellular components and the ultimate lysis of the cell (pg. 8, col. 1, para. 3).
It would have been prima facie obvious for one of ordinary skill in the art to modify the carrier W of US’574 to the linear protein, ε-polylysine, with the ability to conjugate multiple saccharidic chains as Liang teaches that ε-polylysine–chitosan conjugate showed strong antibacterial activity against Escherichia coli, Staphylococcus aureus, Bacillus subtilis and beer yeast (Abstract). One of ordinary skill in the art would have a reasonable expectation of success because Liang teaches that the ε-polylysine–chitosan conjugate showed strong antibacterial activity against Escherichia coli .
Regarding claim 1, US’574 teaches conjugates bound to a carrier W from the reducing end of the oligosaccharide sequence of compounds of the formula (I) and (Ia) as mentioned above with Y is absent or Fucα4, and k is 3.
Regarding claim 2, US’574 teaches k is 3 in the conjugates.
Regarding claim 3, Liang teaches conjugates with ε-polylysine.
Regarding claim 5, US’574 teaches the value of n as 2 and 50 exemplars of the polysaccharide chain, preferably 30; 29; 28; 27; 26; 25; 24; 23; 22; 21; 20;19; 18; 17; 16; 15; 14; 13; 12; 11; 10; 9; 8; 7; 6; 5; 4; 3 or 2 exemplars of the polysaccharide chain (pg. 6, col. 1, [0115]).
Regarding claim 6, of the 20 oligosaccharides listed, US’574 teaches the oligosaccharides Fucα2Galβ3; Fucα2Galβ3GlcNAcβ3Galβ4Glcβ1; Galα3(Fucα2)Galβ3GlcNAcβ3Galβ4Glcβ1; GalNAcα3(Fucα2)Galβ3GlcNAcβ3Galβ4Glcβ1; GalNAcα3(Fucα2)Galβ3(Fucα4)GlcNAcβ3Galβ4Glcβ1; Galα3(Fucα2)Galβ3(Fucα4)GlcNAcβ3Galβ4Glcβ1; GalNAcα3(Fucα2)Galβ3GlcNAcβ3Galβ3GlcNAcβ3Galβ4Glcβ1; GalNAcα3(Fucα2)Galβ3GalNAcβ3Galα4Galβ4Glcβ1 and GalNAcα3(Fucα2)Galβ3GalNAcα3(Fucα2)Galβ3GlcNAcβ3Galβ4Glcβ1.
Regarding claims 8 – 12, the claim limitations are met as US’574 teaches that the compounds are for use as a medicine in the treatment of F18+ E. coli infections in pigs, in the treatment of post weaning diarrhea and edema disease in pigs (pg. 4, col. 1, [0056]), as a pharmaceutical composition (pg. 4, col. 2, [0068]), and as a pig feed supplemented with a compound, a molecule, a pharmaceutical composition or a food additive (pg. 4, col. 2, [0069]).
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over US 2011/0306574 (IDS 09/05/2023) and Liang et al (Structure and antimicrobial mechanism of ε-polylysine-chitosan conjugates through Maillard reaction, International Journal of Biological Macromolecules 70, (2014), 427-434 (PTO-892)) as applied to claims 1 – 3, 5, 6, and 8 – 12 above, and further in view of Katopodis et al (Removal of anti-Galα1,3Gal xenoantibodies with an injectable polymer, J Clin Invest. 2002, 110 (12): 1869 – 1877 (PTO-892)).
The teachings of US’574 and Liang are as discussed above.
The combined teachings of US’574 and Liang differ from the instantly claimed invention in that US’574 and Liang do not teach the average molecular weight of the carrier in the conjugates or the average degree of polymerization.
Katopodis teaches the removal of anti-Galα1,3Gal xenoantibodies with an injectable polymer, wherein the injectable polymer is GAS914, a soluble trisaccharide-polylysine conjugate of approximately 500 kDa that effectively competes for αGal binding by αGal IgM (IC50, 43 nM) and IgG (IC50, 28 nM) in vitro, and conclude that GAS914 may be used therapeutically for the specific removal of Galα1,3Gal terminating carbohydrate chains (αGal Ab’s) (Title and Abstract). Katopodis teaches that maximal increase in avidity relative to the monomer was achieved with GAS914, a linear polylysine backbone with an average length of 1,000 lysines and with 25% of side chains conjugated to Linear B trisaccharide. In vitro, GAS914 is a potent inhibitor of the binding of both αGal IgG and IgM as well as the complement-dependent hemolysis of pig erythrocytes by human serum (pg. 2, col. 1, para. 2, refers to Figure 1 on pg. 4). Katopodis teaches that GAS914 is also highly efficacious in vivo in eliminating circulating αGal Ab’s in primates without side effects and with minimal complement activation and no immune response against either the carbohydrate or the backbone. This mode of antigen-specific treatment promises to protect pig organs transplanted into primates (pg. 2. col. 1, para. 3). Katopodis teaches the Equivalent weight calculation. Values for inhibition in the αGal Ab ELISA or hemolytic assay are based on the equivalent weight per Linear B trisaccharide, rather than on the average molecular weight of the polymer. This equivalent weight is a function of the fraction (x) of glycosylated monomer (determined by NMR) and is independent of the degree of polymerization (n). Equivalent weight is calculated by the formula: [(mol wtglycosylated monomer)x + (mol wtthioglycerol monomer)(1 – x)]/x. For x = 0.25, the equivalent weight is calculated as: [(872)0.25 + (276)0.75]/0.25 = 1,700. A polymer of average degree of polymerization (n) = 1,000 and x = 0.25 would have an average nx of 250 carbohydrate antigens per polymer molecule. The average molecular weight for x = 0.25 is calculated as [(872)0.25 + (276)0.75]n, e.g. 425,000 when n = 1000. This method allows direct comparison of potencies between different size and loading of polymers (pg. 2, col. 2, para. 3).
It would have been prima facie obvious to combine US’574 and Liang, with Katopodis before the effective filing date of the claimed invention to use a linear polylysine backbone having recognized MW and DP for the attachment of the saccharidic chains, and to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reasonable expectation of success because Katopodis teaches that maximal avidity relative to the monomer was achieved with GAS914, a linear polylysine backbone with an average length of 1,000 lysines and with 25% of side chains conjugated to Linear B trisaccharide, similarly as blood group A/B/H determinant on Type 1 Core glycosphingolipids chains act as recognition point for the FedF protein of F18-fimbriated Enterotoxigenic and verotoxinogenic Escherichia coli, the carbohydrate structures that are recognized by F18+ E. coli could be conjugated with a linear polylysine backbone to ward off E. coli infections.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over US 2011/0306574 (IDS 09/05/2023) and Liang et al (Structure and antimicrobial mechanism of ε-polylysine-chitosan conjugates through Maillard reaction, International Journal of Biological Macromolecules 70, (2014), 427-434 (PTO-892)) as applied to claims 1 – 3, 5, 6, and 8 – 12 above, and further in view of Gildersleeve et al (Improved procedure for direct coupling of carbohydrates to proteins via reductive amination, Bioconjugate Chem. 2008, 19, 1485-1490 (PTO-892)).
The teachings of US’574 and Liang are as discussed above.
The combined teachings of US’574 and Liang differ from the instantly claimed invention in that US’574 and Liang do not teach that the n saccharidic chains are covalently grafted to a linear protein W, by the saccharidic unit corresponding to their reducing end which is open and acyclic and has been coupled by its aldehyde function to a primary amino function of the linear protein by reductive amination.
Gildersleeve teaches an improved procedure for direct coupling of carbohydrates to proteins via reductive amination (Title). Carbohydrate-protein conjugates are utilized extensively in basic research and as immunogens in a variety of bacterial vaccines and cancer vaccines. As a result, there have been significant efforts to develop simple and reliable methods for the construction of these conjugates. While direct coupling via reductive amination is an appealing approach, the reaction is typically very inefficient. Gildersleeve teaches improved reaction conditions providing an approximately 500% increase in yield. In addition to optimizing a series of standard reaction parameters, Gildersleeve found that addition of 500 mM sodium sulfate improves the coupling efficiency. To illustrate the utility of these conditions, a series of high mannose BSA conjugates were produced and incorporated into a carbohydrate microarray. Ligand binding to ConA could be observed and apparent affinity constants (Kds) measured using the array were in good agreement with values reported by surface plasmon resonance. The results show that the conditions are suitable for microgram-scale reactions, are compatible with complex carbohydrates, and produce biologically active conjugates (Abstract). Gildersleeve teaches that one of the most appealing strategies is direct coupling of oligosaccharides to proteins in a single step. Glycans containing a free reducing end can be covalently attached to protein amino groups via reductive amination. The reducing end of a sugar exists as an equilibrium mixture composed of the cyclic hemiacetal form (lactol) and the open-chain aldehyde form (see Scheme 1, pg. 2). Under suitable conditions, amine groups will condense with the aldehyde to form an iminium ion which can be reduced to an amine. The process results in ring opening of the reducing end monosaccharide. When coupling to proteins, this reaction is carried out in aqueous buffer. Several factors make reductive amination of sugars to proteins
challenging. First, the reducing agent must be stable in water, unreactive with aldehydes, and yet reactive with iminium ions. Sodium cyanoborohydride meets these requirements and is by far the most common reducing reagent used for reductive amination of aldehydes to proteins. (pg. 1, col. 1, para. 2 and para. 3). Gildersleeve teaches that MALDI-TOF MS analysis showed that the resulting glycoconjugates contained an average of 7 oligosaccharide chains per molecule of BSA. The results verify that the improved conditions for reductive amination can be successfully applied to a variety of expensive, complex oligosaccharides on a microgram scale (pg. 4, col. 1, para. 1).
It would have been prima facie obvious to combine US’574 and Liang, with Gildersleeve before the effective filing date of the claimed invention by conjugating the saccharidic chains to ε-polylysine via the reducing end of the saccharidic chain which will be coupled by its aldehyde function to the amino function of the linear protein by reductive amination to prepare conjugates that would exhibit desired antimicrobial activity, to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reasonable expectation of success because Gildersleeve teaches the preparation of glycoconjugates containing an average of 7 oligosaccharide chains per molecule of BSA, and that the improved conditions for reductive amination can be successfully applied to a variety of expensive, complex oligosaccharides on a microgram scale.
Claims 13 – 15 are rejected under 35 U.S.C. 103 as being unpatentable over US 2011/0306574 (IDS 09/05/2023) in view of Liang et al (Structure and antimicrobial mechanism of ε-polylysine-chitosan conjugates through Maillard reaction, International Journal of Biological Macromolecules 70, (2014), 427-434 (PTO-892)) and Gildersleeve et al (Improved procedure for direct coupling of carbohydrates to proteins via reductive amination, Bioconjugate Chem. 2008, 19, 1485-1490 (PTO-892)).
US’574 teaches blood group A/B/H determinant on Type 1 Core glycosphingolipids chains as recognition point for the FedF protein of F18-fimbriated Enterotoxigenic and verotoxinogenic Escherichia coli and the use of compounds comprising such determinants for the treatment of F18+ E. coli infections in pigs and in screening methods (pg. 1, col. 1, [0001]).
US’574 teaches the use of a compound for binding to F18+ E. coli, F18 fimbriae, F18 adhesin, FedF or the receptor binding domain of FedF wherein said compound is a compound of formula (I)
[X(Fucα2)Galβ3(Y)TV]n-W (I)
X is absent, Galα3 or GalNAcα3 and when X is absent, then Y is absent;
Y is absent or Fucα4;
T is absent or ZNAcε3; and wherein Z is Glc or Gal; and ε is α or β;
V is absent or a mono-or polysaccharide;
n is 1 or more; and
W is absent or a carrier capable of binding n (one or more) polysaccharide chains (pg. 3, col. 2, ([0036] – [0045]). Further, W is a mono- or polysaccharide, a protein, a lipid, a glycolipid, a glycoprotein, a glycosphingolipid or a ceramide (pg. 3, col. 2, [0047]).
US’574 teaches the use of a compound wherein said compound is a compound of formula (Ia)
[X(Fucα2)Galβ3(Y)ZNAcε3UGalβ4Glcβ1]n-W (Ia)
wherein U is absent, Galα4, Galβ3GlcNAcβ3, or (Fucα2)Galβ3GlcNAcβ3 (pg. 3, col. 2, [([0051] – [0052]).
US’574 teaches the use of a compound, wherein said compound is
[Fucα2Galβ3]n-W;
[Fucα2Galβ3GlcNAcβ3Galβ4Glcβ1]n-W;
[Galα3(Fucα2)Galβ3GlcNAcβ3Galβ4Glcβ1]n-W;
[GalNAcα3(Fucα2)Galβ3GlcNAcβ3Galβ4Glcβ1]n-W;
[GalNAcα3(Fucα2)Galβ3(Fucα4)GlcNAcβ3Galβ4Glcβ1]n-W;
[Galα3(Fucα2)Galβ3(Fucα4)GlcNAcβ3Galβ4Glcβ1]n-W;
[GalNAcα3(Fucα2)Galβ3GlcNAcβ3Galβ3GlcNAcβ3Galβ4Glcβ1]n-W;
[GalNAcα3(Fucα2)Galβ3GalNAcβ3Galα4Galβ4Glcβ1]n-W; or
[GalNAcα3(Fucα2)Galβ3GalNAcα3(Fucα2)Galβ3GlcNAcβ3Galβ4Glcβ1]n-W (pg. 3, col. 2, [0054]).
US’574 teaches the above described compounds for use as a medicine, for use in the treatment of F18+ E. coli infections in pigs in particular in the treatment of post weaning diarrhea and edema disease in pigs or for the manufacture of a medicament for the treatment of F18+ E. coli infections in pigs in particular in the treatment of post weaning diarrhea and edema disease in pigs (pg. 4, col. 1, [0056]).
US’574 teaches a pharmaceutical composition comprising pharmaceutically acceptable carriers and as an active ingredient a therapeutically effective amount of a compound as described above. US’574 teaches a process of preparing such a pharmaceutical composition wherein the pharmaceutically acceptable carriers and a compound as described above are intimately mixed (pg. 4, col. 2, [0068]).
US’574 teaches a food or drink additive comprising a compound or a molecule as described above. It further teaches a pig feed supplemented with a compound, a molecule, a pharmaceutical composition or a food additive as described above (pg. 4, col. 2, [0069]).
US’574 teaches that when W is a multivalent carrier of the polysaccharide chain it can carry more than one, more than 1000 exemplars of the polysaccharide chain, between 2 and 1000 exemplars of the polysaccharide chain, between 500 to 1000 exemplars of the polysaccharide chain, between 2 and 500 exemplars of the polysaccharide chain, between 2 and 300 exemplars of the polysaccharide chain, between 2 and 100 exemplars of the polysaccharide chain, between 2 and 50 exemplars of the polysaccharide chain, preferably 30; 29; 28; 27; 26; 25; 24; 23; 22; 21; 20;19; 18; 17; 16; 15; 14; 13; 12; 11; 10; 9; 8; 7; 6; 5; 4; 3 or 2 exemplars of the polysaccharide chain (pg. 6, col. 1, [0115]). US’547 teaches that when bound to the carrier W, the oligosaccharide sequence is preferably conjugated from the reducing end of the oligosaccharide sequence, as a conjugate, in particular a polyvalent conjugate from the reducing end of the oligosaccharide residue (pg. 6, col. 1, [0117]).
US’574 teaches oligosaccharides conjugated to HSA (Human Serum Albumin), FIG. 8: Effect of pre-incubation of F18+ E. coli with multivalent blood group sugars. F18+ E. coli strain 107/86 was incubated with different concentrations of blood group H type 1 pentasaccharide conjugated to HSA (H5-1/HSA) or blood group A type 1 hexasaccharide conjugated to HSA (A6-1/HSA) in PBS for 1 h at room temperature (pg. 5, col. 1, [0080]).
The teachings of US’574 differ from the instantly claimed invention in that US’574 does not teach the carrier W to be a linear protein, and the method of making the conjugates via reductive amination.
Liang teaches the formation, and antimicrobial activity of ε-polylysine–chitosan conjugate through Maillard reaction, and that the conjugate showed strong antibacterial activity against Escherichia coli, Staphylococcus aureus, Bacillus subtilis and beer yeast (Abstract). Liang teaches that a novel conjugate formed by the ε-polylysine and chitosan was prepared for food preservation. Browning and fluorescence reaction of heated ε-polylysine and chitosan indicated the presence of Maillard reaction products. The shift of amide/amino bands and the DSC (Differential scanning calorimetric measurement) peak shift of the conjugate further testified the formation and structural characteristics of the conjugate. The antimicrobial and antifungal activities of the conjugate were stronger than chitosan alone. Ultra-structural analysis by TEM (transmission electron microscopy) provided an intuitionistic evidence that the cytoplasmic membrane disruption and lysis were generated by conjugates in E. coli and S.aureus. The integrity, OM (outer membrane) and IM (inner membrane) permeability of cell membranes in E. coli and S. aureus implied that the conjugates killed bacteria by disrupting their OM and IM, which led to the damage of structure, function and permeability, leakage of intracellular components and the ultimate lysis of the cell (pg. 8, col. 1, para. 3).
Gildersleeve teaches an improved procedure for direct coupling of carbohydrates to proteins via reductive amination (Title). Carbohydrate-protein conjugates are utilized extensively in basic research and as immunogens in a variety of bacterial vaccines and cancer vaccines. As a result, there have been significant efforts to develop simple and reliable methods for the construction of these conjugates. While direct coupling via reductive amination is an appealing approach, the reaction is typically very inefficient. Gildersleeve teaches improved reaction conditions providing an approximately 500% increase in yield. In addition to optimizing a series of standard reaction parameters, Gildersleeve found that addition of 500 mM sodium sulfate improves the coupling efficiency. To illustrate the utility of these conditions, a series of high mannose BSA conjugates were produced and incorporated into a carbohydrate microarray. Ligand binding to ConA could be observed and apparent affinity constants (Kds) measured using the array were in good agreement with values reported by surface plasmon resonance. The results show that the conditions are suitable for microgram-scale reactions, are compatible with complex carbohydrates, and produce biologically active conjugates (Abstract). Gildersleeve teaches that one of the most appealing strategies is direct coupling of oligosaccharides to proteins in a single step. Glycans containing a free reducing end can be covalently attached to protein amino groups via reductive amination. The reducing end of a sugar exists as an equilibrium mixture composed of the cyclic hemiacetal form (lactol) and the open-chain aldehyde form (see Scheme 1, pg. 2). Under suitable conditions, amine groups will condense with the aldehyde to form an iminium ion which can be reduced to an amine. The process results in ring opening of the reducing end monosaccharide. When coupling to proteins, this reaction is carried out in aqueous buffer. Several factors make reductive amination of sugars to proteins challenging. First, the reducing agent must be stable in water, unreactive with aldehydes, and yet reactive with iminium ions. Sodium cyanoborohydride meets these requirements and is by far the most common reducing reagent used for reductive amination of aldehydes to proteins. (pg. 1, col. 1, para. 2 and para. 3). Gildersleeve teaches that MALDI-TOF MS analysis showed that the resulting glycoconjugates contained an average of 7 oligosaccharide chains per molecule of BSA. The results verify that the improved conditions for reductive amination can be successfully applied to a variety of expensive, complex oligosaccharides on a microgram scale (pg. 4, col. 1, para. 1).
It would have been prima facie obvious for one of ordinary skill in the art to modify the carrier W of US’574 to the linear protein, ε-polylysine, with the ability to conjugate multiple saccharidic chains as Liang teaches that ε-polylysine–chitosan conjugate showed strong antibacterial activity against Escherichia coli, and to prepare the conjugates by covalently coupling the saccharidic chains to ε-polylysine via the reducing end of the saccharidic chain which will be coupled by its aldehyde function to the amino function of the linear protein by improved reductive amination taught by Gildesleeve which would result in conjugates that exhibit desired antimicrobial activity, to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reasonable expectation of success because Liang teaches that the ε-polylysine–chitosan conjugate showed strong antibacterial activity against Escherichia coli, and Gildersleeve teaches the preparation of glycoconjugates containing an average of 7 oligosaccharide chains per molecule of BSA, and that the improved conditions for reductive amination can be successfully applied to a variety of expensive, complex oligosaccharides on a microgram scale.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
US 8,703,722
Claims 1 – 15 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 7, 9, and 10 of U.S. Patent No. 8,703,722 in view of Katopodis et al (Removal of anti-Galα1,3Gal xenoantibodies with an injectable polymer, J Clin Invest. 2002, 110 (12): 1869 – 1877 (PTO-892)), Liang et al (Structure and antimicrobial mechanism of ε-polylysine-chitosan conjugates through Maillard reaction, International Journal of Biological Macromolecules 70, (2014), 427-434 (PTO-892)), and Gildersleeve et al (Improved procedure for direct coupling of carbohydrates to proteins via reductive amination, Bioconjugate Chem. 2008, 19, 1485-1490 (PTO-892)).
Although the claims at issue are not identical, they are not patentably distinct from each other because claims 1 – 7, 9, and 10 of the ‘722 patent are drawn to compounds containing polysaccharide chains, similar to the instant application, bound to a carrier selected from the group consisting of a protein, a lipid, a glycolipid, a glycoprotein, a glycosphingolipid, a ceramide, a lectin, an antibody, an immunoglobuline, a synthetic mimic of the aforementioned carrier, an organic molecule, a small molecule, a chemical, a nanoparticle, a bead, or a gel, and the compounds are used to treat or prevent F18+ E. coli infections in pigs, to treat pigs suffering from post weaning diarrhea or edema disease, and the compounds are administered as a pig feed supplement.
The claims of the ‘722 patent differ from the instantly claimed invention in that the ‘722 patent does not claim the carrier W is a linear protein, a polylysine, in particular, ε-poly-L-lysine.
Katopodis teaches the removal of anti-Galα1,3Gal xenoantibodies with an injectable polymer, wherein the injectable polymer is GAS914, a soluble trisaccharide-polylysine conjugate (Title and Abstract). Liang teaches the formation and antimicrobial activity of ε-polylysine–chitosan conjugate through Maillard reaction, and that the conjugate showed strong antibacterial activity against Escherichia coli, Staphylococcus aureus, Bacillus subtilis and beer yeast (Abstract). Gildersleeve teaches an improved procedure for direct coupling of carbohydrates to proteins via reductive amination (Title).
It would have been prima facie obvious to modify the claims of ‘722 patent with the combined teachings of Katopodis, Liang, and Gildersleeve before the effective filing date of the claimed invention by conjugating the saccharidic chains to ε-polylysine via the reducing end of the saccharidic chain which will be coupled by its aldehyde function to the amino function of the linear protein by reductive amination in the presence of a reducing agent, such as NaBH3CN to prepare conjugates that would exhibit desired antimicrobial activity, to arrive at the instantly claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to modify the carrier W of the ‘773 patent to a linear protein, such as polylysine, as Katopodis teaches that GAS914, a linear polylysine backbone with an average length of 1,000 lysines and with 25% of side chains conjugated to Linear B trisaccharide is also highly efficacious in vivo in eliminating circulating αGal Ab’s in primates without side effects and with minimal complement activation and no immune response against either the carbohydrate or the backbone, and Liang teaches that ε-polylysine–chitosan conjugate showed strong antibacterial activity against Escherichia coli, Staphylococcus aureus, Bacillus subtilis and beer yeast, and Gildersleeve teaches the improved conditions for reductive amination can be successfully applied to a variety of expensive, complex oligosaccharides on a microgram scale to achieve carbohydrate protein conjugates. One of ordinary skill in the art would have a reasonable expectation of success because Liang teaches that the ε-polylysine–chitosan conjugate showed strong antibacterial activity against Escherichia coli.
This is a nonstatutory double patenting rejection.
Conclusion
Claims 1 – 15 are rejected. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JANAKI ANANTH MAHADEVAN whose telephone number is (571)272-0230. The examiner can normally be reached Monday-Friday 8-5PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Scarlett Goon can be reached at 5712705241. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JANAKI ANANTH MAHADEVAN/Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693
Prosecution Insights