DETAILED ACTION
Election/Restrictions
Applicant’s election without traverse of Group I, claims 13-19, in the reply filed on 6/18/26 is acknowledged.
Claims 33, 34, 38, 66, 67, 94 and 95 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention.
Claim Objections
Claim 13 is objected to because of the following informalities: the “a” was deleted by Applicants in line 1 of the claim, but it should not have been. Appropriate correction is required.
Specification
The disclosure is objected to because of the following informalities: on page 2, the deposit number needs to be updated. Currently, line 3 in paragraph [0008], in paragraph [0012] on page 4 in several lines, page 6 in paragraph [0014] in several lines, paragraphs [0015]-[0016], last line on page 10, page 11, paragraph [0062], paragraphs [0083], [0084], [0087], [0089], [0092], [0094]-[0096], [00103], recite: NRRL deposit no. xxxxx.
Applicants are also advised to review the Biological Deposit requirements. See MPEP
Appropriate correction is required.
Claim Rejections - 35 USC § 112-2nd paragraph
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 13-19 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 13 is vague and indefinite because it recites “a formulation comprising a strain of Bifidobacterium longum subsp. infantis comprising at least one DNA sequence from Bifidobacterium longum subsp. infantis” and then recites that the bacteria has enhanced uptake, utilization or both of, N.-glycans, or plant-derived polysaccharides, or both. This is vague and confusing because any Bifidobacterium longum subsp. infantis strain would possess at least one DNA sequence from Bifidobacterium longum subsp. infantis so it is unclear if this is a modified DNA sequence, a naturally-occurring sequence or a heterologous sequence. Additionally, the claim does not link the DNA sequence to the recited functions. For example, it is unclear what structure allows for these enhanced functions. The structure is vital to the function, and it is not recited in the claims. The functions are also vague and confusing because it is unclear what are encompassed by “plant derived polysaccharides.” The term “derived” does not provide the character or properties from the source that are to be retained in the final product, e.g., paper is derived from wood but is very different from wood. While the specification can be used to provide definitive support, the claims are not read in a vacuum. Rather, the claim must be definite and complete in and of itself. Limitations from the specification will not be read into the claims. The claims as they stand are incomplete and fail to provide adequate structural properties to allow one to identify what is being claimed. Appropriate clarification and/or correction is required.
Claims 14-16 are vague and indefinite because it is unclear if these sequences are inherent to a Bifidobacterium longum subsp. infantis strain. It appears that they are, but the claims do not clearly recite any modification to these sequences which would cause any of the enhanced functions recited in claim 13 and this is critical to the claim to allow for one to identify the strain. While the specification can be used to provide definitive support, the claims are not read in a vacuum. Rather, the claim must be definite and complete in and of itself. Limitations from the specification will not be read into the claims. The claims as they stand are incomplete and fail to provide adequate structural properties to allow one to identify what is being claimed. Appropriate clarification and/or correction is required.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 13-19 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter because the claims are drawn to naturally occurring bacteria that exist in nature. The claimed bacterium is not markedly different from what naturally exists in nature. Even though isolation structurally changes a bacterium from its natural state, the resultant difference is not enough to render the isolated bacterium markedly different because the genetic structure and cell has not been altered. The term “formulation” is an intended use only and there is no structural difference between the claimed invention and naturally occurring bacterium. The nucleic acid sequences recited in the claims appear to be inherent DNA sequences that would be found in any Bifidobacterium longum subsp. infantis. The claims allow for up to 100% identity to these claims and include naturally occurring variant sequences as well. See Myriad, 133 S.Ct. at 2166-18.
Sequence Compliance
It is noted that page 59 (Table 1) and pages 77-83 (Table 8) of the instant specification recite nucleotide/amino acid sequences which are encompassed by the definitions for nucleotide sequences as set forth in 37 C.F.R. 1.821(a)(1) and (a)(2). The M.P.E.P., Section 2422.02, 37 CFR 1.821(b) requires exclusive conformance, with regard to the manner in which the nucleotide/amino acid sequences are presented and described, with the sequence rules for all applications that include nucleotide sequences that fall within the definitions. When a sequence is presented in the specification, the sequence must still be included in the Sequence Listing and the sequence identifier (“SEQ ID NO:X”) must be inserted into the body of the specification directly following the sequence. APPLICANT MUST COMPLY WITH THE SEQUENCE RULES WITHIN THE SAME TIME PERIOD AS IS GIVEN FOR RESPONSE TO THIS ACTION, 37 C.F.R. 1.821-25. Failure to comply with these requirements will result in ABANDONMENT of the application under 37 C.F.R. 1.821(g). Extensions of time may be obtained by filing a petition accompanied by the extension fee under the provisions of 37 C.F.R. 1.136. In no case may an applicant extend the period for response beyond the six month statutory period.
Claim Rejections - 35 USC § 112-Written Description
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 13-19 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 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.
The instant claims recite, for example:
13. (Currently amended) A formulation comprising a strain of Bifidobacterium longum subsp. infantis comprising at least one DNA sequence from Bifidobacterium longum subsp. infantis such that the bacteria has enhanced uptake, or utilization, or both, of N-glycans, or plant derived polysaccharides, or both.
14. (Original) The formulation of claim 13, wherein the at least one DNA sequence is selected from one or more polynucleotide sequences with more than 60% sequence identity to at least one of SEQ ID Nos: 2-23.
15. (Original) The formulation of claim 14, wherein the strain comprises at least two, at least three, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18 at least 19 or at least 20 polynucleotide sequences with more than 60% sequence identity to SEQ ID Nos: 2-23.
16. (Original) The formulation of claim 14, wherein the strain comprises one or more polynucleotide sequences with more than 60% sequence identity to each of SEQ ID NOS. 2-23.
The purpose of the "written description" requirement is broader than tomerely explain how to "make and use"; the applicant must convey with reasonableclarity to those skilled in the art that, as of the filing date sought, he or she was inpossession of the invention. The invention is, for purposes of the "writtendescription" inquiry, whatever is now claimed. See Vas-Cath, Inc. v. Mahurkar,935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991).Furthermore, the written description provision of 35 USC § 112 is severable fromits enablement provision; and adequate written description requires more than amere statement that it is part of the invention and reference to a potential methodfor isolating it. The nucleic acid itself (bacterium) is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing the invention was 'ready for patenting' such as by disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention.
Moreover, because the claims encompass a genus of variant species, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was "ready for patenting" by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus'" (Id. at 1106); accordingly, it follows that an adequate written description of a genus cannot be achieved in the absence of a disclosure of at least one species within the genus.
It is noted that MPEP 2111.01 states that "[d]uring examination, the claims must be interpreted as broadly as their terms reasonably allow." In this case, in light of the specification, the examiner has broadly interpreted the claims to include naturally occurring Bifidobacterium longum sups. Infantis, as well as countless other mutant/variant Bifidobacterium longum sups. Infantis with countless different nucleic acid sequences and variations. The Court of Appeals for the Federal Circuit has recently held that a "written description of an invention involving a chemical genus, like a description of a chemical species, 'requires a precise definition, such as by structure, formula [or] chemical name,' of the claimed subject matter sufficient to distinguish it from other materials." University of California v. Eli Lilly and Co., 1997 U.S. App. LEXIS 18221, at *23, quoting Fires v. Revel, 25 USPQ2d 1601, 1606 (Fed. Cir. 1993). To fully describe a genus of genetic material, which is a chemical compound, applicants must (1) fully describe at least one species of the claimed genus sufficient to represent said genus whereby a skilled artisan, in view of the prior art, could predict the structure of other species encompassed by the claimed genus and (2) identify the common characteristics of the claimed molecules, e.g., structure, physical and/or chemical characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or a combination of these (paraphrased from Enzo Biochemical). University of Rochester v. G.D. Searle & Co. (69 USPQ2d 1886 (2004)) specifically points to the applicability of both Lilly and Enzo Biochemical to methods of using products, wherein said products lack adequate written description. While in University of Rochester v. G.D. Searle & Co. the methods were held to lack written description because not a single example of the product used in the claimed methods was described, the same analysis applies wherein the product, used in the claimed methods, must have adequate written description (see Enzo paraphrased above).
In the instant case, there is no structure associated with function with regard to the members of a genus of Bifidobacterium longum subsp. infantis with exogenous gene additions and variant gene additions, or with different mutations to the genome. The specification does not describe the structure for any or all B. longum sp. infantis with at least 1, 1o, 20, 17, 6, etc., from nucleic acid sequences that vary as much as 40% from known sequences, e.g., at least 60%. As stated in the 112, 2nd paragraph above, it is unclear if these are bacteria that are naturally isolated and found to have these genes or if these bacteria are genetically altered in some manner. The specification does not provide written description for the extremely large scope of these claims and they have not shown the particular combinations or structures which provided the recited functions in the claims.
The prior art clearly teaches the "Practical Limits of Function Prediction":
Devos et al., (Proteins: Structure, Function and Genetics, 2000, Vol. 41: 98-107), teach that the results obtained by analyzing a significant number of true sequence similarities, derived directly from structural alignments, point to the complexity of function prediction. Different aspects of protein function, including (i) enzymatic function classification, (ii) functional annotations in the form of key words, (iii) classes of cellular function, and conservation of binding sites can only be reliably transferred between similar sequences to a modest degree. The reason for this difficulty is a combination of the unavoidable database inaccuracies and plasticity of proteins (Abstract, page 98) and the analysis poses interesting questions about the reliability of current function prediction exercises and the intrinsic limitation of protein function prediction (Column 1, paragraph 3, page 99) and conclude that "Despite widespread use of database searching techniques followed by function inference as standard procedures in Bioinformatics, the results presented here illustrate that transfer of function between similar sequences involves more difficulties than commonly believed. Our data show that even true pair-wise sequence relations, identified by their structural similarity, correspond in many cases to different functions (column 2, paragraph 2, and page 105).Whisstock et al., (Quarterly Reviews of Biophysics 2003, Vol. 36 (3): 307-340,) also highlight the difficulties associated with "Prediction of protein function from protein sequence and structure": "To reason from sequence and structure to function is to step onto much shakier ground", closely related proteins can change function, either through divergence to a related function or by recruitment for a very different function, in such cases, assignment of function on the basis of homology, in the absence of direct experimental evidence, will give the wrong answer (page 309, paragraph 4), it is difficult to state criteria for successful prediction of function, since function is in principle a fuzzy concept. Given three sequences, it is possible to decide which of the three possible pairs is most closely related. Given three structures, methods are also available to measure and compare similarity of the pairs. However, in many cases, given three protein functions, it would be more difficult to choose the pair with most similar function, although it is possible to define metrics for quantitative comparisons of different protein sequences and structures, this is more difficult for proteins of different functions (page 312, paragraph 5), in families of closely related proteins, mutations usually conserve function but modulate specificity i.e., mutations tend to leave the backbone conformation of the pocket unchanged but to affect the shape and charge of its lining, altering specificity (page 313, paragraph 4), although the hope is that highly similar proteins will share similar functions, substitutions of a single, critically placed amino acid in an active-site residue may be sufficient to alter a protein's role fundamentally (page 323, paragraph 1). C. This finding is reinforced in the following scientific teachings for specific proteins in the art that suggest, even highly structurally homologous polypeptides do not necessarily share the same function and many functionally similar proteins will have little or no structural homology to disclosed proteins. For example, proteins having similar structure have different activities (structure does not always correlate to function); Witowski et al., (Biochemistry 38:11643-11650, 1999) teaches that one conservative amino acid substitution transforms a beta -ketoacyl synthase into a malonyl decarboxylase and completely eliminates beta-ketoacyl synthase activity. The art also teaches that functionally similar molecules have different structures; Kisselev L., (Structure, 2002, Vol. 10: 8-9) teach that polypeptide release factors in prokaryotes and eukaryotes have same function but different structures.
As stated above, no information beyond the characterization of has been provided by the applicants’, which would indicate that they had the possession of the claimed genus of Bifidobactterum longum subsp. infantis strains with the claimed functions and/or the numerous different combinations of recited nucleic acid. The claimed genera of genetically modified and/or naturally isolated microorganisms containing any polynucleotides or any one or more of the 23 recited variants of up to 40% identity have widely variable structures and associated functions. As it is discussed above, a minor change in structure may result in changes affecting function, since, the specification provided no additional information correlating structure with function, one skilled in the art cannot reasonably conclude that applicant had possession of the claimed invention at the time the instant application was filed. Furthermore, "Possession may not be shown by merely describing how to obtain possession of members of the claimed ,genus or how to identify their common structural features" (See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895). A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the .gene does (function), rather what it is (structure), see University of California v. Eli Lilly & Co., 43 USPQ2d 1938, thus above claims lack adequate written description.
Applicant is referred to the revised guidelines concerning compliance with the written description requirement of U.S.C. 112, first paragraph, published in the Official Gazette and also available at www.uspto.gov
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 13-16 and 18 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Garrido et al (US 2021/0308235; provided by Applicants).
Garrido discloses an isolated strain of Bifidobacterium longum subspecies infantis comprising at least one DNA sequence from Bifidobacterium longum subspecies infantis that enhances uptake of N-glycans, plant derived polysaccharides, or both; or enhances utilization of N-glycans, plant derived polysaccharides, or both, compared to a strain of the same background without the at least one DNA sequence (Bifidobacterium isolates. A: Time deglycosylation of RNAseB by B. infantis ATCC 15697, Para. [0018]; B. longum subsp. infantis (B. infantis) ATCC 15697, Para. [0003]; B. infantis strains including the sequence found in strain ATCC 15697 (termed GH18a), Para. [0132]; deglycosylating enzymes belong to the GH18 and GH85 families of endoglycosidases. These enzymes are capable of cleaving a much broader range of N-glycans from N-glycosylated proteins than previously characterized deglycosylating enzymes, Para. [0083]; GH18 enzyme-expressing bacteria, can use various glycoproteins as a carbon source Bifidobacterium isolates can grow well on N-linked glycans as a main carbon source, Para. [0139]). Garrido et al teaches a DNA sequence 97.7% identical to Applicants’ SEQ ID NO: 22 (Garrido SEQ ID NO: 11).
Garrido also discloses wherein the strain comprises at least one DNA sequence comprising a polynucleotide sequence from Bifidobacterium longum subspecies infantis, or a DNA sequence that is completely absent from the genomes of related Bifidobacterium isolates, wherein the DNA sequence enhances uptake of N-glycans, plant derived polysaccharides, or both; or enhances utilization of N-glycans, plant derived polysaccharides, or both, compared to a strain of the same background without the at least one DNA sequence (Bifidobacterium isolates. A: Time deglycosylation of RNAseB by B. infantis ATCC 15697, Para. [0018]; B. longum subsp. infantis (B. infantis) ATCC 15697, Para. [0003]; B. infantis strains including the sequence found in strain ATCC 15697 (termed GH18a), Para. [0132]; deglycosylating enzymes belong to the GH18 and GH85 families of endoglycosidases. These enzymes are capable of cleaving a much broader range of N-glycans from N-glycosylated proteins than previously characterized deglycosylating enzymes, Para. [0083]; GH18 enzyme-expressing bacteria can use various glycoproteins as a carbon source Bifidobacterium isolates can grow well on N-linked glycans as a main carbon source, Para. [0139]). Garrido discloses an isolated strain of Bifidobacterium longum subsp. Infantis (Bifidobacterium isolates. A: Time deglycosylation of RNAseB by B. infantis ATCC 15697, Para. [0018]; B. longum subsp. infantis (B. infantis) ATCC 15697, Para. [0003]).
A “formulation” is an intended use only. A recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim.
Claim(s) 13-16 and 18 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Mills et al (US20100113383) Note: WO2008033520-A2 and US Patent No. 8,361,756 correspond to this publication.
Mills et al teach Bifidobacterium longum sps. Infantis with a Bifidobacterium alpha-L-fucosidase I gene, SEQ ID 18 is 98.4% identical to Applicants’ SEQ ID NO: 23, a Bifidobacterium sialidase I gene, SEQ ID 1 is 97.4% identical to Applicants’ SEQ ID NO: 21, a Bifidobacterium N-acetyl-beta-hexosaminidase I gene, SEQ ID 8 is 96.3% identical to Applicants’ SEQ ID NO: 20, and a Bifidobacterium N-acetyl-beta-hexosaminidase III gene, SEQ ID 10 is 96.9% identical to Applicants’ SEQ ID No: 19. See sequence alignment in public PAIR. They teach nucleic acids nucleic acid encoding a polypeptide involved in oligosaccharide modification, useful for producing a baby formula or food or a supplemented milk product for promoting growth of Bifidobacteria in a human gastrointestinal tract. See paragraph: [0051] The inventors have identified gene sequences that are associated with a bifidobacterial strain, Bifidobacterium longum bv. infantis. The gene sequences disclosed herein encode activities related to the catabolism of HMOs. Thus, the sequences of this invention encode proteins with the capacity to cleave and metabolize complex milk carbohydrates. Accordingly, these genes would provide a significant growth advantage to the cognate bifidobacterial strain for growth on milk oligosaccharides, or milk oligosaccharide mimics, and thus provide a means for selective bifidobacterial strain enrichment within animal gastrointestinal tracts. Among other uses, these gene sequences enable rationale screens for new bifidobacterial strains that can be selectively enriched through growth on milk oligosaccharides, or milk oligosaccharide mimics. Paragraph [0052] teaches that the proteins encoded by these gene sequences can also be used in the construction of HMO mimics by promoting the reverse reactions catalyzed by these catabolic enzymes. In particular, these enzymes can be used to synthesize particular oligosaccharide structures. For instance, once a complex oligosaccharide structure present in a biological sample, such as human breast milk, has been identified as having a beneficial use, these enzymes can be used to synthesize these structures from a variety of starting materials including lactose or other milk derived materials including simpler oligosaccharide structures or by decorating plant derived oligosaccharides. See paragraph: [0104] The catabolic activity of bifidobacterial strains in HMO metabolism was measured by monitoring sialidase and fucosidase activities required to deconstruct complex glycan structures. Enzymatic assays showed that B. longum bv. infantis has a 16.6- and 33.7-fold higher sialidase activity when grown on lactose as compared to B. longum and B. breve, respectively. (See Table 1.) These data suggest that B. longum bv. infantis has an inherent and constitutive ability to process sialylated compounds. Furthermore, among the three strains tested, fucosidase activity was only present in B. longum bv. infantis and was only detected upon growth on HMO. Such catabolic activities may be reversed, thus assembling larger oligosaccharides from smaller ones.
A “formulation” is an intended use only. A recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim.
Claim(s) 13-16 and 18 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Turroni et al (ISME Journal (2016), 10(7), 1656-1668).
Turroni teaches that the intricacies of cooperation and competition between microorganisms are poorly investigated for particular components of the gut microbiota. In order to obtain insights into the manner by which different bifidobacterial species coexist in the mammalian gut, we investigated possible interactions between four human gut commensals, Bifidobacterium bifidum PRL2010, Bifidobacterium adolescentis 22L, Bifidobacterium breve 12L and Bifidobacterium longum subsp. infantis ATCC15697, in the intestine of conventional mice. The generated information revealed various ecol./metabolic strategies, including glycan-harvesting, glycan-breakdown and cross-feeding behavior, adopted by bifidobacteria in the highly competitive environment of the mammalian intestine. Introduction of two or multiple bifidobacterial strains caused a clear shift in the microbiota composition of the murine cecum. Whole-genome transcription profiling coupled with metagenomic analyses of single, dual or multiple associations of bifidobacterial strains revealed an expansion of the murine gut glycobiome toward enzymic degradation of plant-derived carbohydrates, such as xylan, arabinoxylan, starch and host-derived glycan substrates. Furthermore, these bifidobacterial communities evoked major changes in the metabolomic profile of the microbiota as observed by shifts in short chain fatty acid production and carbohydrate availability in the murine cecum. Overall, these data support a role of bifidobacteria acting directly or through cross-feeding activities in shaping the gut murine microbiome to instigate an enrichment of saccharolytic microbiota. Turroni would inherently possess at least one or more of the naturally occurring B.longum sp.infantis nucleic acid sequences at least 60% identical to any one of SEQ ID NOS: 2-23 as they are inherent to the species, and the Bifidobacterium longum subsp. infantis strain taught by Turrin has the same functional activities,e.g, an expansion of the murine gut glycobiome toward enzymic degradation of plant-derived carbohydrates, such as xylan, arabinoxylan, starch and host-derived glycan substrates. Since the Patent Office does not have the facilities for examining and comparing Applicant's strain with the strain of the prior art, the burden of proof is upon applicants to show an unobvious distinction between the material structural and functional characteristics of the claimed strains and the strain of the prior art. See In re Best, 195 USPQ 430, 433 (CCPA 19&&).
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.
Claim(s) 17 and 19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Garrido et al (US 2021/0308235; provided by Applicants), Mills et al (US20100113383) and Turroni et al (ISME Journal (2016), 10(7), 1656-1668) in view of Collins et al (US20030092163).
The teachings of Garrido, Mills and Turroni are set forth above. However, they do not particularly exemplify formulations by their cfu per gram or that a formulation can contain both viable and non-viable cells.
Collins et al teaches Bifidobacterium longum infantis strains AH208, AH209, AH210, AH211, AH212 and AH214 and their use as probiotic bacteria. Collins teaches in paragraph [0051] that although the general use of probiotic bacteria is in the form of viable cells, it can also be extended to non-viable cells such as killed cultures or compositions containing beneficial factors expressed by the probiotic bacteria. This could include thermally killed micro-organisms or micro-organisms killed by exposure to altered pH or subjection to pressure. With non-viable cells product preparation is simpler, cells may be incorporated easily into pharmaceuticals and storage requirements are much less limited than viable cells. Accordingly, it would have been prima facie obvious to one of ordinary skill in the art to include viable, non-viable and or both in a formulation. While Collins does not specifically recite the nucleic acid sequences in their bacteria, they inherently would comprise some of the naturally occurring sequences as recited in in SEQ ID NOS: 2-23.
Garrido, Mills and Turroni teach that Bifidobacterium longum subsp. infantis was long known in the prior art to be used as a probiotic, particularly in infant formulas. The amount of bacteria in a probiotic formulation can vary. It has long been settled to be no more than routine experimentation for one of ordinary skill in the art to discover an optimum value of a result effective variable. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation." Application of Aller, 220 F.2d 454, 456, 105 USPQ 233, 235-236 (C.C.P.A. 1955). "No invention is involved in discovering optimum ranges of a process by routine experimentation." Id. at 458, 105 USPQ at 236-237. The "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." Application of Boesch, 617 F.2d 272, 276, 205 USPQ 215, 218-219 (C.C.P.A. 1980). Since Applicant has not disclosed that the specific limitation in the claim is for any particular purpose or solve any stated problem and the prior art teaches that different concentrations of bacteria in probiotic formulations often vary according to situations, absent unexpected results, it would have been obvious for one of ordinary skill to discover the optimum workable ranges of the for the bacteria by normal optimization procedures known in the art.
Prior art not presently relied upon:
Sarup-Lytzen et al (WO2022013269-A1)
20-JAN-2022.
Match to Applicants’ SEQ ID NO: 22 (to SEQ ID NO: 17) Sequence 2349 BP;
Query Match 97.7%; Best Local Similarity 98.6%;
New recombinant probiotic Gram-negative bacterium comprises genes
encoding outer membrane oligosaccharide transporter, periplasmic space
glycosidases, where glycosidases are capable of cleaving oligosaccharides
imported by transporter.The present invention relates to a recombinant probiotic Gram-negative
bacterium useful for prebiotic-responsive control of colonization. The
Gram-negative bacterium comprises genes encoding: (a) an outer membrane
oligosaccharide transporter; and (b) at least one of periplasmic space
glycosidases, where glycosidases are capable of cleaving oligosaccharides
imported by transporter. The invention further discloses: (1) a
composition comprising recombinant probiotic Gram-negative bacterium and
at least one of oligosaccharides; and (2) a kit used as a medicament,
Comprising medicinal composition, and a prebiotic. The bacterium has
ability to colonize the mammalian gut and is responsive to the supply of
carbohydrate, is safe to consume, and is capable of robust and
competitive growth in the gut microenvironment. The bacterium of the
invention is useful for preventing or treating of a bowel-related
Disorder, treatment-resistant depression, Parkinson's disease,
Alzheimer's, dopamine-responsive dystonia, Pterin deficiency, and Cerebral folate deficiency.
TITLE: Potential applications of
endo-β-N-acetylglucosaminidase from
bifidobacterium longum subspecies infantis in
designing value-added, next-generation infant formulas
AUTHOR(S): Duman, Hatice; Kaplan, Merve; Arslan, Aysenur;
Sahutoglu, Arif Sercan; Kayili, Haci Mehmet; Frese,
Steven A.; Karav, Sercan
CORPORATE SOURCE: Department of Molecular Biology and Genetics,
Canakkale Onsekiz Mart University, Canakkale, Turk.
SOURCE: Frontiers in Nutrition (2021) 646275
CODEN: FNRUBM; ISSN: 2296-861X
URL: http://www.frontiersin.org/Nutrition
DIGITAL OBJECT ID: 10.3389/fnut.2021.646275
PUBLISHER: Frontiers Media S.A.
DOCUMENT TYPE: Journal; General Review; (online computer file)
LANGUAGE: English
ED Entered STN: 21 Sep 2021
AB A review. Among many other health benefits, human milk can stimulate the
development of a Bifidobacterium-rich microbiome through human milk
oligosaccharides (HMOs). In recent years, the development of novel
formulas has placed particular focus on incorporating some of the
beneficial functional properties of human milk. These include adding
specific glycans aimed to selectively stimulate the growth of
Bifidobacterium. However, the bifidogenicity of human milk remains
unparalleled. Dietary N-glycans are carbohydrate structures
conjugated to a wide variety of glycoproteins. These glycans have a
remarkable structural similarity to HMOs and, when released, show a strong
bifidogenic effect. This review discusses the biocatalytic potential of
the endo-β-N-acetylglucosaminidase enzyme (EndoBI-1) from
Bifidobacterium longum subspecies infantis (B. infantis), in
releasing N-glycans inherently present in infant formula as means to
increase the bifidogenicity of infant formula. Finally, the potential
implications for protein deglycosylation with EndoBI-1 in the development
of value added, next-generation formulas are discussed from a tech.
perspective. Human milk is the optimal source of infant nutrition.
TITLE: N-glycans from human milk glycoproteins are
selectively released by an infant gut symbiont in vivo
AUTHOR(S): Karav, Sercan; Casaburi, Giorgio; Arslan, Aysenur;
Kaplan, Merve; Sucu, Berfin; Frese, Steven
CORPORATE SOURCE: Department of Molecular Biology and Genetics,
Canakkale Onsekiz Mart University, Canakkale, Turk.
SOURCE: Journal of Functional Foods (2019), 61, 103485
CODEN: JFFOAX; ISSN: 1756-4646
DIGITAL OBJECT ID: 10.1016/j.jff.2019.103485
PUBLISHER: Elsevier Ltd.
DOCUMENT TYPE: Journal; (online computer file)
LANGUAGE: English
ED Entered STN: 20 Aug 2019
AB Complex, indigestible free oligosaccharides as well as conjugated
glycans are found in milk that shape the gut microbiome of infants. The
activity of an endo-β-N-acetylglucosaminidase from B. longum
subsp. infantis (B. infantis) is known to release N-glycans from
native milk glycoproteins under physiol. conditions. We investigated
whether this enzyme is active in vivo in breastfed infants fed B.
infantis EVC001. Using mass spectrometry, we found 19 N-glycans
related to human milk glycoproteins increased in abundance, similar to
previous work using bovine milk glycoproteins, and these 19 N-glycans
matched unique specificities of this enzyme. Twenty N-glycans were
unique to infants fed B. infantis EVC001. Bifidobacteriaceae were
correlated with these glycans, confirming the relationship between B.
infantis and released N-glycans. This suggests that this enzyme is
active in vivo and releases N-glycans from milk glycoproteins, and may
play a role in B. infantis EVC001 colonization of the gut microbiome.
: Persistence of Supplemented Bifidobacterium longum
subsp. infantis EVC001 in Breastfed Infants
AUTHOR(S): Frese, Steven A.; Hutton, Andra A.; Contreras, Lindsey
N.; Shaw, Claire A.; Palumbo, Michelle C.; Casaburi,
Giorgio; Xu, Gege; Davis, Jasmine C. C.; Lebrilla,
Carlito B.; Henrick, Bethany M.; Freeman, Samara L.;
Barile, Daniela; German, J. Bruce; Mills, David A.;
Smilowitz, Jennifer T.; Underwood, Mark A.
CORPORATE SOURCE: Evolve Biosystems, Inc., Davis, CA, USA
SOURCE: mSphere (2017), 2(6), 1-15
CODEN: MSPHCI; ISSN: 2379-5042
DIGITAL OBJECT ID: 10.1128/msphere.00501-17
PUBLISHER: American Society for Microbiology
DOCUMENT TYPE: Journal; (online computer file)
LANGUAGE: English
ED Entered STN: 18 Oct 2018
AB Attempts to alter intestinal dysbiosis via administration of probiotics
have consistently shown that colonization with the administered microbes
is tran- sient. This study sought to det. whether provision of an initial
course of Bifido- bacterium longum subsp. infantis (B. infantis) would
lead to persistent colonization of the probiotic organism in breastfed
infants. Mothers intending to breastfeed were recruited and provided with
lactation support. One group of mothers fed B. infantis EVC001 to
their infants from day 7 to day 28 of life (n = 34), and the second group
did not administer any probiotic (n = 32). Fecal samples were collected
during the first 60 postnatal days in both groups. Fecal samples were
assessed by 16S rRNA gene sequencing, quant. PCR, mass spectrometry, and
endotoxin measure- ment. B. infantis-fed infants had significantly
higher populations of fecal Bifidobacte- riaceae, in particular B.
infantis, while EVC001 was fed, and this difference persisted more
than 30 days after EVC001 supplementation ceased. Fecal milk
oligosaccha- rides were significantly lower in B. infantis
EVC001-fed infants, demonstrating higher consumption of human milk
oligosaccharides by B. infantis EVC001. Concns. of acetate and
lactate were significantly higher and fecal pH was significantly lower in
infants fed EVC001, demonstrating alterations in intestinal fermn.
Infants colonized by Bifidobacteriaceae at high levels had 4-fold-lower
fecal endotoxin levels, consistent with obsd. lower levels of Gram-neg.
Proteobacteria and Bacte- roidetes. The gut microbiome in early life
plays an important role for long- term health and is shaped in large part
by diet. Probiotics may contribute to i.m.- provements in health, but
they have not been shown to alter the community com- position of the gut
microbiome. Here, we found that breastfed infants could be stably
colonized at high levels by provision of B. infantis EVC001, with
significant changes to the overall microbiome compn. persisting more than
a month later, whether the infants were born vaginally or by caesarean
section. This observation is consistent with previous studies
demonstrating the capacity of this subspecies to utilize human milk
glycans as a nutrient and underscores the importance of pairing a
probiotic organism with a specific substrate. Colonization by B.
infantis EVC001 re- sulted in significant changes to fecal microbiome
compn. and was assocd. with improvements in fecal biochem. The
combination of human milk and an infant-assocd. Bifidobacterium sp. shows,
for the first time, that durable changes to the human gut microbiome are
possible and are assocd. with improved gut function.
IT INDEXING IN PROGRESS
Correspondence regarding this application should be directed to Group Art Unit 1645. Papers related to this application may be submitted to Group 1600 by facsimile transmission. Papers should be faxed to Group 1600 via the PTO Fax Center located in Remsen. The faxing of such papers must conform with the notice published in the Official Gazette, 1096 OG 30 (November 15,1989). The Group 1645 Fax number is 571-273-8300 which is able to receive transmissions 24 hours/day, 7 days/week.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jennifer E. Graser whose telephone number is (571) 272-0858. The examiner can normally be reached on Monday-Friday from 8:00 AM-4 PM.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Thomas Visone, can be reached on (571) 270-0684.
Any inquiry of a general nature or relating to the status of this application should be directed to the Group receptionist whose telephone number is (571) 272-0500.
/JENNIFER E GRASER/ Primary Examiner, Art Unit 1645 8/11/26
Prosecution Insights