DETAILED ACTION
Claims 1-11 and 13 are currently pending.
Applicants’ election without traverse of Group I, claims 1-7, 11 and 13, in the reply filed on 8/11/26 is acknowledged.
Applicants noted in their response that claim 13 is drawn to the microorganism and not a fermentation product or culture of Group III as recited in the Restriction Requirement. Accordingly, claim 13 is placed in elected Group I and will be examined.
Claims 8-10 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention.
Claim Objections
Claims 2 and 6 are objected to because of the following informalities: the Genus/species should be italicized. Appropriate correction is required.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 4/10/26 was considered by the examiner. However, the references which are ‘struck out’ were not considered because the copies were illegible and unable to be read.
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 1-7, 11 and 13 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 is vague and indefinite because a name alone “heterologous nicotinamide transhydrogenase protein derived from any microorganism of the genus Corynebacterium” is vague and indefinite because the mere recitation of a name to describe the invention is not sufficient to satisfy the Statute's requirement of adequately describing and setting forth the inventive concept. The claim should provide any structural properties, such as the amino acid sequence of the protein or the nucleic acid sequence which encodes it, which would allow for one to identify the protein/nucleic acid without ambiguity. The mere recitation of a name does not adequately define the claimed transformed microorganism. Appropriate correction and/or clarification is required.
Claim 1 is also vague and indefinite for the recitation of “or a derivative thereof” of the L-amino acid. It is unclear what structure this would be and the metes and bounds of the term is not readily understood. Further, the use of the term “derived,” e.g., derived from a microorganism is also unclear. 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. Appropriate clarification and/or correction is required.
Claims 1-7, 11 and 13 are also vague and indefinite because it appears nicotinamide transhydrogenase protein is native to Corynebacterium. For example, the microorganism is of the Genus Corynebacterium, and the nicotinamide transhydrogenase is also from Corynebacterium. So, it is unclear if this is another additional nicotinamide transhydrogenase gene being added to the same microorganism? There is no mention of a vector or plasmid insertion either. Additionally, it appears the strain is critical to the function and to produce for instance, L-valine, the Corynebacterium would need to be an L-valine producing strain. Appropriate clarification and/or correction is required.
Claims 2-7 and 11 are also vague and indefinite due the use of the term “derived,” e.g., derived from a microorganism is also unclear. 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. Appropriate clarification and/or correction is required.
Claims 3 and 4 are vague and indefinite because a name alone, eg., pntAB gene, alpha subunit PntA and beta subunit PntB, is vague and indefinite because the mere recitation of a name to describe the invention is not sufficient to satisfy the Statute's requirement of adequately describing and setting forth the inventive concept. The claim should provide any structural properties, such as the amino acid sequence or the nucleic acid sequence, which would allow for one to identify the protein/nucleic acid without ambiguity. The mere recitation of a name does not adequately define the heterologous genes/protein in the claimed transformed microorganism. Appropriate correction and/or clarification is required.
Claims 6, 7 and 11 are vague and indefinite for the recitation of “or a derivative thereof” of the L-amino acid. It is unclear what structure this would be and the metes and bounds of the term is not readily understood. Appropriate clarification and/or correction is required.
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 1-7, 11 and 13 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:
[Claim 1] (Original) A microorganism of the genus Corynebacterium having improved ability to produce an L-amino acid or a derivative thereof, into which a polynucleotide encoding a heterologous nicotinamide nucleotide transhydrogenase protein derived from a microorganism of the genus Corynebacterium is introduced.
[Claim 2] (Original) The microorganism according to claim 1, wherein the heterologous nicotinamide nucleotide transhydrogenase is derived from Corynebacterium variabile or Corynebacterium zhongnanshanii.
[Claim 3] (Original) The microorganism according to claim 1, wherein the heterologous nicotinamide nucleotide transhydrogenase derived from a microorganism of the genus Corynebacterium is encoded by a pntAB gene.
[Claim 4] (Original) The microorganism according to claim 1, wherein the heterologous nicotinamide nucleotide transhydrogenase derived from a microorganism of the genus Corynebacterium consists of an alpha subunit PntA and a beta subunit PntB.
[Claim 5] (Original) The microorganism according to claim 1, wherein the alpha subunit PntA of the heterologous nicotinamide nucleotide transhydrogenase derived from a microorganism of the genus Corynebacterium comprises an amino acid sequence of SEQ ID NO: 20 or 30 or an amino acid sequence having at least 80% sequence identity thereto, and the beta subunit PntB comprises an amino acid sequence of SEQ ID NO: 21 or 31 or an amino acid sequence having at least 75% sequence identity thereto.
To fulfill the written description requirements set forth under 35 USC § 112, first paragraph, the specification must describe at least a substantial number of the members of the claimed genus, or alternatively describe a representative member of the claimed genus, which shares a particularly defining feature common to at least a substantial number of the members of the claimed genus, which would enable the skilled artisan to immediately recognize and distinguish its members from others, so as to reasonably convey to the skilled artisan that Applicant has possession the claimed invention. Applicants have not described the genus of claimed nicotinamide nucleotide transhydrogenase proteins/genes such that the specification might reasonably convey to the skilled artisan that Applicants had possession of the claimed invention at the time the application was filed. Even with the designation of “75% identical to SEQ ID NO: 21 or 31; or 80% identical to SEQ ID NO: 20 or 30” in some claims, the written description is inadequate to support this breadth.
With the written description of a genus, however, merely drawing a fence around a perceived genus is not a description of the genus. One needs to show that one has truly invented the genus, i.e., that one has conceived and described sufficient representative species encompassing the breadth of the genus. Otherwise, one has only a research plan, leaving it to others to explore the unknown contours of the claimed genus. See Ariad, 598 F.3d at 1353 (The written description requirement guards against claims that "merely recite a description of the problem to be solved while claiming all solutions to it and . . . cover any compound later actually invented and determined to fall within the claim's functional boundaries."). Abbvie Deutschland GmbH & Co. v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 U.S.P.Q.2d 1780, 1790, 2014 BL 183329, 12 (Fed. Cir. 2014).
To fulfill the written description requirements set forth under 35 USC § 112, first paragraph, the specification must describe at least a substantial number of the members of the claimed genus, or alternatively describe a representative member of the claimed genus, which shares a particularly defining feature common to at least a substantial number of the members of the claimed genus, which would enable the skilled artisan to immediately recognize and distinguish its members from others, so as to reasonably convey to the skilled artisan that Applicant has possession the claimed invention. Applicants have not described the genus of claimed fructanases such that the specification might reasonably convey to the skilled artisan that Applicants had possession of the claimed invention at the time the application was filed.
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 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." 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 any heterologous nicotinamide nucleotide transhydrogenase protein from any microorganism of the genus Corynebacterium, with the added function of having improved ability to produce an L-amino acid or derivative thereof when introduced into any microorganism of the genus Corynebacterium; or for any alpha subunit PntA or beta subunit PntB from any species of Corynebacterium. Further, there is no written description for PntA variants of a gene which is at least 80% identical to the amino acid sequence of SEQ ID NO: 20 or 30, or PntB variants of a gene which is at least 75% identical to the amino acid sequence of SEQ ID NO: 21 or 31.
The specification does not describe the structure for a representative number of genes from the Genus, with the required functionality in the claim. An argument can be made that the recited genus of polypeptides is adequately described by the disclosure of the structure of PntA of SEQ ID NO: 20 or 30, or PntB of SEQ ID NO: 21 or 31, or said genes obtained any genus of Corynebacterium and one could use structural homology to isolate those genes encoding polypeptides and the encoding polynucleotides recited in the claims. However, as described below, the 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.
Because the art is unpredictable and the scope of the claim includes numerous structural variants, and the genus is highly variant because a significant number of structural differences between genus members is permitted. The specification does not describe any members of the claimed genus by complete structure. One of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genus, and thus, that the applicant was not in possession of the claimed genus. The claimed subject matter is not supported by an adequate written description because a representative number of species has not been described.
There are no drawings or structural formulas disclosed of any of thesefragments or variants of the claimed polynucleotides. There is no teaching in thespecification regarding which 15-20% of the structure can be varied and still produce a polypeptide which has the function of providing any Corynebacterium with improved ability to produce any L-amino acid or any derivative thereof. Although the disclosure of SEQ ID NOs: 20, 21, 30 and 31combined with the knowledge in the art, may put one in possession of peptides that are at least 75-80% identical to SEQ ID NOs: 20, 30, 21 and 31, the level of skill and knowledge in the art is such that one of ordinary skill would not be able to identify without further testing which of those peptides would have the required functional activities. Based on the lack of knowledge and predictability in the art, those of ordinary skill in the art would not conclude that the applicant was in possession of the claimed genus of modified Corynebacterium.
As stated above, no information beyond the characterization of a few genes encoding nicotinamide nucleotide transhydrogenase protein, which would indicate that they had possession of the claimed genus of polypeptides and the encoding polynucleotides, and with the recited function when used in a host cell. The claimed genera of have widely variable structures and associated functions. As is discussed above, a minor change in structure may result in changes affecting function, since, the specification provided no additional information (species/variant/mutant) 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 available at www.uspto.gov
Claim Rejections - 35 USC § 112-Enablement
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 1-7, 11 and 13 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The instant claims, for example, recite:
[Claim 1] (Original) A microorganism of the genus Corynebacterium having improved ability to produce an L-amino acid or a derivative thereof, into which a polynucleotide encoding a heterologous nicotinamide nucleotide transhydrogenase protein derived from a microorganism of the genus Corynebacterium is introduced.
[Claim 2] (Original) The microorganism according to claim 1, wherein the heterologous nicotinamide nucleotide transhydrogenase is derived from Corynebacterium variabile or Corynebacterium zhongnanshanii.
[Claim 3] (Original) The microorganism according to claim 1, wherein the heterologous nicotinamide nucleotide transhydrogenase derived from a microorganism of the genus Corynebacterium is encoded by a pntAB gene.
[Claim 4] (Original) The microorganism according to claim 1, wherein the heterologous nicotinamide nucleotide transhydrogenase derived from a microorganism of the genus Corynebacterium consists of an alpha subunit PntA and a beta subunit PntB.
[Claim 5] (Original) The microorganism according to claim 1, wherein the alpha subunit PntA of the heterologous nicotinamide nucleotide transhydrogenase derived from a microorganism of the genus Corynebacterium comprises an amino acid sequence of SEQ ID NO: 20 or 30 or an amino acid sequence having at least 80% sequence identity thereto, and the beta subunit PntB comprises an amino acid sequence of SEQ ID NO: 21 or 31 or an amino acid sequence having at least 75% sequence identity thereto.
The specification does not enable these claims. First, the specification only demonstrates using vectors expressing pntAB from Corynebacterium variabile SEQ ID NO: 20 PntA and SEQ ID NO: 21 PntB) and pntAB (SEQ ID NO: 30 PntA and SEQ ID NO: 31 PntB) from Corynebacterium zhongnanshanii, which showed superior improvement in the producing ability. Additionally, the vectors were inserted into the Corynebacterium strains that already produced the particular L-amino acid. The claims do not recite the particular Genus/species and do not require it to be a particular L-amino acid producing strain. The specification demonstrates in the Examples that introducing the vectors expressing pntAB from Corynebacterium variabile SEQ ID NO: 20 PntA and SEQ ID NO: 21 PntB) and pntAB (SEQ ID NO: 30 PntA and SEQ ID NO: 31 PntB) from Corynebacterium zhongnanshanii into strains which produce a particular L-amino acid can help improve the production of that amino acid (and not any derivatives).
Example 2 on pages 37-38 of the instant specification demonstrates the construction of L-threonine producing strains into which heterologous pntAB is introduced. Corynebacterium glutamicum producing L-threonine is used as the host cell. As a result, as shown in Table 3, it was confirmed that the parent strain Corynebacterium glutamicum CA09-0903 produced about 3.4 g/L of threonine. Among the strains expressing pntAB derived from foreign microorganisms, the strain expressing pntAB derived from Corynebacterium variabile, CA09-0903 AN1287(13032) PgapA_pntAB(C.va), exhibited a threonine-producing ability increased by 65% relative to the parent strain. In addition, the strain expressing pntAB derived from Corynebacterium zhongnanshanii, CA09-0903 N1287(13032):PgapA_pntAB(C.zh), exhibited a threonine-producing ability increased by 79% relative to the parent strain. Among the six types of vectors constructed in Example 1, vectors expressing pntAB derived from Corynebacterium variabile and pntAB derived from Corynebacterium zhongnanshanii, which showed superior improvement in the producing ability in Example 2-1, were introduced into an arginine-producing strain. Specifically, transformation was performed by electroporation into an arginine-producing strain, Corynebacterium glutamicum CJ1R (Korean Patent Application No. 10-2021-0045262), to construct strains expressing heterologous pntAB.
Example 2-3: Construction of L-homoserine-producing strains into which heterologous pntAB was introduced and evaluation of L-homoserine-producing ability Among the six types of vectors constructed in Example 1, vectors expressing pntAB derived from Corynebacterium variabile and pntAB derived from Corynebacterium zhongnanshanii, which showed superior improvement in the producing ability in Example 2-1, were transformed by electroporation into a homoserine-producing strain, Corynebacterium glutamicum KCCM 12120P (Korean Patent No. 10-1947959), to construct strains expressing heterologous pntAB.
Example 2-4: Construction of L-valine-producing strains into which heterologous pntAB was introduced and evaluation of L-valine-producing ability Among the six types of vectors constructed in Example 1, vectors expressing pntAB derived from Corynebacterium variabile and pntAB derived from Corynebacterium zhongnanshanii, which showed superior improvement in the producing ability in Example 2-1, were introduced into a valine-producing strain.
Example 2-5: Construction of L-lysine-producing strains into which heterologous pntAB was introduced and evaluation of L-lysine-producing ability. Among the six types of vectors constructed in Example 1, vectors expressing pntAB derived from Corynebacterium variabile and pntAB derived from Corynebacterium zhongnanshanii, which showed superior improvement in the producing ability in Example 2-1, were introduced into a lysine-producing strain. Specifically, transformation was performed by an electric pulse method (Van der Rest et al., Appl. Microbiol. Biotechnol. 52:541-545, 1999)into a lysine-producing strain, Corynebacterium glutamicum CJ3P (U.S. Patent No. 9,556,463 B2), to construct a strain expressing heterologous pntAB.
Among the six types of vectors constructed in Example 1, vectors expressing pntAB derived from Corynebacterium variabile and pntAB derived from Corynebacterium zhongnanshanii, which showed superior improvement in the producing ability in Example 2-1, were transformed by electroporation into a pantothenic acid-producing strain, CJVB5-01 (Korean Patent No. 10-2389327), and through a second crossover process, a strain in which NCgl1287 was deleted on the chromosome and a strain in which NCgl1287 was deleted and heterologous pntAB was introduced were obtained.
Accordingly, the Corynebacterium strain has to already produce the particular L-amino acid in the wild-type cell for the vectors expressing vectors expressing pntAB derived from Corynebacterium variabile (SEQ ID NOS: 20 and 21) and pntAB derived from Corynebacterium zhongnanshanii, (SEQ ID NOS: 30 and 31) to boost production.
With respect to variant pntAB genes from Corynebacterium variabile and pntAB derived from Corynebacterium zhongnanshanii, the specification only enables the vectors expressing pntAB derived from Corynebacterium variabile (SEQ ID NOS: 20 and 21) and pntAB derived from Corynebacterium zhongnanshanii, (SEQ ID NOS: 30 and 31). While the specification states that substitutions, additions, or deletions, may be made to the defined sequences; however, the specification provides no guidance as which nucleic acids or amino acids may be changed without causing a detrimental effect to the enzyme and with the added enzymatic function requirement. It is unpredictable as to which amino acids could be removed and which could be added. While it is known that many amino acid substitutions are possible in any given protein, the position within the protein’s sequence where amino acid substitutions can be made with a reasonable expectation of success are limited. Other positions are critical to the protein’s structure/function relationship, e.g., such as various positions or regions directly involved in binding, catalysis in providing the correct three-dimensional spatial orientation of binding and catalytic sites. These regions can tolerate only very little or no substitutions. Selective point mutation to one key residue could eliminate the function of the polypeptide. It could eliminate its functional properties. If the range of decreased binding ability after single point mutation of a protein antigen varies, one could expect point mutations in the protein antigen to cause varying degrees of loss of protection/function, depending on the relative importance to the binding interaction of the altered residue. Alternatively, the combined effects of multiple changes, as instantly claimed, in an antigenic determinant could again result in loss of function. A protein having multiple point mutations, or accumulated point mutations at key residues could create a new antigen that is precipitously or progressively unrecognizable. As stated above, Applicants have not shown the particular substitution and the result it produces. Applicants have provided no guidance to enable one of ordinary skill in the art how to determine, without undue experimentation, the effects of different amino substitutions and the nature and extent of the changes that can be made. It is expensive and time consuming to make amino acid substitutions at more than one position, in a particular region of the protein, in view of the many fold possibilities for change in structure and the uncertainty as to what utility will be possessed. See Mikayama et al. (Nov.1993. Proc.Natl.Acad.Sci. USA, vol. 90 : 10056-10060) which teaches that the three-dimensional structure of molecules is important for their biological function and even a single amino acid difference may account for markedly different biological activities. Rudinger et al. (June 1976. Peptide Hormones. Biol.Council. pages 5-7) also teaches that amino acids owe their ‘significance’ to their inclusion in a pattern which is directly involved in recognition by, and binding to, the receptor and the significance of the particular amino acids and sequences for different amino acids cannot be predicted a priori, but must be determined from case to case by painstaking experimental study. The instant claims allow for substitutions with amino acids of vastly different properties and they do not recite the specific changes in the claims.
Genentech Inc. v. Novo Nordisk A/S (CAFC) 42 USPQ2d 1001 clearly states: “Patent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable. See Brenner v. Manson, 383 U.S. 519, 536, 148 USPQ 689, 696 (1966) (stating, in context of the utility requirement, that "a patent is not a hunting license. It is not a reward for the search, but compensation for its successful conclusion.") Tossing out the mere germ of an idea does not constitute enabling disclosure. While every aspect of a generic claim certainly need not have been carried out by an inventor, or exemplified in the specification, reasonable detail must be provided in order to enable members of the public to understand and carry out the invention.”
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
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.
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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 8/25/26
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