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 .
Detailed Action
Amended claims 1-12 (dated 08/09/2023) are pending and now under consideration.
Priority
Acknowledgment is made of applicants’ claim for foreign priority under 35 U.S.C. 119(a)-(d). This application is a 371 of PCT/KR2021/003408 filed on 03/19/2021 and claims the priority date of Korea application 10-2020-0101894 filed on 08/13/2020; however, no English translation of said foreign priority application has been provided. Therefore, the priority date for instant claims under consideration is deemed to be the filing date of 371 of PCT/KR2021/003408 filed on 03/19/2021.
Information disclosure statement
The information disclosure statements (IDS) submitted on 02/13/2023 and 03/27/2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS statements are considered and initialed by the examiner.
Claim Rejections: 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
I. Claims 1-12 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention.
Claims 1-12 are indefinite in the recitation of “derived”. The metes and bounds of the term “derived” is not clear in the context of the claim. It is not clear to the examiner what are the structures encompassed in “derived”? or is a representative member of a genus/merely exemplary. Furthermore, in claims 1-12 are indefinite in the recitation of “derived”; as written, one cannot determine if the term refers to ‘functions of several real variables” or ‘structural variables’ of claimed “derived” polypeptides (unlimited structures or structurally undefined molecules or functionally variable molecules and the extent of variability is unclear). The metes and bounds of the claims are unclear. For examination purposes, no patentable weight will be given to the terms. It is not clear to the examiner as to what the phrase “derived” means in the context of the above claims, is this synonymous with “obtained from specific source or having specific structures? or does it include natural and man-made variants of unlimited/undefined structures thereof from any source? Examiner suggests amending the claims to recite ”obtained from…”. Clarification and correction required.
II. Claim 4 is rejected under 35 U.S.C. 112, second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
Claim 4 recites the phrase “weakened activity of bifunctional ornithine acetyltransferase/N-acetylglutamate synthase (argJ)”. For the record no specific structure for ornithine acetyltransferase/N-acetylglutamate synthase (argJ) is recited in the claims; it is not clear variants are compared to specific corresponding wildtype ornithine acetyltransferase/N-acetylglutamate synthase (argJ), clarification is required; the phrase “weakened activity of bifunctional ornithine acetyltransferase/N-acetylglutamate synthase (argJ)” in claim 4 renders the claim indefinite and considered to be a relative term and the specification is limited to teaching the activity of wildtype sequence comprising the sequence of SEQ ID NO: 5 and its activity ornithine acetyltransferase/N-acetylglutamate synthase, and one of ordinary skill in the art would not be able to reasonably determine the metes and bounds, as “weakened activity of bifunctional ornithine acetyltransferase/N-acetylglutamate synthase (argJ)” includes many undefined and unlimited structures and varies widely depending on the individual situation as well as the person making the determination and is dependent upon set of conditions defined by the individual situation. Clarification and correction is required. For examination purposes “weakened activity of bifunctional ornithine acetyltransferase/N-acetylglutamate synthase (argJ)” encompasses many undefined and unlimited structures.
Claim Rejections: 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(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 and 10-12 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The purpose of the written description requirement is to ensure that the inventor had possession, at the time the invention was made, of the specific subject matter claimed. For a broad generic claim, the specification must provide adequate written description to identify the genus of the claim.
“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." Fiers, 984 F.2d at 1171, 25 USPQ2d 1601; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284985 (CCPA 1973) (“In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus.”). Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
MPEP § 2163 further states that if a biomolecule is described only by a functional characteristic, without any disclosed correlation between function and structure of the biomolecule, it is "not sufficient characteristic for written description purposes, even when accompanied by a method of obtaining the claimed biomolecule.”
“The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice . . ., reduction to drawings . . ., or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.” MPEP 2163.
Furthermore, a “‘representative number of species’ means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure ‘indicates that the patentee has invented species sufficient to constitute the gen[us].’ See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) (‘[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.’). ‘A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed.’ In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004).” MPEP 2163.
The claims recite the following broadly claimed genera:
Claims 1-7 and 10-12 recite a genera of polypeptides in a microorganism of the genus Corynebacterium having putrescine producing ability i.e., “an N-acetyltransferase derived from a strain of the genus Corynebacterium” and “an acetylornithine deacetylase (argE) derived from E. coli” activities; said genera of polypeptides having a sequence identity of 90% thereto with SEQ ID NO: 1 and SEQ ID NO: 3 (as in claims 1-3, 5-7 and 10-12); and wherein the microorganism has weakened activity of bifunctional ornithine acetyltransferase/N-acetylglutamate synthase (argJ) of undefined and unlimited structures derived from a strain of the genus Corynebacterium (as in claim 4; also see and 35 U.S.C. 112(b) rejection for claims interpretation).
The structural elements recited in claims 1-7 and 10-12 are not sufficient structure to form “an N-acetyltransferase”, “an acetylornithine deacetylase’ and “weakened activity of bifunctional ornithine acetyltransferase/N-acetylglutamate synthase (argJ)“ having no specific structural elements of any kind and having associated activity. There in inherent unpredictability in regards to which amino acid sequences may have the associated function i.e., “an N-acetyltransferase”, “an acetylornithine deacetylase’ and “weakened activity of bifunctional ornithine acetyltransferase/N-acetylglutamate synthase (argJ)“ activity and possibly fall within the claims and those amino acid sequences that do not have “an N-acetyltransferase”, “an acetylornithine deacetylase’ and “weakened activity of bifunctional ornithine acetyltransferase/N-acetylglutamate synthase (argJ)“ activity. As such, claims 1-7 and 10-12 recite a genera of biomolecules described only by a functional characteristics (i.e., being “an N-acetyltransferase”, “an acetylornithine deacetylase’ and “weakened activity of bifunctional ornithine acetyltransferase/N-acetylglutamate synthase (argJ)“), without any disclosed correlation between function and structure of the biomolecule, it is "not sufficient characteristic for written description purposes, even when accompanied by a method of obtaining the claimed biomolecule.” Further, without any structural limitations for structural features that actually provide for “an N-acetyltransferase”, “an acetylornithine deacetylase’ and “weakened activity of bifunctional ornithine acetyltransferase/N-acetylglutamate synthase (argJ)“ activity, claims 1-7 and 10-12 have no defined outer bounds for the scope of “an N-acetyltransferase”, “an acetylornithine deacetylase’ and “weakened activity of bifunctional ornithine acetyltransferase/N-acetylglutamate synthase (argJ)“ that fall within the scope of the claims. Due to the literal unlimited structural scope of the claims, it is not possible to provide for a representative number of species that adequately described are representative of the entire genus having no fixed structural outer boundaries. Further, such genera of altered enzymes as recited lack “a precise definition, such as by structure, formula, [or] chemical name, of the claimed subject matter sufficient to distinguish it from other materials” and without any required structure that is sufficient for providing the recited enzyme activity, the recited genera lack disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. The claims lack adequate written description in the as-filed specification for the reasons stated.
No information, beyond the characterization of specific structures and having the comprising the amino acid sequences of SEQ ID NO: 1; SEQ ID NO: 3 and SEQ ID NO: 5 and the encoding polynucleotides, isolated specific strain of Corynebacterium glutamicum host cell comprising the encoding polynucleotides, method of making and method of use (see Examples 1-5, pages 27-42 of specification), has been provided by the applicants’, which would indicate that they had possession of the claimed genera of polypeptides in a microorganism of the genus Corynebacterium having putrescine producing ability i.e., “an N-acetyltransferase derived from a strain of the genus Corynebacterium” and “an acetylornithine deacetylase (argE) derived from E. coli” activities; said genera of polypeptides having a sequence identity of 90% thereto with SEQ ID NO: 1 and SEQ ID NO: 3 (as in claims 1-3, 5-7 and 10-12); and wherein the microorganism has weakened activity of bifunctional ornithine acetyltransferase/N-acetylglutamate synthase (argJ) of undefined and unlimited structures derived from a strain of the genus Corynebacterium (as in claim 4; also see and 35 U.S.C. 112(b) rejection for claims interpretation).
The genus of polypeptides and encoding polynucleotides required in the claimed invention is an extremely large structurally and functionally variable genus. While the argument can be made that the recited genus of polypeptides is adequately described by the disclosure of the structures and the characterization of the variants/mutants of amino acid sequence of SEQ ID NO: 1 and the encoding polynucleotides, since one could use structural homology to isolate those polypeptides and the encoding polynucleotides recited in the claims. The art clearly teaches the “Practical Limits of Function Prediction”: (a) 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 (iv) 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, page 105).
(b) 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 polynucleotides and encoded polypeptides do not necessarily share the same function. For example, Witkowski et al., (Biochemistry 38:11643-11650, 1999), teaches that one conservative amino acid substitution transforms a b-ketoacyl synthase into a malonyl decarboxylase and completely eliminates b-ketoacyl synthase activity. Seffernick et al., (J. Bacteriol. 183(8): 2405-2410, 2001), teaches that two naturally occurring Pseudomonas enzymes having 98% amino acid sequence identity catalyze two different reactions: deamination and dehalogenation, therefore having different function. Broun et al., (Science 282:1315-1317, 1998), teaches that as few as four amino acid substitutions can convert an oleate 12-desaturase into a hydrolase and as few as six amino acid substitutions can transform a hydrolase to a desaturase.
As stated above, no information beyond the characterization of specific structures and having the comprising the amino acid sequences of SEQ ID NO: 1; SEQ ID NO: 3 and SEQ ID NO: 5 and the encoding polynucleotides, isolated specific strain of Corynebacterium glutamicum host cell comprising the encoding polynucleotides, method of making and method of use (see Examples 1-5, pages 27-42 of specification), has been provided by the applicants’, which would indicate that they had possession of the claimed genera of polypeptides in a microorganism of the genus Corynebacterium having putrescine producing ability i.e., “an N-acetyltransferase derived from a strain of the genus Corynebacterium” and “an acetylornithine deacetylase (argE) derived from E. coli” activities; said genera of polypeptides having a sequence identity of 90% thereto with SEQ ID NO: 1 and SEQ ID NO: 3 (as in claims 1-3, 5-7 and 10-12); and wherein the microorganism has weakened activity of bifunctional ornithine acetyltransferase/N-acetylglutamate synthase (argJ) of undefined and unlimited structures derived from a strain of the genus Corynebacterium (as in claim 4; also see and 35 U.S.C. 112(b) rejection for claims interpretation). As the claimed genera of polypeptides and encoding polynucleotides having widely variable structures and associated function, since minor changes in structure may result in changes affecting function and no additional information (species/variant/mutant) correlating structure with function has been provided. 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).
Therefore, one skilled in the art cannot reasonably conclude that applicant had possession of the claimed invention at the time the instant application was filed. Applicants are referred to the revised guidelines concerning compliance with the written description requirement of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, published in the Official Gazette and also available at www.uspto.gov.
Enablement
Claims 1-7 and 10-12 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification is enabling for the characterization of specific structures and having the comprising the amino acid sequences of SEQ ID NO: 1; SEQ ID NO: 3 and SEQ ID NO: 5 and the encoding polynucleotides, isolated specific strain of Corynebacterium glutamicum host cell comprising the encoding polynucleotides, method of making and method of use (see Examples 1-5, pages 27-42 of specification). However, specification does not reasonably provide enablement for a genera of polypeptides in a microorganism of the genus Corynebacterium having putrescine producing ability i.e., “an N-acetyltransferase derived from a strain of the genus Corynebacterium” and “an acetylornithine deacetylase (argE) derived from E. coli” activities; said genera of polypeptides having a sequence identity of 90% thereto with SEQ ID NO: 1 and SEQ ID NO: 3 (as in claims 1-3, 5-7 and 10-12); and wherein the microorganism has weakened activity of bifunctional ornithine acetyltransferase/N-acetylglutamate synthase (argJ) of undefined and unlimited structures derived from a strain of the genus Corynebacterium (as in claim 4; also see and 35 U.S.C. 112(b) rejection for claims interpretation). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Factors to be considered in determining whether undue experimentation is required are summarized in In re Wands (858 F.2d 731, 8 USPQ 2nd 1400 (Fed. Cir. 1988)) as follows: (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claim(s).
Claims 1-7 and 10-12 are so broad as to encompass: a genera of polypeptides in a microorganism of the genus Corynebacterium having putrescine producing ability i.e., “an N-acetyltransferase derived from a strain of the genus Corynebacterium” and “an acetylornithine deacetylase (argE) derived from E. coli” activities; said genera of polypeptides having a sequence identity of 90% thereto with SEQ ID NO: 1 and SEQ ID NO: 3 (as in claims 1-3, 5-7 and 10-12); and wherein the microorganism has weakened activity of bifunctional ornithine acetyltransferase/N-acetylglutamate synthase (argJ) of undefined and unlimited structures derived from a strain of the genus Corynebacterium (as in claim 4; also see and 35 U.S.C. 112(b) rejection for claims interpretation). The scope of the claim is not commensurate with the enablement provided by the disclosure with regard to the extremely large number of polynucleotides and encoded polypeptides broadly encompassed by the claims. Since the amino acid sequence of a protein encoded by a polynucleotide determines its structural and functional properties, predictability of which changes can be tolerated in a protein's amino acid sequence and obtain the desired activity requires a knowledge of and guidance with regard to which amino acids in the protein's sequence and the respective codons in its polynucleotide, if any, are tolerant of modification and which are conserved (i.e., expectedly intolerant to modification), and detailed knowledge of the ways in which the encoded proteins' structure relates to its function. However, in this case the disclosure is limited to the characterization of specific structures and having the comprising the amino acid sequences of SEQ ID NO: 1; SEQ ID NO: 3 and SEQ ID NO: 5 and the encoding polynucleotides, isolated specific strain of Corynebacterium glutamicum host cell comprising the encoding polynucleotides, method of making and method of use (see Examples 1-5, pages 27-42 of specification). It would require undue experimentation of the skilled artisan to make and use the claimed polypeptides i.e., a genera of polypeptides in a microorganism of the genus Corynebacterium having putrescine producing ability i.e., “an N-acetyltransferase derived from a strain of the genus Corynebacterium” and “an acetylornithine deacetylase (argE) derived from E. coli” activities; said genera of polypeptides having a sequence identity of 90% thereto with SEQ ID NO: 1 and SEQ ID NO: 3 (as in claims 1-3, 5-7 and 10-12); and wherein the microorganism has weakened activity of bifunctional ornithine acetyltransferase/N-acetylglutamate synthase (argJ) of undefined and unlimited structures derived from a strain of the genus Corynebacterium (as in claim 4; also see and 35 U.S.C. 112(b) rejection for claims interpretation). The specification but provides no guidance with regard to the making of variants and mutants or with regard to other uses. In view of the great breadth of the claims, amount of experimentation required to make and use the claimed polypeptides, the lack of guidance, working examples, and unpredictability of the art in predicting function from a polypeptide primary structure (for example, see Whisstock et al., Prediction of protein function from protein sequence and structure. Q Rev Biophys. 2003, Aug. 36 (3): 307-340. Review), the claimed invention would require undue experimentation. As such, the specification fails to teach one of ordinary skill how to make and use the full scope of the polypeptides encompassed by the claims. However, claims reading on significant numbers of inoperative embodiments would render claims non-enabled when the specification does not clearly identify the operative embodiments and undue experimentation is involved in determining those that are operative.” Atlas Powder Co. v. E.I. duPont de Nemours & Co., 750 F.2d 1569, 1577, 224 USPQ 409, 414 (Fed. Cir. 1984); In re Cook, 439 F.2d 730, 735, 169 USPQ 298, 302 (CCPA 1971); MPEP 2164.08(b). Here, the claims read on a significant number of inoperative embodiments.
While enzyme isolation techniques, recombinant and mutagenesis techniques are known, and it is not routine in the art to screen for multiple substitutions or multiple modifications as encompassed by the instant claims, the specific amino acid positions within a protein's sequence where amino acid modifications can be made with a reasonable expectation of success in obtaining the desired activity/utility are limited in any protein and the result of such modifications is unpredictable. In addition, one skilled in the art would expect any tolerance to modification for a given protein to diminish with each further and additional modification, e.g. multiple substitutions.
The specification does not support the broad scope of the claims which encompass: a genera of polypeptides in a microorganism of the genus Corynebacterium having putrescine producing ability i.e., “an N-acetyltransferase derived from a strain of the genus Corynebacterium” and “an acetylornithine deacetylase (argE) derived from E. coli” activities; said genera of polypeptides having a sequence identity of 90% thereto with SEQ ID NO: 1 and SEQ ID NO: 3 (as in claims 1-3, 5-7 and 10-12); and wherein the microorganism has weakened activity of bifunctional ornithine acetyltransferase/N-acetylglutamate synthase (argJ) of undefined and unlimited structures derived from a strain of the genus Corynebacterium (as in claim 4; also see and 35 U.S.C. 112(b) rejection for claims interpretation), because the specification does not establish: (A) a rational and predictable scheme for modifying specific amino acid residues in any “N-acetyltransferase”, “acetylornithine deacetylase’ and “weakened activity of bifunctional ornithine acetyltransferase/N-acetylglutamate synthase (argJ)“ having no specific structural elements and an expectation of obtaining the desired biological/biochemical function; (B) a rational and predictable scheme for modifying any amino acid residue with an expectation of obtaining the desired biological/biochemical function; (C) defined core regions/motifs involved in the desired catalytic activity of encoded polypeptide; (D) the tertiary structure of the molecule and folding patterns that are essential for the desired activity and tolerance to modifications; and (E) the specification provides insufficient guidance as to which of the essentially infinite possible choices is likely to be successful.
While as discussed above, the specification provides guidance with regard to the characterization of specific structures and having the comprising the amino acid sequences of SEQ ID NO: 1; SEQ ID NO: 3 and SEQ ID NO: 5 and the encoding polynucleotides, isolated specific strain of Corynebacterium glutamicum host cell comprising the encoding polynucleotides, method of making and method of use (see Examples 1-5, pages 27-42 of specification), however, the scope of claims 1-7 and 10-12 is so broad and the lack of guidance either in the specification or in the prior art, the claims remains not commensurate in scope with the enabled invention and therefore for the rejected claims, this would clearly constitute undue experimentation. While enablement is not precluded by the necessity for routine screening, if a large amount of screening is required, the specification must provide a reasonable amount of guidance with respect to the direction in which the experimentation should proceed (guided mutants). Such guidance has not been provided in the instant specification or in the prior art. The art also teaches the following regarding complexity of the structure/function relationship: The reference of Chica et al., (Curr. Opin. Biotechnol., 2005, Vol. 16: 378-384) teaches that the complexity of the structure/function relationship in enzymes has proven to be the factor limiting the general application of rational enzyme modification and design, where rational enzyme modification and design requires in-depth understanding of structure/function relationships. The reference of Sen et al., (Appl. Biochem. Biotechnol., 2007, Vol.143: 212-223), teaches in vitro recombination techniques such as DNA shuffling, staggered extension process (STEP), random chimera genesis on transient templates (RACHITT), iterative truncation for the creation of hybrid enzymes (ITCHY), recombined extension on truncated templates (RETT), and so on have been developed to mimic and accelerate nature's recombination strategy. However, such rational design and directed evolution techniques only provide guidance for searching and screening for the claimed polypeptide which is not guidance for making and/or using the claimed polypeptide. Additionally, knowledge is not extant in the art to assay all possible enzymatic activities, how to express all possible enzymes or how predictably assay for such activities. For example, the reference of Banerjee et al., (Bioenerg. Res. 2010, Vol. 3: 82-92), on page 84, right column, second paragraph, describe that “enzymes have critical properties besides specific activity and thermal tolerance that must be considered but which can be difficult to assay in vitro. For example, besides catalyzing a particular chemical reaction, enzymes must be efficiently translated and secreted, able to resist proteases, act cooperatively with other enzymes, and have low product and feedback inhibition. One can easily imagine that an “improved” enzyme, based on assay in isolation on a model substrate, might perform poorly in a real-world situation”.
Thus, applicants’ have not provided sufficient guidance to enable one of ordinary skill in the art to make and use the claimed invention in a manner reasonably correlated with the scope of the claims broadly including polynucleotides and encoded polypeptides with an enormous number of modifications. The scope of the claim must bear a reasonable correlation with the scope of enablement (In re Fisher, 166 USPQ 19 24 (CCPA 1975)). Without sufficient guidance, determination of polypeptides/enzymes having the desired biological characteristics is unpredictable and the experimentation left to those skilled in the art is unnecessarily, and improperly, extensive and undue. See In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988).
Claim Rejections: 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) 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.
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 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.
Claims 1-7 and 9-12 are rejected under 35 U.S.C. 103(a) as being unpatentable over Park et al., (US 10,640,753 B2) and further in view of Qin et al., (US 2020/0270654 A1) and Nakagawa et al., (US 7,332,310 B2).
Claims 1-7 and 9-12 as interpreted are directed to a genera of polypeptides in a microorganism of the genus Corynebacterium having putrescine producing ability i.e., “an N-acetyltransferase derived from a strain of the genus Corynebacterium” and “an acetylornithine deacetylase (argE) derived from E. coli” activities; said genera of polypeptides having a sequence identity of 90% thereto with SEQ ID NO: 1 and SEQ ID NO: 3 (as in claims 1-7 and 9-12); and wherein the microorganism has weakened activity of bifunctional ornithine acetyltransferase/N-acetylglutamate synthase (argJ) of undefined and unlimited structures derived from a strain of the genus Corynebacterium (as in claim 4; also see and 35 U.S.C. 112(b) rejection for claims interpretation).
Park et al., (US 10,640,753 B2) discloses a modified microorganism producing putrescine or ornithine, and a method for producing putrescine or ornithine using the same; wherein said reference microorganism producing putrescine comprising an acetylornithine deacetylase (argE) obtained from E. coli, said reference acetylornithine deacetylase having 100% sequence identity to SEQ ID NO: 3 of the instant invention (see provided sequence alignment) and further comprising weakened activity of bifunctional ornithine acetyltransferase/N-acetylglutamate synthase (argJ); said reference microorganism is Corynebacterium glutamicum host cell. Applicants are also directed to following sections in Park et al., (US 10,640,753 B2): Abstract; Fig. 1-2; claims; and entire document.
The disclosure of Park et al., is described above in the rejection above. However, Park et al., does not teach a modified microorganism producing putrescine, wherein activity of an N-acetyltransferase derived from a strain of the genus Corynebacterium is introduced and said N-acetyltransferase having a sequence identity of 90% thereto with SEQ ID NO: 1 (as in claims 1-2).
Regarding claims 1-2, Qin et al., (US 2020/0270654 A1) provides teaching, suggestion, motivation including the structural and functional elements of the instant invention i.e., a modified microorganism producing putrescine, wherein activity of an N-acetyltransferase [EC 2.3.1.35] derived from a strain of the genus Corynebacterium is introduced and overexpressed to produce ornithine and putrescine; see Abstract; Fig. 1-2; ¶ [0100-0111] and [0102], reproduced below:
[0110] Thus, in an embodiment, the microbial cell is genetically modified for overexpression of at least one enzyme selected from a group consisting of ornithine decarboxylase (ODC) [EC 4.1.1.17]; N-acetylglutamate synthase (NAGS) [EC 2.3.1.1], also referred to as amino-acid-N-acetyltransferase; acetylglutamate kinase [EC 2.7.2.8]; N-acetyl-gamma-glutamyl-phosphate reductase [EC 1.2.1.38]; acetylornithine aminotransferase [EC 2.6.1.11], also referred to as acetylornithine transaminase; acetylornithine deacetylase [EC 3.5.1.16] and ornithine acetyltransferase [EC 2.3.1.35], also referred to as glutamate N-acetyltransferase.
[0111] As is more clearly shown in FIG. 1, the above mentioned enzymes are involved in the putrescine biosynthesis pathway involving synthesis of putrescine from a carbon source, such as glucose. In more detail, the above mentioned enzymes are involved in the synthesis of putrescine from α-ketoglutarate, which in turn is the output of the tricarboxylic acid (TCA) cycle.
[0102] In an embodiment, the microbial cell is a prokaryotic cell selected from a group consisting of Neisseria, Spirillum, Pasteurella, Brucella, Yersinia, Francisella, Haemophilus, Bordetella, Escherichia, Salmonella, Shigella, Klebsiella, Proteus, Vibrio, Pseudomonas, Bacteroides, Acetobacter, Aerobacter, Agrobacterium, Azotobacter, Spirilla, Serratia, Vibrio, Rhizobium, Chlamydia, Rickettsia, Treponema, Fusobacterium, Actinomyces, Bacillus, Clostridium, Corynebacterium, Erysipelothrix, Lactobacillus, Listeria, Mycobacterium, Myxococcus, Nocardia, Staphylococcus, Streptococcus, and Streptomyces. Examples of prokaryotic cells that can be used include Escherichia coli, Bacillus subtilis and/Corynebacterium glutamicum.
Regarding claims 1-2, Nakagawa et al., (US 7,332,310 B2) provides the structural and functional information of an N-acetyltransferase derived from a strain of the genus Corynebacterium is introduced into a modified microorganism producing putrescine, and said reference N-acetyltransferase having a sequence identity of 99.8% to SEQ ID NO: 1 of the instant invention and functionally annotated as acetyltransferase (GNAT) or N-terminal acetylating enzyme.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to generate a microorganism of the genus Corynebacterium having putrescine producing ability, into which activity of an N-acetyltransferase derived from a strain of the genus Corynebacterium and activity of an acetylornithine deacetylase (argE) derived from E. coli are introduced, as suggested by Qin et al., and to include the structural information of Nakagawa et al., in the construction of the claimed microorganism of the genus Corynebacterium having putrescine producing ability and to modify the teaching of Park et al., such that the microorganism of the genus Corynebacterium having putrescine producing ability would be potentially employed for the utilization substrates in the production of precursors and the final desired product putrescine. A person of ordinary skill in the art is motivated to make such change, because an amino-acid-N-acetyltransferase [EC 2.3.1.1] with biochemical properties for the conversion of N-acetyl ornithine to ornithine and said precursor ornithine is utilized for the production of desired product putrescine (see Fig. 1; Qin et al., (US 2020/0270654 A1)), and a skilled artisan would realize such a modification would be useful to increase the production of putrescine. One of ordinary skill in the art has a reasonable expectation of success at adding the nucleic acid sequences and the encoding polypeptides proteins of Nakagawa et al., in the construction of the claimed microorganism of the genus Corynebacterium having putrescine producing ability, because the molecular biology techniques required to construct the claimed microorganism of the genus Corynebacterium having putrescine producing ability and enzymes of interest are well known in the art. Therefore, the inventions as a whole lack an inventive step over the prior art. The expectation of success is high, because the combined teachings of Park et al., Qin et al., and Nakagawa et al., also provide the structural and functional elements of the instant invention (Teaching, Suggestion and Motivation).
Given this extensive teaching in prior art (Park et al., Qin et al., and Nakagawa et al.,) a genera of polypeptides in a microorganism of the genus Corynebacterium having putrescine producing ability i.e., “an N-acetyltransferase derived from a strain of the genus Corynebacterium” and “an acetylornithine deacetylase (argE) derived from E. coli” activities; said genera of polypeptides having a sequence identity of 90% thereto with SEQ ID NO: 1 and SEQ ID NO: 3; and wherein the microorganism has weakened activity of bifunctional ornithine acetyltransferase/N-acetylglutamate synthase (argJ) of undefined and unlimited structures derived from a strain of the genus Corynebacterium (also see and 35 U.S.C. 112(b) rejection for claims interpretation)as taught by the instant invention and as claimed in claims 1-7 and 9-12 is not of innovation but of ordinary skill in the art and the expectation of success is extremely high i.e., “a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely that product [was] not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under § 103.”KSR, 550 U.S. at, 82 USPQ2d at 1397”.
Hence, claims 1-7 and 9-12 are rejected under 35 U.S.C. 103(a) as being unpatentable over Park et al., (US 10,640,753 B2) and further in view of Qin et al., (US 2020/0270654 A1) and Nakagawa et al., (US 7,332,310 B2).
Allowable Subject Matter/Conclusion
None of the claims are allowable.
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/GANAPATHIRAMA RAGHU/ Primary Examiner, Art Unit 1652