DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-6 are pending and under consideration in this Office Action.
Claim Objections
Claims 1-6 are objected to for reciting “[Claim 1]”, “[Claim 2]”, “[Claim 3]”, “[Claim 4]”, “[Claim 5]”, “[Claim 6]”. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b) or 35 U.S.C. 112 (pre-AIA ) 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 1-6 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.
Claim 1 encompasses any enzyme having enhanced activity of 3-methyl-2-oxobutanoate hydroxymethyltransferase derived from Escherichia Coli. However, the claim is vague and indefinite because the specific amino acid sequence and structure of the enzyme is not known and not recited in the claim. Further the specific genetic modification to the enzyme which results in enhanced activity of 3-methyl-2-oxobutanoate hydroxymethyltransferase is not known and not recited in the claim. Dependent claims 2-6 are also rejected because they do not correct the defect.
Claim Rejections - 35 USC § 112
The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
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 1-6 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 claims are drawn to a broad and widely varying genus of microorganisms of the genus of Corynebacterium producing a pantothenic acid or pantoic acid, which has an enhanced activity of 3-methyl-2-oxobutanoate hydroxymethyltransferase activity, wherein the 3-methyl-2-oxobutanoate hydroxymethyltransf erase is derived from Escherichia Coli and is of any amino acid sequence and structure. According to MPEP 2163:
“For each claim drawn to a genus: 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 (see i)(A), above), reduction to drawings (see i)(B), above), 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 (see i)(C), above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
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. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014)…”
According to MPEP 2163.02:
“The courts have described the essential question to be addressed in a description requirement issue in a variety of ways. An objective standard for determining compliance with the written description requirement is, "does the description clearly allow persons of ordinary skill in the art to recognize that he or she invented what is claimed." In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989). Under Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Fed. Cir. 1991), to satisfy the written description requirement, an applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention, and that the invention, in that context, is whatever is now claimed. The test for sufficiency of support in a parent application is whether the disclosure of the application relied upon "reasonably conveys to the artisan that the inventor had possession at that time of the later claimed subject matter." Ralston Purina Co. v. Far-Mar-Co., Inc., 772 F.2d 1570, 1575, 227 USPQ 177, 179 (Fed. Cir. 1985) (quoting In re Kaslow, 707 F.2d 1366, 1375, 217 USPQ 1089, 1096 (Fed. Cir. 1983)).”
The reference of Chica et al. (Curr Opin Biotechnol. 2005 Aug;16(4):378-84; PTO 892) 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 Singh et al. (Curr Protein Pept Sci. 2017, 18, 1-11; ; PTO 892) reviews protein engineering methods including directed evolution, rational design, semi-rational design, and de-novo design; and states that despite the availability of a growing database of protein structures and highly sophisticated computational algorithms, protein engineering is still limited by the incomplete understanding of protein functions, folding, flexibility, and conformational changes (see entire publication especially Figs.1 and 3, and page 7, left column, lines 8-17). The reference teachings only provide guidance for searching and screening for the microorganism of genus of Corynebacterium producing a pantothenic acid or pantoic acid, which has an enhanced activity of 3-methyl-2-oxobutanoate hydroxymethyltransferase activity.
The specification as originally filed does not disclose a representative number of species encompassed by the claimed genus by actual reduction to practice. The specification as originally filed does not provide a correlation between function and structure to enable one of ordinary skill in the art to predict which amino acid sequences and structures correlate with 3-methyl-2-oxobutanoate hydroxymethyltransferase activity.
The specification as originally filed discloses a 3-methyl-2-oxobutanoate hydroxymethyltransferase comprising the amino acid sequence of SEQ ID NO: 37.
Hence, the specification does not provide sufficient written description to inform one of ordinary skill in the art that applicants were in possession at the time the application was filed of the claimed broad and widely varying genus of microorganisms of the genus of Corynebacterium producing a pantothenic acid or pantoic acid, which has an enhanced activity of 3-methyl-2-oxobutanoate hydroxymethyltransferase activity, wherein the 3-methyl-2-oxobutanoate hydroxymethyltransf erase is derived from Escherichia Coli and is of any amino acid sequence and structure.
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 of this title, 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.
Claims 1-6 are rejected under 35 U.S.C. 103 as being unpatentable over WO2010018196 (2010-02-18; PTO 892) in view of Accession AAU34445 (15-JUN-2007; PTO 892), Bornscheuer et al. (Curr Protoc Protein Sci. 2011 Nov;Chapter 26:Unit26.7; PTO 892).
WO2010018196 teaches the following in the claims:
1. A modified polynucleotide comprising at least one mutation, wherein the polypeptide encoded by said modified polynucleotide has ketopantoate hydroxymethyl transferase activity being at least 5% less sensitive to feedback inhibition compared to a polypeptide encoded by a non-modified polynucleotide, said non-modified polynucleotide is selected from the group consisting of:
(a) polynucleotides encoding the polypeptide comprising the amino acid sequence according to SEQ ID NO:2;
(b) polynucleotides comprising the nucleotide sequence according to SEQ ID NO: 1 ; (c) polynucleotides comprising a nucleotide sequence obtainable by nucleic acid amplification such as polymerase chain reaction, using genomic DNA from a microorganism as a template and a primer set according to SEQ ID NO: 3 and SEQ ID NO:4;
(d) polynucleotides comprising a nucleotide sequence encoding a fragment or derivative of a polypeptide encoded by a polynucleotide of any of (a) to (c) wherein in said derivative one or more amino acid residues are conservatively substituted compared to said polypeptide, and said fragment or derivative has ketopantoate hydroxymethyl transferase activity;
(e) polynucleotides the complementary strand of which hybridizes under stringent conditions to a polynucleotide as defined in any one of (a) to (d) and which encode a ketopantoate hydroxymethyl transferase polypeptide; and
(f) polynucleotides which are at least 60%, such as 70, 85, 90 or 95% identical to a polynucleotide as defined in any one of (a) to (d) and which encode a ketopantoate hydroxymethyl transferase polypeptide; or the complementary strand of such a polynucleotide.
2. A polynucleotide according to claim 1 said polynucleotide being selected from the group consisting of:
(a) polynucleotides encoding a polypeptide comprising the amino acid sequence according to SEQ ID NO:6, 8 or 10; (b) polynucleotides comprising the nucleotide sequence according to SEQ ID NO:5, 7 or 9;
(c) polynucleotides comprising a nucleotide sequence obtainable by nucleic acid amplification such as polymerase chain reaction, using genomic DNA from a microorganism as a template and a primer set according to SEQ ID NO: 3 and SEQ ID NO:4; (d) polynucleotides comprising a nucleotide sequence encoding a fragment or derivative of a polypeptide encoded by a polynucleotide of any of (a) to (c) wherein in said derivative one or more amino acid residues are conservatively substituted compared to said polypeptide, and said fragment or derivative has the activity of modified ketopantoate hydroxymethyl transferase;
(e) polynucleotides the complementary strand of which hybridizes under stringent conditions to a polynucleotide as defined in any one of (a) to (d) and which encode a ketopantoate hydroxymethyl transferase polypeptide; and
(f) polynucleotides which are at least 60%, such as 70, 85, 90 or 95% identical to a polynucleotide as defined in any one of (a) to (d) and which encode a ketopantoate hydroxymethyl transferase polypeptide; or the complementary strand of such a polynucleotide and wherein the sequences depicted under SEQ ID NOs: 5 to 10 are referred to as modified or mutated sequences and wherein said polynucleotide comprises at least one mutation leading to an enzyme which is at least 5% less sensitive to feedback inhibition compared to the corresponding wild-type polynucleotide.
3. A polypeptide encoded by a polynucleotide according to claim 1 or 2.
4. A microorganism genetically engineered with a polynucleotide according to claim 1 or 2.
5 A microorganism according to claim 4 wherein the yield and/or efficiency of pantothenate production is improved by at least 5% compared to the wild-type microorganism.
6. A microorganism according to claim 4 or 5 capable of producing at least 11% more pantothenate compared to production of pantothenate using a wild type microorganism.
7. A microorganism according to any one of claims 4 to 6 producing a polypeptide according to claim 3 with at least 5% reduced sensitivity to feedback inhibition compared to the wild type microorganism.
8. A microorganism according to any one of claims 4 to 7 wherein said microorganism is further genetically engineered in the panE gene, said microorganism producing at least 5% more pantothenate compared to the microorganism according to claims 4 to 7.
9. A microorganism according to any one of claims 4 to 8 selected from the group consisting of Bacillus, Corynebacterium, Lactobacillus, Lactococcus, Streptomyces, Escherichia coli, and Pseudomonas.
10. Use of a polynucleotide according to claim 1 or 2 or of a microorganism according to any one of claims 4 to 9 for the production of pantothenate.
11. Use of a polynucleotide according to claim 1 or 2 for increasing the pantothenate production in a microorganism capable of producing pantothenate.
12. Process for the production of a microorganism according to any one of claims 4 to 9 comprising the steps of: (a) providing a suitable microorganism capable of pantothenate production,
(b) genetically engineering said microorganism with a polynucleotide according to claim l or 2.
13. Process for reducing feedback inhibition of PanB in a microorganism capable of pantothenate production comprising introducing into said microorganism a polynucleotide according to claim 1 or 2.
14. Process for the production of a recombinant microorganism producing 5% more pantothenate compared to a wild-type microorganism, said process comprising the introduction of at least one mutation in the panB gene, said panB gene being selected from the group consisting of: polynucleotides encoding the polypeptide comprising the amino acid sequence according to SEQ ID NO:2;
(b) polynucleotides comprising the nucleotide sequence according to SEQ ID NO: 1 ;
(c) polynucleotides comprising a nucleotide sequence obtainable by nucleic acid amplification such as polymerase chain reaction, using genomic DNA from a microorganism as a template and a primer set according to SEQ ID NO: 3 and SEQ ID NO:4;
(d) polynucleotides comprising a nucleotide sequence encoding a fragment or derivative of a polypeptide encoded by a polynucleotide of any of (a) to (c) wherein in said derivative one or more amino acid residues are conservatively substituted compared to said polypeptide, and said fragment or derivative has ketopantoate hydroxymethyl transferase activity;
(e) polynucleotides the complementary strand of which hybridizes under stringent conditions to a polynucleotide as defined in any one of (a) to (d) and which encode a ketopantoate hydroxymethyl transferase polypeptide; and (f) polynucleotides which are at least 60%, such as 70, 85, 90 or 95% identical to a polynucleotide as defined in any one of (a) to (d) and which encode a ketopantoate hydroxymethyl transferase polypeptide; or the complementary strand of such a polynucleotide.
15. Process according to claim 13 or 14 wherein the microorganism is selected from the group consisting of Bacillus, Corynebacterium, Lactobacillus, Lactococcus, Streptomyces, Escherichia coli, and Pseudomonas.
16. Process for the production of pantothenate wherein a microorganism according to any one of claims 4 to 9 is incubated in an aqueous medium under conditions that allow the production of pantothenate from a given substrate and optionally isolating and/or purifying the produced pantothenate from the reaction mixture.
17. Process for the production of pantothenate comprising the steps of:
(a) providing a microorganism capable of pantothenate production,
(b) introducing of at least one mutation in a polynucleotide encoding a polypeptide having ketopantoate hydroxymethyl transferase activity,
(c) selecting a microorganism which is at least 5% less sensitive to feedback inhibition of said polypeptide having ketopantoate hydroxymethyl transferase activity,
(d) cultivation of the microorganism according to (c) in a suitable medium and optionally isolating pantothenate from the cultivation medium.
The teachings of the reference differ from the claims in that the reference does not teach the claimed microorganism of genus of Corynebacterium producing a pantothenic acid or pantoic acid, which has an enhanced activity of 3-methyl-2-oxobutanoate hydroxymethyltransferase activity, wherein the 3-methyl-2-oxobutanoate hydroxymethyltransferase is derived from Escherichia Coli.
Accession AAU34445 teaches 3-methyl-2-oxobutanoate hydroxymethyltransferase having an amino acid sequence that is 100% identical to SEQ ID NO: 37 of the instant application (see attached alignment).
Bornscheuer et al. teach protein engineering strategies to improve or change the properties of proteins, teach concepts for protein engineering using rational design including substitution and/or deletion of amino acids, directed evolution, and combinations of them where different strategies are presented for identifying the best mutagenesis method, how to identify desired variants by screening or selection, and examples for successful applications are shown which enable researchers to choose the most promising tools to solve their protein engineering challenges (see entire publication especially pages 26.7.1- 26.7.10 and Tables 26.7.1, 26.7.2, and 26.7.3).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the protein engineering strategies of Bornscheuer et al. on the 3-methyl-2-oxobutanoate hydroxymethyltransferase of Accession AAU34445 to obtain 3-methyl-2-oxobutanoate hydroxymethyltransferase having enhanced activity, transforming the encoding polynucleotide into the Corynebacterium microorganism taught by WO2010018196, culturing the Corynebacterium microorganism in the method taught by WO2010018196 to produce pantothenic acid or pantoic acid, and recovering the pantothenic acid or pantoic acid. One of ordinary skill in the art at the time the invention was made would have been motivated to do this in order to obtain 3-methyl-2-oxobutanoate hydroxymethyltransferase having enhanced activity which can be used for further study or used in a process to products including of pantothenic acid or pantoic acid. One of ordinary skill in the art at the time the invention was made would have a reasonable expectation of success because making enzyme variants comprising modified amino acid sequences are known in the art as shown by the above reference teachings. Hence, the claimed invention as a whole is prima facie obvious.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP §§ 706.02(l)(1) - 706.02(l)(3) for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-6 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-9 of US Patent 12668823, claims 1-6 of US Patent 12624344. Although the conflicting claims are not identical, they are not patentably distinct from each other for the following reasons.
The claims and/or specification of the patents teach the claimed microorganism of genus of Corynebacterium producing a pantothenic acid or pantoic acid, which has an enhanced activity of 3-methyl-2-oxobutanoate hydroxymethyltransferase activity,wherein the 3-methyl-2-oxobutanoate hydroxymethyltransferase is derived from Escherichia Coli. Thus, the teachings read on and anticipate the claimed invention.
Claims 1-6 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of copending Application 19634381. Although the conflicting claims are not identical, they are not patentably distinct from each other for the following reasons.
The claims and/or specification of the copending application teach the claimed microorganism of genus of Corynebacterium producing a pantothenic acid or pantoic acid, which has an enhanced activity of 3-methyl-2-oxobutanoate hydroxymethyltransferase activity,wherein the 3-methyl-2-oxobutanoate hydroxymethyltransferase is derived from Escherichia Coli.. Thus, the teachings read on and anticipate the claimed invention.
Conclusion
No claims are allowed.
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/CHRISTIAN L FRONDA/Primary Examiner, Art Unit 1652
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