DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
This application claims benefit of priority to Foreign Application No. CN202210381525.9 filed 04/12/2022. This application is also a 371 of PCT/CN2023/087593 filed 04/11/2023. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. However, an English translation of the foreign patent document was not provided, therefore, for the purposes of applying prior art, the effective filing date of the claimed invention is 04/11/2023.
Information Disclosure Statement
The Information Disclosure Statements filed 10/15/2024 and 06/19/2026 have been acknowledged and considered.
Election/Restrictions
Applicant's election with traverse of Group I, claims 1, 4-7 and 12-13, in the reply filed on 08/28/2026 is acknowledged. The traversal is on the ground(s) that the product claims have Unity of Invention with the elected group because the product claims have been amended to encompass the exact Escherichia coli recombinant biomaterial used in the method of claim 1. This is not found persuasive for multiple reasons. First, claim 15 has not been amended to recite a recombinant E. coli, therefore claim 15 does not share Unity of Invention with the elected group. Second, while claim 14 has been amended to recite the recombinant E. coli, the isomerase gene ILEP and the acyltransferase gene Hpa3, which shares Unity of Invention with Group I a priori as they share the same technical feature, this special feature does not make a contribution over the prior art in view of Lothar et al. (DE 102010025124 A1, 12/29/2011), Mutaguchi et al. (Journal of Bacteriology, 10/24/2013) (IDS Reference of 10/15/2024, 10 Pages) and Yow et al. (Arch. Microbiology, 2004). Lothar et al. disclose a method for producing D-amino acids wherein a racemase, reading on an L-amino acid isomerase, is introduced into a microorganism, being E. coli, which produces an L-amino that is transformed into a D-amino acid via the racemase in vivo.
Lothar et al. do not disclose the D-amino is transformed into an N-acetyl-D-amino acid with an acyltransferase, the specific L-amino acid isomerase gene ILEP or the specific acyltransferase gene Hpa3.
However, Mutaguchi et al. disclose a novel amino acid racemase, isoleucine 2-epimerase from Lactobacillus that was able to effectively transform L-Ile, L-Leu and L-Val into D-allo-Ile, D-Leu and D-Val, respectively, with a higher specificity than other known Leu, Val and Ala racemases seen in other bacterial species.
Additionally, Yow et al. disclose Hpa2p and Hpa3p from Saccharomyces cerevisiae are D-amino acid N-acetyltransferases that act specifically on D-amino acids with Hpa3p acting on a wide range of D-amino acids and Hpa2p acting specifically on L-lysine and D-lysine. Yow et al. further disclose D-amino acids at high concentrations are toxic but Hpa3p participates in the detoxification of D-amino acids at moderate concentrations.
Thus, it would have been obvious to one of ordinary skill in the art to incorporate the ILEP gene into the E. coli of Lothar et al. because it was a known and effective racemase for transforming L-amino acids into D-amino acids as taught by Mutaguchi et al. and Lothar et al. is directed to a cell for producing D-amino acids from L-amino acids via racemases. It would have been further obvious to one of ordinary skill in the art to incorporate an acyltransferase gene, specifically Hpa3, into the E. coli of Lothar et al. because it was known that high concentrations of D-amino acids are toxic but Hpa3p participates in the detoxification as taught by Yow et al. Therefore, the special technical feature does not make a contribution over the prior art.
The requirement is still deemed proper and is therefore made FINAL.
Applicant’s further election of Escherichia coli and in vivo as where the transformation takes place (1), ILEP as the specific L-amino acid isomerase gene (2), Hpa3 as the specific acyltransferase gene (3) and plasmid expression as the genetic engineering method (4) in the reply filed on 08/28/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)). Specifically, Applicant did not indicate whether the elections of species were made with or without traverse.
Amendments and Claim Status
In the reply filed 08/28/2026, Applicant amended claims 1, 4-6 and 12-15 and cancelled claims 2-3 and 7-11. Claims 14-15 are withdrawn as they are not encompassed by the elected group.
Claims 1, 4-6 and 12-15 are currently pending.
Claims 14-15 are withdrawn.
Claims 1, 4-6 and 12-13 are under examination.
Specification Objections
The disclosure is objected to because of the following informalities: The instant Specification recites multiple specific genes without the gene names being italicized. For example, the genes ILEP, dadX, murI, ygeA, alr, Hpa3 and Hpa2 are recited at the top of Page 3 without being italicized. The genes are further recited without being italicized throughout the instant Specification, including on Page 4.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1 and 4-6 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites “wherein the transformation is completed in vivo in a recombinant Escherichia coli added for fermentation culture” in lines 6-7. It is unclear exactly what this limitation is intended to mean. It is unclear if this limitation is intended to mean the recombinant E. coli is produced for fermenting or if the limitation is intended to mean the E. coli is added to a fermentation culture or something else. Thus, claim 1 is indefinite because it is unclear what “wherein the transformation is completed in vivo in a recombinant Escherichia coli added for fermentation culture” is intended to mean. Additionally, all claims dependent upon claim 1 are rendered indefinite as they do not clear up the indefiniteness.
Claim 1 recites the limitation "wherein the transformation is completed in vivo in a recombinant Escherichia coli added for fermentation culture" in lines 6-7. There is insufficient antecedent basis for this limitation in the claim because ‘the transformation is completed in vivo’ is limiting the transformation to being in vivo, however, there are two transformations, being transforming an L-amino acid into a D-amino acid (1) and transforming the D-amino acid into an N-acetyl-D-amino acid (2), recited prior to ‘the transformation.’ Thus, there is insufficient antecedent basis for this limitation in the claim because there are two transformations recited, ‘the transformation’ indicates one transformation and it is therefore unclear which transformation is being limited to being in vivo.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim 12 is rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Mitsuhashi et al. (US 6514742 B1, 02/04/2003) (IDS Reference of 10/15/2024).
Regarding claim 12, it noted claim 12 is an independent claim. While claim 12 indicates the N-acetyl-D-amino acid is obtained by the method as claimed in claim 1, this is a product-by-process limitation as presented in claim 12. The structure of an N-acetyl-D-amino acid as obtained by the method of claim 1 and the same N-acetyl-D-amino acid obtained by a different method would have the same structure. Thus, any N-acetyl-D-amino acid meets the limitation of an N-acetyl-D-amino acid. As such, Mitsuhashi et al. disclose a D-aminoacylase useful for efficiently producing D-amino acids from N-acetyl-D-amino acids (See entire document, Abstract). Mitsuhashi et al. further disclose the present invention relates to a method for producing D-amino acids using a D-aminoacylase (Column 4, Lines 16-19). More specifically, Mitsuhashi et al. teach performing a reaction utilizing crude enzyme, being D-aminoacylase, and an N-Ac-D-amino acid to produce D-amino acids (Example 3 of Mitsuhasi et al.). Utilizing crude enzyme reads on in vitro. Thus, Mitsuhasi et al. anticipate instant claim 12 insofar as disclosing producing D-amino acids from N-acetyl-D-amino acids using a D-aminoacylase in vitro.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1 and 4-6 are rejected under 35 U.S.C. 103 as being unpatentable over Lothar et al. (DE 102010025124 A1, 12/29/2011), Mutaguchi et al. (Journal of Bacteriology, 10/24/2013) (IDS Reference of 10/15/2024, 10 Pages) and Yow et al. (Arch. Microbiology, 2013).
Regarding claim 1, Lothar et al. disclose a method for producing D-amino acids, a microorganism, and a vector (See entire document, Abstract). According to the invention, a racemase is introduced into a microorganism which produces an L-amino which racemizes an L-amino acid in vivo into a D-amino acid (Abstract). Racemase reads on an L-amino acid isomerase. As the host bacterium, an L-amino acid-producing microorganism is used, preferably the microorganism is E. coli (Page 2, Line 31). The microorganisms are genetically engineered to be able to express an amino acid racemase, for example, genes which code for an amino acid racemase can be inserted into the genome of the microorganism via vectors such as plasmids containing the amino acid racemase gene (Page 2, Lines 40-45). All amino acid racemases and the DNA coding therefore can be used, including alanine racemase (alr) (Page 3, Lines 1-14). Preferable genes include isoleucine racemase and valine racemase (Page 5, Lines 8-10). Lother et al. further disclose the amino acid racemase is more intensely expressed compared to the wild type, reading on overexpresses the racemase.
Lothar et al. do not disclose the D-amino is transformed into an N-acetyl-D-amino acid with an acyltransferase, the specific L-amino acid isomerase gene ILEP or the specific acyltransferase gene Hpa3.
However, Mutaguchi et al. disclose a novel amino acid racemase, isoleucine 2-epimerase from Lactobacillus (See entire document, Title). Isoleucine 2-epimerase reads on the ILEP gene. Mutaguchi et al. state the isoleucine 2-epimerase from Lactobacillus that they discovered was able to effectively transform L-Ile, L-Leu and L-Val into D-allo-Ile, D-Leu and D-Val, respectively, with a higher specificity than other known Leu, Val and Ala racemases seen in other bacterial species (Page 5209, Right Column, Last Paragraph – Page 5210, Left Column, First Paragraph).
Further, Yow et al. disclose D-amino acid N-acetyltransferase is a unique enzyme that acts on D-amino acids (See entire document, Abstract). Hpa2p and Hpa3p from Saccharomyces cerevisiae are D-amino acid N-acetyltransferases that act specifically on D-amino acids with Hpa3p acting on a wide range of D-amino acids and Hpa2p acting specifically on L-lysine and D-lysine (Abstract). Yow et al. teach D-amino acids at high concentrations are toxic but Hpa3p participates in the detoxification of D-amino acids at moderate concentrations (Page 402, Right Column, Last Paragraph – Page 403, Left Column, First Paragraph). Yow et al. further disclose plasmid transformation of E. coli cells with Hpa3p and Hpa2p (Page 398).
Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have utilized the isoleucine 2-epimerase from Lactobacillus (ILEP) gene disclosed by Mutaguchi et al. in the method of Lothar et al. motivated by the desire to effectively transform L-amino acids into their corresponding D-amino acids because Mutaguchi et al. teach the isoleucine 2-epimerase from Lactobacillus was able to effectively transform L-Ile, L-Leu and L-Val into D-allo-Ile, D-Leu and D-Val. One of ordinary skill in the art would have utilized the ILEP gene in the method of Lothar et al. because Lothar et al. disclose the racemase can be an isoleucine racemase and/or a valine racemase and the ILEP gene was a known and effective leucine racemase and valine racemase as taught by Mutaguchi et al.
It would have been further obvious to one of ordinary skill in the art to further transform the produced D-amino acids in the method of Lothar et al. into an N-acetyl-D-amino acid with an acetyltransferase, reading on an acyltransferase, specifically with the genes Hpa3p and Hpa2p, because high concentrations of D-amino acids can be toxic and Hpa3p is known to participate in the detoxification of D-amino acids as taught by Yow et al. One of ordinary skill in the art would have utilized Hpa3p and Hpa2p because they are both known and effective acetyltransferase genes with the ability to act on D-amino acids that can be utilized in recombinant E. coli cells as taught by Yow et al.
Regarding claim 4, as discussed above, Lothar et al. disclose the racemase can be alr.
Lothar et al. do not disclose the use of Hpa2.
However, as discussed above, Yow et al. disclose D-amino acid N-acetyltransferase is a unique enzyme that acts on D-amino acids (See entire document, Abstract). Hpa2p and Hpa3p from Saccharomyces cerevisiae are D-amino acid N-acetyltransferases that act specifically on D-amino acids with Hpa3p acting on a wide range of D-amino acids and Hpa2p acting specifically on L-lysine and D-lysine (Abstract). Yow et al. teach D-amino acids at high concentrations are toxic but Hpa3p participates in the detoxification of D-amino acids at moderate concentrations (Page 402, Right Column, Last Paragraph – Page 403, Left Column, First Paragraph). Yow et al. further disclose plasmid transformation of E. coli cells with Hpa3p and Hpa2p (Page 398)
Thus, it would have been obvious to one of ordinary skill in the art to further include the Hpa2p gene in the recombinant E. coli of Lothar et al. because Hpa2p was a known and effective acetyltransferase capable of acting on L-lysine and D-lysine that can be utilized in E. coli cells as taught by Yow et al.
Regarding claim 5, as discussed above, Lothar et al. disclose the microorganisms are genetically engineered to be able to express genes wherein the genes can be inserted into the genome of the microorganism via vectors such as plasmids containing the genes (Page 2, Lines 40-45).
Regarding claim 6, as discussed above, Lothar et al. disclose the microorganisms are genetically engineered to be able to express genes wherein the genes can be inserted into the genome of the microorganism via vectors such as plasmids containing the genes (Page 2, Lines 40-45) and the microorganism is E. coli (Page 2, Line 31). Lothar et al. further disclose fusing the gene to a promoter, wherein suitable promoters include lac, tac and trc (Page 3, Lines 54-56). Lac, tac and trc are all IPTG inducible promoters.
Lothar et al. do not disclose ligating the acyltransferase-encoding gene into the plasmid.
However, as disclosed above, it would have been obvious to one of ordinary skill in the art to further transform the produced D-amino acids in the E.coli of Lothar et al. into an N-acetyl-D-amino acid with an acetyltransferase, reading on an acyltransferase, specifically with the genes Hpa3p and Hpa2p, because high concentrations of D-amino acids can be toxic and Hpa3p is known to participate in the detoxification of D-amino acids as taught by Yow et al.
Thus, it would have been obvious to ligate the acetyltransferase gene into the plasmid vector with the racemase gene as that is how Lothar et al. transform their recombinant E. coli strain. Therefore, it would have been obvious to one of ordinary skill in the art to insert both genes, the racemase gene which reads on an isomerase gene and an acetyltransferase gene which reads on an acyltransferase gene into the plasmid vector of Lothar et al. because that was the known and effective means of incorporating genes into recombinant E. coli as utilized by Lothar et al.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Paquet et al. (CA 1261855 A, 09/26/1989) (IDS Reference of 10/15/2024, 27 Pages) and Mitsuhashi et al. (US 6514742 B1, 02/04/2003) (IDS Reference of 10/15/2024).
Regarding claim 13, as discussed above with claim 12, claim 13 is an independent claim and the N-acetyl-D-amino acid is a product-by-process limitation. Thus, any N-acetyl-D-amino acid meets the limitation of an N-acetyl-D-amino acid. As such, Paquet et al. disclose a method of making Sorbyl-D-tryptophan (Top of Page 6), reading on a D-amino acid derivative. The method includes adding succinimidyl sorbate, sodium bicarbonate, water and acetone to a suspension containing D-tryptophan (Top of Page 6).
Paquet et al. do not disclose transforming a N-acetyl-D-amino acid to a D-amino acid prior to transforming the D-amino acid to a D-amino acid derivative.
However, Mitsuhashi et al. disclose a method for producing D-amino acids using a D-aminoacylase (Column 4, Lines 16-19). More specifically, Mitsuhashi et al. teach performing a reaction utilizing crude enzyme, being D-aminoacylase, and an N-Ac-D-amino acid to produce D-amino acids (Example 3 of Mitsuhasi et al.).
Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have utilized the method of Mitsuhashi et al. to produce a D-amino acid in the method of Paquet et al., such as D-tryptophan, because it was a known and effective means of producing D-amino acids and a D-amino acid is the starting substrate in the method of Paquet et al. Therefore, one of ordinary skill in the art would be motivated to utilize the method of Mitsuhashi et al. to produce a D-amino acid in the method of Paquet et al. because it produces the required starting substrate for the method of Paquet et al.
Conclusion
Claims 1, 4-6 and 12-13 are rejected.
No claims are allowed.
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/A.T.W./Examiner, Art Unit 1653
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653
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