The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant's election with traverse of Group II, claims 10-11, to lacto-N-tetraose (LNT), ketopantoate reductase (PanE), in the reply filed on July 15, 2026 is acknowledged. The traversal is on the ground(s) that the technical feature linking the inventions of Groups I-III is that the genetically engineered for the production of the oligosaccharide of interest possesses a low level or no intracellular biosynthesis of pantothenic acid. This is not found persuasive because the reasons are the same as noted in the text of the restriction requirement (see at least p. 3-5). As noted, Group III, was drawn to a composition comprising an oligosaccharide of interest. Therefore, the technical feature linking the inventions of Groups I-III is that they all relate to an oligosaccharide of interest, and as noted, Jennewein et al. (US 20180305724) disclose an oligosaccharide of interest. Therefore, the technical feature linking the inventions of Groups I-III does not constitute a special technical feature as defined by PCT Rule 13.2, as it does not define a contribution over the prior art. See also the reasons noted on at least p. 3-5 of the restriction requirement.
The requirement is still deemed proper and is therefore made FINAL.
Claims 1-14 are canceled. Claims 15-34 are newly presented. Claims 15-23 are directed to the subject matter of Group I. Claims 15-23 have been withdrawn from further consideration by the examiner because they are drawn to non-elected inventions. Claims 24-34 are directed to the subject matter of elected Group II. Claims 24-34, to lacto-N-tetraose (LNT), ketopantoate reductase (PanE), are under consideration.
Priority: This application is a 371 of PCT/EP2022/086205, filed December 15, 2022, which claims benefit of foreign application EP 21217103, filed December 22, 2021. A copy of the foreign priority document has been received in the instant application on June 20, 2024 and is in the English language.
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 33-34 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.
Claims 33-34 recite the limitation "the E. coli K-12 ketopantoate reductase" in the claims. There is insufficient antecedent basis for this limitation in the claims.
Claim Rejections - 35 USC § 103
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 (i.e., changing from AIA to pre-AIA ) 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.
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.
Claims 24-33 are rejected under 35 U.S.C. 103 as being unpatentable over Lu et al. (2021 ACS Synth Biol 10: 923-938, published April 28, 2021) in view of Eggeling et al. (US 7632663; IDS 06.20.24) and Oldiges et al. (2014 Appl Microbiol Biotechnol 98: 5859-5870).
Lu et al. disclose human milk oligosaccharides (HMOs) are one of the important ingredients in human milk, which have attracted interest due to their beneficial effect on the health of newborns (at least p. 923). Lu et al. disclose the production of HMOs has been researched using engineered microbial routes due to their availability, safety, and low cost of host strains (at least p. 923). Lu et al. disclose the structure of main HMOs produced and studied using engineered microbial routes, including lacto-N-tetraose (LNT) (at least p. 923-924, 928). Lu et al. disclose microbial systems for HMO production include engineered E. coli, engineered yeast, engineered B. subtilis (Bacillus subtilis), and C. glutamicum (Corynebacterium glutamicum) (at least p. 928-933). Lu et al. disclose the pathway for LNnT/LNT production in a microbial system (at least p. 931, Fig. 4). Lu et al. disclose C. glutamicum is a Gram-positive bacterium mainly used in production of amino acids and that with the rapid development of synthetic biology and bioengineering, has been designed as an efficient microbial platform (p. 933). Lu et al. disclose recent studies show that C. glutamicum can also be used as a host strain for HMOs production (at least p. 933). Lu et al. do not teach that the engineered C. glutamicum has a low level of or no intracellular biosynthesis of pantothenic acid.
Eggeling et al. disclose that the amino acid L-valine is a commercially significant product that is used in animal and human nutrition as well as in medicine and that there is widespread interest in the improved production of valine (at least col. 1 lines 9-12). Eggeling et al. disclose that various types of bacteria including among others E. coli and C. glutamicum, produce valine when in a nutrient solution containing glucose (at least col. 1 lines 21-25). Eggeling et al. disclose an engineered C. glutamicum having reduced synthesis of pantothenate, which is achieved by weakening or eliminating the corresponding biosynthesis enzymes or their activities (at least col. 5 lines 15-27, 41-58, see also Fig. 1), and producing valine.
Oldiges et al. also disclose L-valine is an essential nutrient for higher organisms, such as animals and humans (at least p. 5859). Oldiges et al. disclose the schematic presentation of the central carbon metabolism of C. glutamicum and E. coli including relevant pathways for the synthesis of branched amino acids, including valine (at least p. 5816, Fig. 1).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate an engineered microbial cell, such as the engineered C. glutamicum having reduced synthesis of pantothenate of Eggeling et al., for the engineered microbial cell comprising a pathway for producing HMO in a method for producing an HMO of interest comprising culturing the engineered microbial cell in a culture medium and conditions that produce the HMO of interest, as suggested in Lu et al., thereby arriving at the claimed method for producing an oligosaccharide of interest (instant claims 24, 27). The motivation to do is given by the prior art, which disclose that engineered microbial systems producing amino acids can also be engineered to produce HMOs. One of ordinary skill would have a reasonable expectation of success because the pathways for producing an HMO of interest in a microbial system (Lu et al. at least p. 931, Fig. 4) do not interfere with a pathway having reduced synthesis of pantothenate and producing valine (Eggeling et al.; Oldiges et al.).
Regarding instant claim 25, Lu et al. disclose the importance of HMOs in neonatal development and health benefits including as adjuvants to enhance function of antibiotics, reducing pathogen infections, promoting immune system development, etc. (p. 923). Therefore, it would be obvious to retrieve the HMO of interest that is produced in the method of Lu et al. in view of Eggeling noted above.
Regarding instant claim 26, Eggeling et al. disclose the culture medium includes sources of carbon, which can be sugars and carbohydrates such as glucose, etc., and sources of nitrogen, which can be organic compounds containing nitrogen such as peptones, yeast extract, meat extract, malt extract, corn steep liquor, soybean meal, etc., and essential growth substances such as amino acids and vitamins (col. 6 lines 4-33). Therefore, it would be obvious that Eggeling et al. reasonably disclose that the culture medium comprises vitamin B5 (pantothenic acid).
Regarding instant claim 28, Lu et al. disclose an HMO produced by engineered microbial routes is LNT (at least p. 923-924, 928, 931, also Fig. 4).
Regarding instant claims 29-31, 32, Eggeling et al. disclose that the reduced pantothenate synthesis can be achieved by weakening or eliminating the corresponding biosynthesis enzymes or their activities (col. 5 lines 15-27), including by targeted recombinant DNA techniques, where the genes panB, panC, panE, and panD that code for the ketopantoate hydroxymethyl transferase, pantothenate ligase, ketopantoic acid reductase or aspartate decarboxylase can be deleted (col. 5 lines 41-46, also Fig. 1). Further regarding instant claim 30, it would be obvious that the level of pantothenic acid can be reduced to factor of at least 10 since Eggeling et al. disclose deletion of the enzymes involved in pantothenate synthesis.
Regarding instant claim 33, as noted above, since Eggeling et al. also disclose alternatively weakening the corresponding pantothenate biosynthesis enzymes or their activities, where the enzyme selected is ketopantoic acid reductase, it would be obvious that an impaired ketopantoic acid reductase has a Km value that is increased compared to a E. coli K12 ketopantoate reductase (wildtype).
Claims 24-33, 34 are rejected under 35 U.S.C. 103 as being unpatentable over Lu et al. (2021 ACS Synth Biol 10: 923-938, published April 28, 2021) in view of Eggeling et al. (US 7632663; IDS 06.20.24), Oldiges et al. (2014 Appl Microbiol Biotechnol 98: 5859-5870), and Ciulli et al. (2007 The Journal of Biological Chemistry 282(11): 8487-8497). The teachings of Lu et al., Eggeling et al., and Oldiges et al. over instant claims 24-33 are noted above.
Regarding instant 34, Ciulli et al. disclose mutants of E. coli ketopantoate reductase (PanE) include among others N98A (at least p. 8487). As noted above, Lu et al. disclose microbial systems for HMO production also include engineered E. coli (at least p. 928-933). It is disclosed that the pathways for producing an HMO of interest in a microbial system (Lu et al. at least p. 931, Fig. 4) do not interfere with a pathway having reduced synthesis of pantothenate and producing valine (Eggeling et al.; Oldiges et al.). Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to arrive at a N98A PanE mutant having impaired activity, which is a variant of the recited E. coli K-12 PanE (N98A), in an engineered E. coli comprising a pathway for producing HMO in a method for producing an HMO of interest comprising culturing the engineered microbial cell in a culture medium and conditions that produce the HMO of interest, as suggested in Lu et al. The motivation to do is given by the prior art, which disclose that engineered microbial systems producing amino acids can also be engineered to produce HMOs. One of ordinary skill would have a reasonable expectation of success because the pathways for producing an HMO of interest in a microbial system (Lu et al. at least p. 931, Fig. 4) do not interfere with a pathway having reduced synthesis of pantothenate and producing valine (Eggeling et al.; Oldiges et al.).
No claim is allowed.
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/Marsha Tsay/Primary Examiner, Art Unit 1656
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