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
The amendment filed 02/11/2026 has been entered. Claims 2 and 7 have been cancelled. Claims 16 and 17 have been newly added. Claims 1, 3-6, and 8-17 are pending and under examination.
Response to Arguments
Applicant’s arguments, with respect to the rejection of claims 1, 3-6, and 8-15 under 35 USC 103, have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
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, 3-6, and 8-17 are rejected under 35 U.S.C. 103 as being unpatentable over Hatt et al., ("SpoA Mutants of Bacillus subtilis with Sigma Factor-specific Defects in Transcription Activation", JOURNAL OF BACTERIOLOGY, July 1998, Vol. 180, p. 3584–3591; previously cited), in view of OligoScience Biotechnology (EP 3438122 A1; previously cited), Shipkowski et al., (Bioinformatic, Genetic, and Biochemical Evidence that Some Glycoside Hydrolase Family 42 β-Galactosidases Are Arabinogalactan Type I Oligomer Hydrolases”, APPLIED AND ENVIRONMENTAL MICROBIOLOGY, Dec. 2006, Vol. 72, No. 12; previously cited), as evidenced by Watzlawick et al., (“Role of ganSPQAB Operon in Degradation of Galactan by Bacillus subtilis” JOURNAL OF BACTERIOLOGY, Vol. 198, No. 20), previously cited, and Tang et al., (WO 2004/011609 A2).
Regarding claim 1, Hatt teaches a Bacillus subtilis spoA mutant (Page 3, Results) and teaches that spoA mutants have decreased percent sporulation (Table 2).
Hatt does not teach that the Bacillus cell has been genetically engineered to possess a lactose permease, a GDP-fucose biosynthesis pathway, and a fucosyltransferase, and does not teach a Bacillus cell that has been engineered by deletion or functional inactivation of the yesZ and ganA genes.
OligoScience Biotechnology teaches a genetically modified microorganism for producing human milk oligosaccharides (para. [0014], item 1), including 2’-fucosyllactose and 3’fucosyllactose (para. [0014], item 51), which are known fucosylated oligosaccharides. OligoScience Biotechnology teaches that bacteria of the Bacillus genus may be used (para. [0043]). OligoScience Biotechnology teaches the overexpression of lacY, which encodes a lactose permease (Page 10, Table 2), overexpression of manB, manC, gmd, and wcaG, which are genes that function in GDP-L-fucose biosynthesis (Page 10, Table 2), and overexpression of futC, which is a fucosyltransferase (Page 10, Table 2).
The combination of Hatt and OligoScience Biotechnology does not teach deletion or functional inactivation of the yesZ and ganA genes.
Shipkowski teaches bacteria, such as B. subtilis, with inactivated lacA and yesZ genes (Abstract; Page 7733, Column 1, “Construction of vectors and knockouts”). lacA is also known as ganA as evidenced by Watzlawick (Page 2888, Column 1, Paragraph 2).
Hatt, OligoScience Biotechnology and Shipkowski do not teach the inactivation of yvmC or cypX.
Tang teaches a mutant Bacillus cell comprising a modification of at least one of the genes cypX and yvmC (Abstract). Tang teaches that the term “modification” includes deletion of the genes, which may be partial or complete (p. 3, lines 21-25).
It would have been obvious to one of ordinary skill in the art, prior to the effective filing date of the claimed invention, to modify the spoA Bacillus subtilis mutant as taught by Hatt to additionally express genes encoding a lactose permease, a GDP biosynthesis pathway, and a fucosyltransferase, as taught by OligoScience Biotechnology, and to inactivate the ganA, also known as lacA, and yesZ genes, as taught by Shipowski, and the yvmC and/or cypX gene as taught by Tang. One of ordinary skill in the art would have been motivated to do so because OligoScience Biotechnology teaches genetic modifications that result in the overexpression of lacY, GDP-L-fucose biosynthesis genes, and futC result in high production of 2-fucosyllactose, which is a fucosylated oligosaccharide (Page 10, Table 2, Title, Rows 1-8). One of ordinary skill in the art would have been motivated to inactivate ganA and yesZ genes, which encode beta-galactosidase enzymes (Shipowski, Column 1, “Construction of vectors and knockouts”), because OligoScience Biotechnology teaches that inactivation of β-galactosidase prevents cleavage of lactose, and that high levels of lactose is desirable for HMO production, as it is the HMO precursor (para. [0054], lines 30-32). One of ordinary skill in the art would have been motivated to inactivate the yvmC and/or cypX gene because Tang teaches that deletion of said genes prevents the production of red pigment, which facilitates recovery and purification of a biological substance of interest (p. 3, line 8-10). One of ordinary skill in the art would have had a reasonable expectation of success because Hatt, OligoScience Biotechnology, Shipkowski, and Tang are in the same field of endeavor of Bacillus genetic engineering.
Regarding claim 3, OligoScience Biotechnology teaches that it is preferred that the lactose permease is E. coli LacY (para. [0055], line 47).
Regarding claim 4, OligoScience Biotechnology teaches overexpression of manB, manC, gmd, and wcaG, (Table 10), which are enzymes that function in the de novo GDP-L-fucose biosynthesis pathway. See Figure 1 detailing the biosynthetic pathway (Page 1; Page 4, item 30). OligoScience Biotechnology teaches that GDP-L-fucose may be generated by the salvage pathway from fucose (Page 11, para. [0058])
Regarding claims 5 and 16, OligoScience Biotechnology teaches that the fucosyltransferase may be α-1,2-fucosyltransferase or α-1,3-fucosyltransferase (Page 4, item 24).
Regarding claim 6, OligoScience Biotechnology teaches that the microorganism may be unable to cleave lactose into glucose and galactose, which may be achieved by inactivating the lacZ gene encoding β-galactosidase (para. [0054]). Therefore, it is interpreted that a Bacillus cell with inactivated lacZ would have reduced β-galactosidase activity compared to wild type Bacillus cells.
Regarding claim 8, OligoScience Biotechnology teaches that the microorganism to be used may be Bacillus subtilis (para. [0043]).
Regarding claim 9, OligoScience Biotechnology teaches genetically microorganisms for the production of human milk oligosaccharides (para. [0038]), and teaches that the microorganism may be of the genus Bacillus (para. [0043]). OligoScience Biotechnology teaches that the microorganism is cultured (para. [0074]. Therefore, a culture medium comprising Bacillus is interpreted as a product comprising a Bacillus cell.
Regarding claims 10 and 13, OligoScience Biotechnology teaches a method for producing human milk oligosaccharides (para. [0073]) using genetically modified microorganisms (para. [0014], item 1). OligoScience Biotechnology teaches that the human milk oligosaccharide may be 2-fucosyllactose (para. [0014], item 22), which is fucosylated oligosaccharide. OligoScience teaches that the production method comprises culturing the microorganism in medium (para. [0074]), and teaches that the human milk oligosaccharide may be retrieved from the medium and/or from the microorganism itself (para. [0088]).
Hatt et al. teach a spoA Bacillus subtilis mutant with a sporulation frequency of 0.006% (Table 2), which is interpreted as non-sporulating. One of ordinary skill in the art would have been motivated to have used the spoA mutant taught by Hatt and Youngman in the method for producing fucosylated oligosaccharides, as taught by OligoScience Biotechnology, to allow for more efficient production of the fucosylated oligosaccharide, as it is known that spores are dormant bacterial that exhibit minimal metabolism.
Regarding claim 11, OligoScience Biotechnology teaches that the medium comprises lactose (Paragraph 0077).
Regarding claim 12, OligoScience Biotechnology teaches that GDP-L-fucose may be generated by the salvage pathway from fucose (Page 11, para. [0058]). Therefore, one of ordinary skill in the art would be reasonably expected to understand that L-fucose may be added to the culture medium to generate GDP-L-fucose via the salvage pathway from L-fucose.
Regarding claims 14, 15, and 17 OligoScience Biotechnology teaches that the purified HMOs of the invention may be used for the preparation for products for the consumption by humans, such as infant nutrition or animal feed (i.e., a nutritional composition) (para. [0093]). As discussed above OligoScience Biotechnology teaches that the HMO may be 2-fucosyllactose, which is a fucosylated oligosaccharide.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RACHEL EMILY MARTIN whose telephone number is (703)756-1416. The examiner can normally be reached M-Th 8:30-16:00, F 8:30-10:00 EST.
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/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/RACHEL EMILY MARTIN/Examiner, Art Unit 1657
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