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 .
Applicant’s response to restriction requirement of 5/22/26 is acknowledged. Applicant elected Group II (claims 45-50 and 52) and species A, drawn to a method of use of a cultivation medium comprising at least one precursor and/or acceptor for producing the 6’sialylated disaccharide or oligosaccharide, with traverse.
In traversal of restriction requirement, applicant has amended some claims and argues that the common technical feature of this invention in contrast to the Examiner’s opinion, is not SEQ ID NO:1 (or DNA encoding it). The common technical feature of this invention according to applicant, is a method of use of alpha-2,6-sialyl transferase for production of 6’sialylated disaccharides or oligosaccharides and Ward (cited by the examiner previously) does not teach such method. Applicant continues by stating that Ward does not establish a method of use of said enzyme and only refers to predicted Uni-Prot entry as CMP-N-acetylneuraminate-beta galactosamide-alpha 1,3, sialyl transferase. Therefore, lack of unity of invention, is improper and should be withdrawn.
This argument was fully considered but was found unpersuasive. This is because instant invention in contrast to applicant’s view, is not merely directed to a method of use of SEQ ID NO:1, which can even occur in a cell-free system. As applicant appreciates, claims 49-59 are directed to vectors and cells comprising SEQ ID NO:1 and the only common feature of said vectors and cells and instantly claimed method is SEQ ID NO:1 (or DNA encoding it). Further, for the sake of argument, even if the common feature of all inventions is a method of use of 6’silayltranserase polypeptide, the art combination cited below, continues to break the unity of invention. Therefore, the examiner finds no reason to rejoin all Groups together.
However, in the spirit of cooperation, the examiner decided to rejoin claims 37-45 and 59 with Group II invention.
It should also be noted that unfortunately, claims 46 in the last office action, was included in Group II invention due to inadvertent error and in fact, said claim belongs to Group III invention. Said claim is withdrawn and from now on, will be rejoined with Group III invention. The examiner regrets any misunderstanding that said error may have caused.
Claims 37-45, 47-48 and 59 are under examination on the merits.
Claims 46, 49-58 are hereby withdrawn as drawn to non-elected invention.
DETAILED ACTION
Claims 37-45, 47-48 and 59 are under examination on the merits.
Specification
The disclosure is objected to for reciting hyperlink language (see for example page 19, line 5). Applicant is advised to delete hyperlink language everywhere in the disclosure in compliance with 37 CFR section 1.57(d).
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph 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 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 37-39, 41-45, 47-48 and 59 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. Claims 37 (and its dependent claims 38-44) and claim 45 (and its dependent claims 47-48) are directed to a genera of methods utilizing a genus of SEQ ID NO:1 homologs as well as a vector comprising said of SEQ ID NO:1 homologs or DNA encoding them (see claim 59) wherein said genus of homologs is inadequately described in the disclosure.
As applicant is aware, SEQ ID NO:1 is made of 314 amino acids total and 80% of 200 amino acids, results in 0.8X200=160 amino acids, leaving the identity of 40 amino acids unknown. This means that out of a total of 314 amino, at least 154 (314-160=154) can be any amino acid residue. So, in fact, base claims 37, and 45 are methods of use of 49% (154/314=49%) homologs of SEQ ID NO:1 and claim 59 recited a genus of DNA molecules (and vectors comprising them, see claim 59) encoding 49% or higher homologs of SEQ ID NO:1, wherein said methods and said vector(s) are extremely broad.
The disclosure fails to teach which amino acids or combinations thereof are in charge of alpha-2,6-silaylytransferase activity and considering that base claims 37, 45 and 59 do not even require that said 200 amino acids (or DNA encoding them) be consecutive, it is totally unknown which exact substitutions at which position(s) among these 154 amino acids in SEQ ID NO:1 (or DNA encoding them) may result in a product with sialyltransferase activity. No examples of such residues or combinations thereof can be found in the disclose either.
The prior art is totally unpredictable as to which amino acids residues at which positions in SEDQ ID NO:1 (or DNA encoding it) should be combined to produce an enzyme with sialyltransferase activity of instant invention.
Therefore, due to lack of adequate structural information regarding a method of use of 80% homologs of 200 amino acid residues of SEQ ID NO:1, and considering that a single amino acid substitution in an enzyme structure may result in its total lack of function, one of skill in the art cannot reasonably conclude that applicant had full possession of vectors recited in claim 59 and methods of use of such sialyltransferase enzyme homologs (or DNA encoding them), before the effective filing of this application.
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.
Claim(s) 37-45, 47-48 and 59 are rejected under 35 U.S.C. 103 as being unpatentable over Rexer et al., “Rexer” (WO 2021/204898, 10/2021 (which will be used to cite relevant text) and also its corresponding US patent publication US2024/0352497), in view of Ward (cited previously).
Rexer under “Description section”, first paragraph (see pages 5-6) recites:
“The present invention relates to a method for producing cytidine 5'-monophospho- N-acetyl-neuraminic acid (CMP-Neu5Ac, 1) from low-cost substrates N- acetyl-D- glucosamine (GlcNac), pyruvate, cytidine and polyphosphate in a single reaction mixture with a set of enzymes comprising N-acylglucosamine 2-epimerase (AGE), an N-acetylneuraminate lyase (NAL), an N-acylneuraminate cytidylyltransferase (CSS), a uridine kinase (UDK), a uridine monophosphate kinase and a polyphosphate kinase 3 (PPK3). Further, said process may be adapted to produce Neu5Acylated, i.e. sialyated biomolecules and biomolecules including a saccharide, a peptide, a protein, a glycopeptide, a glycoprotein, a glycolipid, a glycan, an antibody, a glycoconjugate, in particular, an antibody drug conjugate, and a carbohydrate conjugate vaccine, or a flavonoid.”.
In page 9, according to Rexer, its invention also refers to a method for producing a Neu5Acylated i.e. sialyated biomolecule comprising i) performing the method as mentioned above to obtain CMP-Neu5Ac, ii) reacting the CMP-Neu5Ac obtained after step i) with a biomolecule, wherein the biomolecule is a saccharide, a glycopeptide, a glycoprotein, a glycolipid, a glycan, a peptide, a protein, an antibody, an antibody drug conjugate, a carbohydrate conjugate vaccine, or a flavonoid by forming an O-glycosidic bond with an hydroxyl group of the biomolecule with removal of CMP group in the presence of a sialyltransferase.
According to Rexer (see pages 15-17), because the receptor substrate may be substantially any monosaccharide or oligosaccharide having a terminal sugar residue, the specific glycosyltransferase exhibits specificity for the terminal saccharide residue, so the substrate can be substituted at the position of its non-reducing end. Therefore, the glycoside acceptor can be monosaccharide, oligosaccharide, sugar or sugar derivative of a fluorescent marker such as aminoglycoside antibiotics, gangliosides, or glycoprotein include antibodies and other Fc-containing protein. In one set of preferred embodiments, the glycoside acceptor is an oligosaccharide, preferably Gal. beta. (1-3) GlcNac, Gal. beta. (1-4) GlcNAc, Gal. beta. (1-3) GalNAc, Gal. beta. (1-4) GalNAc, Man alpha (1, 3) Man, Man alpha (1, 6) Man, GalNAc beta (1-4) - mannose. In a particularly preferred embodiment, the oligosaccharide acceptor and the CH2 domain of the Fc-containing protein is attached.
Rexer’s preferred enzymes are listed as beta-galactosamide alpha-2, 6- sialyltransferase (EC 2.4.99.1), alpha-N-acetylgalactosaminide alpha-2,6- sialyltransferase (EC 2.4.99.3), beta-galactoside alpha-2, 3-sialyltransferase (EC 2.4.99.4), N-acetyllactosaminide alpha-2, 3-sialyltransferase (EC 2.4.99.6), alpha- N-acetyl-neuraminide alpha-2, 8-sialyltransferase (EC 2.4.99.8); and lactosylceramide alpha-2, 3-sialyltransferase (EC 2.4.99.9). These enzymes use CMP-Neu5Ac as a glycosyl donor.
According to said patent, "saccharide" refers to but not restricted to monosaccharide, disaccharide, trisaccharide, tetrasaccharide, pentasaccharide, hexasaccharide, heptasaccharide, octasaccharide, oligosaccharide, glycan and polysaccharide. The saccharide comprises preferably at least one of monosaccharide units selected from:D-Arabinose, D-Lyxose, D-Ribose, D-Xylose, L-Arabinose, L-Lyxose, L-Ribose, L-Xylose, D-Ribulose, D-Xylulose, L-Ribulose, L-Xylulose, D-Deoxyribose, L-Deoxyribose, D-Erythrose, D-Threose, L-glycerol-D-manno-Heptose, D-glycerol-D- manno-Heptose, D-Allose, D-Altrose, D-Glucose, D-Mannose, D-Gulose, D-ldose, D-Galactose, D-Talose, D-psicose, D-fructose, D-sorbose, D-tagatose, 6-Deoxy-L- altrose etc.
In table 15 and Example 3, Rexer describes that its enzymes can be overexpressed in, isolated from or prepared by recombinant methods from microbiological cultures comprising bacterial cultures, such as E. coli (see table 15 and Example 3), virus and phage cultures and eukaryotic cell cultures.
In Example H, also genes and vectors utilized in Rexer’s patent are disclosed.
In Example 4-2, Rexer discloses:
“Production of 6'-Sialyllactose (6'-SL)”
For the synthesis of 6'-SL from lactose and CMP-Neu5Ac, 70 μL of previously detailed one-pot reaction mix containing CMP-Neu5Ac (see Table 16) as the product was mixed with lactose (20 mM), MnCl.sub.2 (20 mM), Tris-HCI (150 mM - pH 8), and 0.3 μg /μL α-2,6-ST to a final volume of 200 μL. The successful production of 6'-SL is confirmed by the HPAEC chromatogram and MS/MS spectra of the reaction mix at the reaction end point (see Figure 28).”.
Rexer however, does not disclose a method of use of a sialyltransferase comprising SEQ ID NO:1 or comprising a peptide derived from SEQ ID NO:1 having at least 80% identity over at least 200 amino acids of SEQ ID NO:1 (or DNA encoding them).
Ward discloses a “3-sialyltransferase” having SEQ ID NO:1 (and DNA encoding it), inherently belonging to EC 2.4.99.4.
Before the effective filing of this application, it would have been obvious to one of ordinary skill in the art to start with the method of preparation of sialyated disaccharides or oligosaccharides of Rexer (see example 4-2) and substitute its generic sialyltransferase (EC 2.4.99) with the Simonsiella muelleri enzyme of Ward with EC 2.4.99.4. (either in recombinant or wild type form). One of ordinary skill in the art, before the effective filing of this application, depending on the target disaccharide or oligosaccharide and the host cell utilized, is motivated to use the enzyme of Ward, which is readily known and available in the art in the method of Rexer to produce at sialyated oligosaccharides/disaccharides, including 6’-sialyl lactose, because said sialyated products are beneficial to infants helping their digestion, rendering claims 37-43, 45, 47-48 and 59 obvious.
With respect to claim 44, Example 4-2 of Rexer suggests a one-pot cell free system for production of sialyated human milk oligosaccharides (HMOs).
Finally, one of ordinary skill in the art has a reasonable expectation of success in using the enzyme of Ward (in recombinant or wild type form) in the method of Rexer because such procedures were fully established in the prior art, before the effective filing of this application.
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARYAM MONSHIPOURI whose telephone number is (571)272-0932. The examiner can normally be reached full-flex.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Melenie L Gordon can be reached at 571-272-8037. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MARYAM MONSHIPOURI/Primary Examiner, Art Unit 1651
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