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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 9/09/2025 has been entered.
Response to Amendments
Applicant's amendments filed 9/09/2025 to claims 1 and 13 have been entered. Claims 5, 6, and 17-23 are canceled. Claims 1-4, 7-13, and 14-16 remain pending, of which claims 1-4 and 7-13 are being considered on their merits. Claims 14-16 remain withdrawn from consideration. References not included with this Office action can be found in a prior action.
The instant amendments to claims 1 and 13 have overcome the 35 U.S.C. § 102 rejections of record over Lin, which are withdrawn. New grounds of rejection are set forth below necessitated by the instant amendments.
Any rejections of record not particularly addressed below are withdrawn in light of the claim amendments and/or applicant’s comments.
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, 7-9, 11, and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Lin et al. (Biotechnol. Prog. (2015), 31:334–346; provided in the ISR dated 9/28/2021) in view of Choi et al. (Glycobiology (2014), 24(2), 159-169).
Lin teaches an in vitro method comprising a step of incubating an alpha 2,3 sialylated glycoprotein with an alpha 2,6 sialyltransferase and a sialic acid source for a sufficient time and under conditions to increase the number of α2,3,- α2,6- disialylgalactose (NeuS5Ac-a2,3(Neu5Ac-a2,6)Gal) N-glycans on the glycoprotein as compared to a glycoprotein that has not been incubated with the alpha 2,6 sialyltransferase and the sialic acid source (e.g. CHO cells in suspension culture in vitro which naturally express ST3gal4 i.e. α2,3 sialyltransferase and recombinantly express ST6gal1 i.e. alpha 2,6 sialyltransferase; see Lin at p336, “Quantitative RT-PCR” and Fig. 6 and p340, “Expression assessment…” for gene expression, Lin at p340, “Two-color FACS….” for quantitation of α2,3,- α2,6 linkages), anticipating claims 1, the embodiment of natural proteins in the cells for claim 8, claim 9, the embodiment of concurrent for claim 11 (e.g. both enzymes expressed simultaneously), and claim 13. Lin teaches that Chinese hamster St6gal1 i.e. α2,6 sialyltransferase (p336, subheading “Overexpression of ST6GAL1), reading in-part on claims 5-7.
Regarding claims 1 and 13, Lin is silent regarding disialylgalactose (NeuS5Ac-a2,3(Neu5Ac-a2,6)Gal) N-glycan linkages in the glycoproteins. Lin is silent regarding the functional properties of claims 2 and 3. However, any product produced by the alpha 2,3 sialyltransferase and alpha 2,6 sialyltransferase present in the cells of Lin must be inherent to the catalytic activity of those enzymes. Because Lin’s CHO cells comprise alpha 2,3 sialyltransferase and alpha 2,6 sialyltransferase, the presence of those two enzymes in Lin’s CHO cells would necessarily lead to the N-glycan linkages of claim 1 and the functional properties of claims 2 and 3 absent any showing to the contrary; see M.P.E.P. § 2112.
Regarding claim 1 and 13, Lin does not teach wherein the α2,6 sialyltransferase is a purified α2,6 sialyltransferase from photobacterium or is an α2,6 sialyltransferase enzyme extract from photobacterium. Regarding claim 7, Lin does not teach wherein the photobacterium is Photobacterium damselae.
Choi teaches methods of mutagenizing α2,3- and α2,6 sialyltransferases to improve the activity of these enzymes (Abstract). Choi teaches α2,6 sialyltransferase obtained from Photobacterium damsela (Abstract), reading on the photobacterium of claims 1, 7, and 13. Choi teaches that the L433S/T and double-mutation I411T/L433T in α2,6 sialyltransferase exhibited 3- and 5-fold enhancement of the α2,6 ST- specific activity compared with the wild-type, respectively, via increase in kcat values (Abstract and Table III), reading on the photobacterium of claims 1, 7, and 13. Choi teaches chromatography-purified enzymes (paragraph spanning p167-168), reading on the purified enzyme of claims 1, 7, and 13.
Regarding claims 1, 7, and 13, it would have been obvious to a person of ordinary skill in the art before the invention was filed to substitute the purified α2,6 sialyltransferase comprising the L433S/T and double-mutation I411T/L433T and obtained from Photobacterium damsela of Choi for the Chinese hamster wildtype α2,6 sialyltransferase of Lin in Lin’s methods. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because Choi teaches the L433S/T and double-mutation I411T/L433T in α2,6 sialyltransferase exhibited 3- and 5-fold enhancement of the α2,6 ST- specific activity compared with the wild-type, respectively, via increase in kcat values and would thus improve upon the glycosylation methods of Lin.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Lin and Choi as applied to claim 1 above, and further in view of Lee et al. (Biotechnol Bioeng (2002), 80: 516–524).
The teachings of Lin and Choi are relied upon as set forth above.
Regarding claim 4, Lin and Choi do not teach wherein the sialic acid source is cytidine- monophosphate-N-Acetyl-Neuraminic-Acid.
Lee teaches methods of producing cytidine-monophosphate-N-Acetyl-Neuraminic-Acid in E. coli. (Abstract; detailed Methods at p517-518), reading on claim 4. Lee teaches there is a need in this art to reduce the cost of producing cytidine-monophosphate-N-Acetyl-Neuraminic-Acid when studying methods of alpha-selective sialylation at the end of carbohydrate moieties (1st paragraph of the Introduction), reading on claim 4.
It would have been obvious to a person of ordinary skill in the art before the invention was filed to substitute the cytidine-monophosphate-N-Acetyl-Neuraminic-Acid of Lee for the unspecified endogenous sialic acid source of Lin in Lin’s methods. The skilled artisan would have been motivated to do so because both Lee and Lee are in-part directed towards the sialylation of proteins by their requisite enzymes. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because Lee teaches there is a need in this art to reduce the cost of producing cytidine-monophosphate-N-Acetyl-Neuraminic-Acid when studying methods of alpha-selective sialylation at the end of carbohydrate moieties, and so the substitution would predictably yield cytidine-monophosphate-N-Acetyl-Neuraminic-Acid as a sialic acid source in Lin’s methods.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Lin and Choi as applied to claim 1 above, and further in view of Schmidt et al. (WO 2018/177758; provided in the IDS dated 9/28/2021) and Stockley et al. (Orphanet Journal of Rare Diseases (2013), 8:149)
The teachings of Lin and Choi are relied upon as set forth above. Lin further teaches glycosylating IgG as a representative species of therapeutic protein (Abstract and 1st paragraph of the Introduction), reading in-part on claim 10.
Regarding claim 10, Lin and Choi do not teach alpha-1 antitrypsin (AAT).
Schmidt teaches methods of recombinantly overexpressing either alpha-2,6-sialytransferase I (ST6Gal1) and/or alpha-2,3-sialytransferase 4 (ST3Gal4) with a glycoprotein (Abstract). Schmidt teaches glycosylating alpha-1 antitrypsin (AAT). As a preferred embodiment (paragraph spanning p3-4), reading on claim 10. Schmidt teaches that the sialyation of glycoproteins reduces the fucosylation on said proteins to make the proteins less immunogenic (Abstract; p2, line 14 through p3, line 2), reading on claim 10. Schmidt teaches a working example overexpressing alpha-2,6-sialytransferase I (ST6Gal1) or alpha-2,3-sialytransferase 4 (ST3Gal4) (Example 1), reading on claim 10.
Stockley teaches methods of administering alpha-1 antitrypsin to subjects in need of treatment thereof for emphysema associated with alpha-1 antitrypsin deficiency (Abstract).
It would have been obvious to a person of ordinary skill in the art before the invention was filed to substitute the alpha1-antitrypsin of Schmidt for the IgG of Lin in Lin’s sialylation methods in view of Stockley. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because both Lin and Schmidt are directed in-part towards in vitro sialylation with alpha-2,3-sialytransferase and/or alpha-2,6-sialytransferase, and because both Lin and Stockley are directed towards sialylation of a potentially therapeutic protein. The skilled artisan would have been motivated to do so because Schmidt teaches that Schmidt teaches that the sialyation of glycoproteins reduces the fucosylation on said proteins to make the proteins less immunogenic, which would improving upon the methods of Lin to generate a sialylated glycoprotein that could then treat subjects for emphysema associated with alpha-1 antitrypsin deficiency as taught by Stockley.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Lin and Choi as applied to claim 1 above, and further in view of Weikert et al. (Nature Biotechnology (1999), 17, 1116-1121).The teachings of Lin and Choi are relied upon as set forth above.
The teachings of Lin and Choi are relied upon as set forth above.
Regarding claim 12, Lin and Choi do not teach wherein the method comprises a prior or concurrent step of incubating the glycoprotein with a β-1,4-galactosyltransferase and a galactose source.
Weikert teaches a CHO cell lines overexpressing β-1,4-galactosyltransferase and α-2,3-sialytransferase, the CHO cell lines secreting further either IgG (Abstract and Fig. 1) Weikert teaches an increase on the molar content of galactose and sialic acid on the IgG ( subheading “TNFR-IgG cells overexpressing GT and/or ST” on p1118-1119 and the paragraph starting “In the present study…”on p1120), reading on claim 12 and thus implying a galactose and sialic acid source.
It would have been obvious to a person of ordinary skill in the art before the invention was filed to add the β-1,4-galactosyltransferase of Weikert to the CHO cells and methods of Lin. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because both Weikert and Lin are directed towards recombinant CHO cells and towards methods of glycosylating IgG. The skilled artisan would have been motivated to do so because combining the two enzymes taught separately by the prior art into a single CHO cell line comprising both enzymes according to known methods would predictably yield a CHO cell line comprising both enzymes and methods for increasing the molar content of galactose and sialic acid on a protein of interest such as IgG; see M.P.E.P. § 2143(I)(A).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Response to Arguments
Applicant's arguments on pages 5-8 of the reply have been fully considered, but not found persuasive of error for the reasons given below.
In response to applicant's argument on pages 5-6 of the reply that Lin and Choi are deficient by not teaching alpha 2,6 sialyltransferase from Photobacterium sp. is capable of adding alpha 2,6 sialic acids to alpha 2,3 glycosylated proteins, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). In this case, Applicant’s arguments are not persuasive because 1) a rationale to combine the references that differs from Applicant’s is permissible, see M.P.E.P. § 2144 (IV), and 2) Applicant has not addressed the specific obviousness rationale to combine Choi with Lin as set forth above, and what the combination would (or would not) suggest to a person of ordinary skill in the art.
As such, Applicant’s remaining arguments on pages 7-8 of the reply are not persuasive because Applicant has not established by any preponderance of evidence that the claimed method otherwise yields any unexpected result reasonably commensurate to the scope of the claims, see M.P.E.P. § 716.02. Applicant’s reliance on the properties of the claimed alpha 2,6 sialyltransferase obtained from Photobacterium is not persuasive because a chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present, see M.P.E.P. § 2112.01(II).
Conclusion
No claims are allowed. No claims are free of the art.
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/Sean C. Barron/Primary Examiner, Art Unit 1653