Office Action 1: Non-Final Rejection (2024-12-02)
Rejection types: Double Patenting

CLAIMS:
What is Claimed is:
1\. A composition comprising oxo-aflibercept, wherein one or more amino acid residues of aflibercept is oxidized and wherein said one or more amino acid residues is phenylalanine and/or tyrosine.
2\. The composition of claim 1, wherein said oxo-aflibercept has a glycosylation profile based on molar percentage selected from the group consisting of about 40% to about 50% total fucosylated glycans, about 30% to about 55% total sialylated glycans, about 2% to about 15% mannose-5, and about 60% to about 79% galactosylated glycans.
3\. The composition of claim 1, further comprising a pharmaceutically acceptable carrier.
4\. The composition of claim 3, wherein said composition is freeze-dried.
5\. The composition of claim 4, wherein said composition is sterile.
6\. The composition of claim 1, wherein said oxo-aflibercept is enzymatically digested resulting in one or more oligopeptides, and wherein said one or more oligopeptides is selected from the group consisting of: SEQ ID NO. 69, SEQ ID NO. 70, SEQ ID NO. 32, and combinations thereof.
7\. The composition of claim 6, wherein said enzymatic digestion is performed using trypsin.
8\. An oxo-aflibercept composition produced in a cell culture media, wherein CDM is added to said cell culture media, wherein one or more amino acid residues of said oxo-aflibercept composition is oxidized and wherein said one or more amino acid residues is phenylalanine and/or tyrosine.
9\. The oxo-aflibercept composition of claim 8, wherein said oxo-aflibercept composition has a glycosylation profile based on molar percentage selected from the group consisting of about 40% to about 50% total fucosylated glycans, about 30% to about 55% total sialylated glycans, about 2% to about 15% mannose-5, and about 60% to about 79% galactosylated glycans.
10\. The oxo-aflibercept composition of claim 9, wherein soy hydrolysate media is added to said cell culture media.
11\. The oxo-aflibercept composition of claim 8, wherein components derived from soy hydrolysate are added to said cell culture media.
12\. The oxo-aflibercept composition of claim 8, wherein plant or animal-derived components are added to said cell culture media.
13\. The oxo-aflibercept composition of claim 8, wherein said oxo-aflibercept composition enzymatically digested resulting in one or more oligopeptides, and wherein said one or more oligopeptides is selected from the group consisting of: SEQ ID NO. 69, SEQ ID NO. 70, SEQ ID NO. 32, and combinations thereof.
14\. The oxo-aflibercept composition of claim 13, wherein said enzymatic digestion is performed using trypsin.
15\. An oxo-aflibercept composition produced in a cell culture media, wherein CDM is a majority component of said cell culture media, wherein one or more amino acid residues of aflibercept is oxidized, and wherein said one or more amino acid residues is histidine and/or tryptophan.
16\. The oxo-aflibercept composition of claim 15, wherein said oxo-aflibercept composition has a glycosylation profile based on molar percentage selected from the group consisting of about 40% to about 50% total fucosylated glycans, about 30% to about 55% total sialylated glycans, about 2% to about 15% mannose-5, and about 60% to about 79% galactosylated glycans.
17\. The oxo-aflibercept composition of claim 16, wherein said cell culture media is supplemented with soy hydrolysate media.
18\. The oxo-aflibercept composition of claim 15, wherein components derived from soy hydrolysate are added to said cell culture media.
19\. The oxo-aflibercept composition of claim 15, wherein plant or animal-derived components are added to cell culture media.
20\. The oxo-aflibercept composition of claim 15, wherein said oxo-aflibercept is enzymatically digested resulting in one or more oligopeptides, and wherein said one or more oligopeptides is selected from the group consisting of: SEQ ID NO. 17, SEQ ID NO. 18, SEQ ID NO. 19, SEQ ID NO. 20, SEQ ID NO. 21, SEQ ID NO. 22, SEQ ID NO. 23, SEQ ID NO. 28, SEQ ID NO. 29, SEQ ID NO. 30, SEQ ID NO. 31, SEQ ID NO. 32 and combinations thereof.
21\. The oxo-aflibercept composition of claim 20, wherein said enzymatic digestion is performed using trypsin.
22\. The oxo-aflibercept composition of claim 15, further comprising a pharmaceutically acceptable carrier.
23\. An oxo-aflibercept composition produced in a cell culture media, wherein CDM is a majority component of said cell culture media, wherein one or more amino acid residues of aflibercept is oxidized, and wherein said one or more amino acid residues is phenylalanine and/or tyrosine.
24\. The oxo-aflibercept composition of claim 23, wherein said oxo-aflibercept composition has a glycosylation profile based on molar percentage selected from the group consisting of about 40% to about 50% total fucosylated glycans, about 30% to about 55% total sialylated glycans, about 2% to about 15% mannose-5, and about 60% to about 79% galactosylated glycans.
25\. The oxo-aflibercept composition of claim 23, wherein said cell culture media is supplemented with soy hydrolysate media.
26\. The oxo-aflibercept composition of claim 23, wherein components derived from soy hydrolysate are added to said cell culture media.
27\. The oxo-aflibercept composition of claim 23, wherein plant or animal-derived components are added to cell culture media.
28\. The oxo-aflibercept composition of claim 23, wherein said oxo-aflibercept is enzymatically digested resulting in one or more oligopeptides, and wherein said one or more oligopeptides is selected from the group consisting of: SEQ ID NO. 69, SEQ ID NO. 70, SEQ ID NO. 32, and combinations thereof.
29\. The oxo-aflibercept composition of claim 28, wherein said enzymatic digestion is performed using trypsin.
30\. The oxo-aflibercept composition of claim 23, further comprising a pharmaceutically acceptable carrier.

OFFICE ACTION:
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 .
Status of the Application
The claims of 20 May 2024 are entered.
Claims 1-30 are pending and are being examined on the merits.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA  as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
1. Claims 15, 16, and 22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 13, 17 and 22 of U.S. Patent No. 11,958,894 B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘894 patent claims an overlapping composition.
The ‘894 patent claims oxo-aflibercept produced in CDM containing oxidized tryptophan (see e.g. claim 1). This overlaps with claim 15.
With respect to claim 16, the ‘894 patent claims the same glycosylation profiles (see e.g. claim 2).
With respect to claim 22, the ‘894 patent claims oxo-aflibercept produced in CDM and placed in a syringe with carriers (see e.g. claims 13, 17, and 22).
2. Claim 15 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 12,012,444 B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘444 patent claims an overlapping composition.
The ‘444 patent claims an oxo-aflibercept produced in CDM that contains an oxidized tryptophan or histidine residue (see e.g. claim 1). This overlaps with claim 15.
3. Claims 15 and 16 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 11,753,459 B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘459 patent claims an overlapping composition.
The ‘459 patent claims an oxo-aflibercept produced in CDM that contains an oxidized histidine or tryptophan residue (see e.g. claim 1). This overlaps with claim 15.
With respect to claim 16, the ‘459 patent also claims the same glycosylation profile (see e.g. claim 1).
4. Claims 15 and 22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 11,542,317 B1. Although the claims at issue are not identical, they are not patentably distinct from each other because the ’317 patent claims an overlapping composition.
The ‘317 patent claims an oxo-aflibercept composition produced in CDM that contains an oxidized histidine or tryptophan residue (see e.g. claim 1). This overlaps with claim 15.
With respect to claim 22, the ‘317 patent also claims the composition as containing an excipient (see e.g. claim 2).
5. Claims 1, 3, 5, 8, 15, 22, 23, and 30 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 11, and 20 of U.S. Patent No. 11,505,593 B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘593 patent claims an overlapping composition.
The ‘593 patent claims a syringe containing oxo-aflibercept produced in CDM, where the aflibercept has oxidized histidine or tryptophan residues (see e.g. claim 1). ‘593 also claims oxo-phenylalanine (see e.g. claim 20). This overlaps with claims 1, 8, 15, and 23.
With respect to claims 3, 22, and 30 the ‘593 patent also claims inclusion of excipients (see e.g. claim 11).
With respect to claim 5, inclusion in a syringe implies sterility.
6. Claim 15 and 20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 of U.S. Patent No. 11,485,770 B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘770 patent claims an overlapping composition.
The ‘770 patent claims a culture media composition containing CDM and oxo-aflibercept, where the oxo-aflibercept contains oxidized histidine or tryptophan residues (see e.g. claim 1). This overlaps with claim 15.
With respect to claim 20, the ‘770 patent also claims the same sequences after enzymatic digestion (see e.g. claim 2).
7. Claims 15 and 20-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 11,306,135 B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘135 patent claims overlapping compositions.
The ‘135 patent claims a composition comprising oxo-aflibercept produced in CDM and containing an oxidized histidine or tryptophan residue (see e.g. claim 14). This overlaps with claim 15.
With respect to claim 20, the ‘135 patent also claims oxo-aflibercept with the same sequences (see e.g. claims 5 and 12).
With respect to claim 21, the ‘135 patent claims digestion with trypsin (see e.g. claims 6 and 13).
With respect to claim 22, the ‘135 patent claims inclusion of a carrier (see e.g. claims 2 and 8).
8. Claim 15 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 13 and 15-21 of U.S. Patent No. 11,548,932 B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘932 patent claims a method of producing aflibercept that results in the same composition.
The ‘932 patent claims a method of producing aflibercept in CDM (see e.g. claim 13). During the process, the ‘932 patent also claims reduction of certain oxidized species including at histidine and tryptophan residues (see e.g. claims 15-21). This results in production during the process of an overlapping oxo-aflibercept composition.
9. Claims 15 and 16 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 10-15 of U.S. Patent No. 11,732,025 B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘025 patent claims a process that results in production of the same composition.
The ‘025 patent claims a process of producing aflibercept in CDM (see e.g. claim 1). The ’025 patent also claims that during production levels of oxidized histidine or tryptophan residues are reduced, which means during the process an overlapping composition was produced that had these oxo-aflibercept species (see e.g. claims 10-15).
With respect to claim 16, the ‘025 patent claims the same glycosylation profiles (see e.g. claim 1).
10. Claim 15 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 13 and 15-21 of U.S. Patent No. 12,012,445 B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘445 patent claims a method of producing aflibercept that results in the same composition.
The ‘445 patent claims a method of producing aflibercept in CDM (see e.g. claim 13). During the process, the ‘445 patent also claims reduction of certain oxidized species including at histidine and tryptophan residues (see e.g. claims 15-21). This results in production during the process of an overlapping oxo-aflibercept composition.
11. Claims 1, 6-8, 13-15, 20, 21, 23, 28, and 29 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 7-11 of U.S. Patent No. 11,104,715 B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘715 patent claims a method of producing aflibercept that results in the same composition.
The ‘715 patent claims a method of producing aflibercept from CDM (see e.g. claim 1). The ‘715 patent further claims that the aflibercept contains oxidized variants including oxidized phenylalanine, tyrosine, histidine, and tryptophan (see e.g. claims 7-10). This overlaps with the oxo-aflibercept of claims 1, 8, 15, and 23.
With respect to claims 6, 13, 20, and 23, the ‘715 patent claims overlapping sequences (see e.g. claim 11).
With respect to claims 7, 14, 21, and 29, since the ‘715 patent claims the same sequences by necessity they would have been digested with trypsin to result in said sequences.
12. Claims 1, 6-8, 13-15, 20, 21, 23, 28, and 29 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 7-9 of U.S. Patent No. 11,535,663 B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘663 patent claims a method of producing aflibercept that results in the same composition.
The ‘663 patent claims a method of producing aflibercept from CDM (see e.g. claim 1). The ‘663 patent further claims that the aflibercept contains oxidized variants including oxidized phenylalanine, tyrosine, histidine, and tryptophan (see e.g. claims 7-10). This overlaps with the oxo-aflibercept of claims 1, 8, 15, and 23.
With respect to claims 6, 13, 20, and 23, the ‘663 patent claims overlapping sequences (see e.g. claim 11).
With respect to claims 7, 14, 21, and 29, since the ‘663 patent claims the same sequences by necessity they would have been digested with trypsin to result in said sequences.
13. Claims 1, 6-8, 13-15, 20, 21, 23, 28, and 29 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 7-11 of U.S. Patent No. 11,472,861 B2. Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘861 patent claims a method of producing aflibercept that results in the same composition.
The ‘861 patent claims a method of producing aflibercept from CDM (see e.g. claim 1). The ‘861 patent further claims that the aflibercept contains oxidized variants including oxidized phenylalanine, tyrosine, histidine, and tryptophan (see e.g. claims 7-10). This overlaps with the oxo-aflibercept of claims 1, 8, 15, and 23.
With respect to claims 6, 13, 20, and 23, the ‘861 patent claims overlapping sequences (see e.g. claim 11).
With respect to claims 7, 14, 21, and 29, since the ‘861 patent claims the same sequences by necessity they would have been digested with trypsin to result in said sequences.
14. Claims 1, 2, 8, 9, 15, 16, 23, and 24 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 9 of copending Application No. 18/638,362 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘362 application claims a method that results in production of overlapping compositions.
The ‘362 application claims a method of producing aflibercept from CDM, where the aflibercept includes oxidized variants at phenylalanine, tyrosine, histidine, or tryptophan (see e.g. claims 1 and 9). This overlaps with claims 1, 8, 15, and 23.
With respect to claims 2, 9, 16, and 24 the ‘362 application claims an overlapping glycosylation profile (see e.g. claim 1).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
15. Claims 15 and 22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 18/917,707 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘707 application claims an overlapping composition.
The ‘707 application claims an oxo-aflibercept formulation produced from CDM, which also contains oxidized histidine or tryptophan residues (see e.g. claim 1). This overlaps with claim 15.
With respect to claim 22, the ‘707 application also claims inclusion of excipients (see e.g. claim 1).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
16. Claims 4 and 5 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 11, and 20 of U.S. Patent No. 11,505,593 B2 OR  claims 1 and 7-11 of U.S. Patent No. 11,104,715 B2 OR claims 1 and 7-9 of U.S. Patent No. 11,535,663 B2 OR claims 1 and 7-11 of U.S. Patent No. 11,472,861 B2 in view of USP 7,807,164 B2.
The relevance of the ‘593, ‘715, ‘663, or ‘861 patents has been set forth above. Each claims an oxo-aflibercept that contains oxidized phenylalanine and/or tyrosine residues.
The difference between the previous patents and the claimed invention is that none claim a freeze-dried or sterile composition.
The ‘164 patent claims lyophilized formulations containing VEGF antagonists, of which the oxo-aflibercept formulations fall (see e.g. claim 1). ‘164 also discloses that the lyophilized formulation can be reconstituted into a sterile formulation (see e.g. Col.4 lines 42-44).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the oxo-aflibercept formulations of ‘593, ‘715, ‘663, or ‘861 by preparing the oxo-aflibercept as a freeze-dried formulation as shown for similar VEGF antagonists in the ‘164 patent. The rationale comes from the overlapping subject matter of VEGF antagonists under which aflibercept falls. There would have been a reasonable expectation of success because freeze-drying of pharmaceutical formulations is routine and ordinary in the art and ‘164 demonstrates such freeze-drying for related compositions. The invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
With respect to claim 5, as discussed above the ‘164 art indicates that preparation of sterile formulations after freeze-drying is desirable.
17. Claims 4 and 5 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 9 of copending Application No. 18/638,362 in view of USP 7,807,164 B2.
The relevance of ‘362 is set forth above.
The difference between ’362 and the claimed invention is that the ‘362 application does not claim a freeze-dried or sterile composition.
The ‘164 patent claims lyophilized formulations containing VEGF antagonists, of which the oxo-aflibercept formulations fall (see e.g. claim 1). ‘164 also discloses that the lyophilized formulation can be reconstituted into a sterile formulation (see e.g. Col.4 lines 42-44).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the oxo-aflibercept formulations of ‘362 by preparing the oxo-aflibercept as a freeze-dried formulation as shown for similar VEGF antagonists in the ‘164 patent. The rationale comes from the overlapping subject matter of VEGF antagonists under which aflibercept falls. There would have been a reasonable expectation of success because freeze-drying of pharmaceutical formulations is routine and ordinary in the art and ‘164 demonstrates such freeze-drying for related compositions. The invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
With respect to claim 5, as discussed above the ‘164 art indicates that preparation of sterile formulations after freeze-drying is desirable.
This is a provisional nonstatutory double patenting rejection.
18. Claims 10-12, 17-19, and 25-27 are rejected on the ground of nonstatutory double patenting as being unpatentable over any of the previously applied U.S. Patent Nos 11,958,894 or 11,753,459 or 11,505,593 or 11,7342,025 or 11,104,715 or 11,535,663 or 11,472,861 as found above in view of Chun et al. (Bioresource Technology 98:1000-1005, published 2007, hereafter referred to Chun).
The previously applied patents all claim oxo-aflibercept produced in CDM, either those with only histidine and/or tryptophan oxidation events or in certain cases those having tyrosine and/or phenylalanine oxidation events.
Note that for brevity the rejection is condensed into a single rejection, but applicability of dependent claims is conditional upon whether the prior patent is the basis for rejection of independent claim 8, 15, and/or 23. The single rejection does not imply, for instance, that a prior patent only rejecting claim 15 is being utilized to also reject claims 10-12 or 25-27.
Patent/Application
Previously Rejected Claims
Dependent Claims Rejected
11,958,894
15, 16
17-19
11,753,459
15, 16
17-19
11,505,593
8, 23
11, 12, 25-27
11,732,025
15, 16
17-19
11,104,715
8, 23
11, 12, 25-27
11,535,663
8, 23
11, 12, 25-27
11,472,861
8, 23
11, 12, 25-27
The difference between the prior patents and the claimed invention is that none of the patents claim inclusion of soy hydrolysate media, soy hydrolysate components, or plant or animal-derived components.
The Chun art discloses that among various protein hydrolysates used as feed supplement in a CDM, soy protein hydrolysates showed better support for cell growth and viability as compared to other hydrolysates (see e.g. Abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention that the prior patents could have been modified by utilizing soy protein hydrolysate as disclosed by Chun as part of the CDM. The rationale comes from Chun disclosing the better performance of soy as compared to other protein hydrolysates. There would have been a reasonable expectation of success because the CDM of the prior patents already supported production of oxo-aflibercept and there would have been an expectation that using a superior ingredient in the form of soy hydrolysate as in Chun would further support oxo-aflibercept production. The invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
With respect to claims 11, 12, 18, 19, 26, and 27, the soy hydrolysate by necessity contains components derived from soy hydrolysate, and the soy itself is a plant-derived component.
19. Claims 10-12, 17-19, and 25-27 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 9 of copending Application No. 18/638,362 in view of Chun et al. (Bioresource Technology 98:1000-1005, published 2007).
The relevance of ‘362 is set forth above. The difference between ‘362 and the claimed invention is that ‘362 does not claim inclusion of soy hydrolysate media, soy hydrolysate components, or plant or animal-derived components.
The relevance of Chun is set forth above.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention that the ‘362 application could have been modified by utilizing soy protein hydrolysate as disclosed by Chun as part of the CDM. The rationale comes from Chun disclosing the better performance of soy as compared to other protein hydrolysates. There would have been a reasonable expectation of success because the CDM of the ‘362 already supported production of oxo-aflibercept and there would have been an expectation that using a superior ingredient in the form of soy hydrolysate as in Chun would further support oxo-aflibercept production. The invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
With respect to claims 11, 12, 18, 19, 26, and 27, the soy hydrolysate by necessity contains components derived from soy hydrolysate, and the soy itself is a plant-derived component.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed.

APPLICANT REBUTTAL: REMARKS
Claims 1-30 are pending in this application. No new matter is added.
Double Patenting
The Office Action states that pending claims of the Application have been rejected on the ground of non-statutory double patenting as being unpatentable over:
" Claims 15, 16, and 22 over claims 1, 2, 13, 17, and 22 of U.S. Patent No. 11,958,894 B2.
" Claim 15 over claim 1 of U.S. Patent No. 12,012,444 B2.
" Claims 15 and 16 over claim 1 of U.S. Patent No. 11,753,459 B2.
" Claims 15 and 22 over claim 1 of U.S. Patent No. 11,542,317 B1.
" Claim 1, 3, 5, 8, 15, 22, 23 and 30 over claims 1, 11, and 20 of U.S. Patent No.
11,505,593 B2.
"  Claims 15 and 20 over claims 1-2 of U.S. Patent No. 11,485,770 B2.
"  Claim 15 over claims 13 and 15-21 of U.S. Patent No. 11,548,932 B2.
"  Claims 15 and 16 over claims 1 and 10-15 of U.S. Patent No. 11,732,025 B2.
"  Claim 15 over claims 13 and 15-21 of U.S. Patent No. 12,012,445 B2.
"  Claims 1, 6-8, 13-15, 20, 21, 23, 28, and 29 over claims 1 and 7-11 of U.S. Patent No.
11,104,715 B2.
"  Claims 1, 6-8, 13-15, 20, 21, 23, 28, and 29 over claims 1 and 7-9 of U.S. Patent No.
11,535,663 B2.
"  Claims 1, 6-8, 13-15, 20, 21, 23, 28, and 29 over claims 1 and 7-11 of U.S. Patent No.
11,472,861 B2.
"  Claims 1, 2, 8, 9, 15, 16, 23, and 23 over claims 1 and 9 of copending Application No.
"  Claims 15 and 22 over claim 1 of copending Application No. 18/917,707.
"  Claims 4 and 5 over claims 1, 11, and 20 of U.S. Patent No. 11,505,593 B2 OR claims 1
and 7-11 of U.S. Patent No. 11,104,715 B2 OR claims 1 and 7-9 of U.S. Patent No.
11,535,663 B2 OR claims 1 and 7-11 of U.S Patent No. 11,472,861 B2 in view of USP
7,807,164 B2.
" Claims 4 and 5 over claims 1 and 9 of copending Application No. 18/638,362 in view of
USP 7,807,164 B2.
"  Claims 10-12, 17-19, and 25-27 over any of the previously applied U.S. Patent Nos.
11,958,894 or 11,753,459 or 11,505,593 or 11,732,025 or 11,104,715 or 11,535,663 or
11,472,861 as found above in view of Chun et al. (Bioresource Technology 98:1000- 1005, published 2007).
"  Claims 10-12, 17-19, and 25-27 over claims 1 and 9 of copending Application No.
18/638,362 in view of Chun et al.
In response to the above rejection, Applicant respectfully submits that a terminal disclaimer has been filed in compliance with 37 CFR 1.321(c). As a result, the non-statutory double patenting rejections are overcome and withdrawal is respectfully requested.
In view of the foregoing, Applicant respectfully submits that the present application is in condition for allowance and early notice thereof is earnestly solicited. If any issues remain, the Examiner is requested to call the undersigned at (212) 715-9488.
It is believed that no fees are due in connection with this submission. However, the
Commissioner is hereby authorized to charge any fees due or credit any overpayment to Deposit Account No.
Respectfully submitted, Date: January 24, 2025

NEXT OFFICE ACTION: 0025ALLOWANCE
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 .
Status of the Application
The claims and remarks of 24 January 2025 are entered.
Claims 1-30 are pending and are being examined on the merits.
The Terminal Disclaimers of 24 January and 13 February 2025 are entered.
The rejections for nonstatutory double patenting are withdrawn in light of the TDs filed on 24 January and 13 February 2025.
Allowable Subject Matter
Claims 1-30 are allowed.
The following is an examiner’s statement of reasons for allowance: The prior art does not recognize oxo-aflibercept compositions where an oxidized phenylalanine and/or tyrosine residue is present. US 2012/0010025 discloses oxidation of aflibercept at methionine residues but is silent on phenylalanine and/or tyrosine residues. US 2018/0326126 A1 and WO 2020/229584 A1 explicitly investigate oxidation events in aflibercept and never observe phenylalanine or tryptophan oxidation. The skilled artisan would conclude from the prior art that aflibercept containing oxidized phenylalanine and/or tryptophan residues did not exist nor was it suggested by the prior art. Therefore, the claimed oxo-aflibercept is novel and unobvious.
Any comments considered necessary by applicant must be submitted no later than the payment of the issue fee and, to avoid processing delays, should preferably accompany the issue fee.  Such submissions should be clearly labeled “Comments on Statement of Reasons for Allowance.”
Conclusion

CITED REFERENCE SUMMARIES: Ref US11958894B2: Claims:
What is claimed is: 1. An oxo-aflibercept composition produced in a cell culture media comprising a cell culture media wherein chemically defined media (CDM) is added to cell culture media and wherein one or more tryptophan amino acid residues of aflibercept is oxidized. 2. The oxo-aflibercept of claim 1, wherein said oxo-aflibercept has a glycosylation profile based on molar percentage selected from the group consisting of about 40% to about 50% total fucosylated glycans, about 30% to about 55% total sialylated glycans, about 2% to about 15% mannose-5, and about 60% to about 79% galactosylated glycans. 3. The oxo-aflibercept composition of claim 2, wherein said oxo-aflibercept has about 51.4% to about 52.4% total fucosylated glycans. 4. The oxo-aflibercept composition of claim 2, wherein said oxo-aflibercept has about 58.2% to about 59.2% total sialylated glycans. 5. The oxo-aflibercept composition of claim 2, wherein said oxo-aflibercept has about 5.19% to about 5.24% mannose-5. 6. The oxo-aflibercept composition of claim 2, wherein said oxo-aflibercept has about 79.6% to about 80.6% galactosylated glycans. 7. The oxo-aflibercept composition of claim 1, wherein said oxo-aflibercept is glycosylated at one or more Asparagines as follows: GO-G1cNAc glycosylation; G1-G1cNAc glycosylation; G1S-G1cNAc glycosylation; GO glycosylation; G1 glycosylation; GIS glycosylation; G2 glycosylation; G2S glycosylation; G2S2 glycosylation; GOF glycosylation; G2F2S glycosylation; G2F2S2 glycosylation; G1F glycosylation; G1FS glycosylation; G2F glycosylation; G2FS glycosylation; G2FS2 glycosylation; G3FS glycosylation; G3FS3 glycosylation; GO-2G1cNAc glycosylation; Man4 glycosylation; Man4 A1 G1 glycosylation; Man4 A1 G1S1 glycosylation; ManS glycosylation; Man5 A1 G1 glycosylation; Man5 A1 G1S1 glycosylation; Man6 glycosylation; Man6 GO+Phosphate glycosylation; Man6+Phosphate glycosylation; and/or Man7 glycosylation. 8. An oxo-aflibercept composition produced in a cell culture media comprising a cell culture media wherein chemically defined media (CDM) is added to cell culture media and wherein one or more amino acid residues of aflibercept is oxidized and wherein said one or more amino acid residues is histidine and/or tryptophan. 9. The oxo-aflibercept composition of claim 8, wherein N-glycosylation of the F(ab′)2 portion of said oxo-aflibercept at Asn36 is between 98.3% and 99.4%. 10. The oxo-aflibercept composition of claim 8, wherein N-glycosylation of the F(ab′)2 portion of said oxo-aflibercept at Asn68 is between 51.9% and 64.9%. 11. The oxo-aflibercept composition of claim 8, wherein N-glycosylation of the F(ab′)2 portion of said oxo-aflibercept at Asn123 is between 98.4% and 99.9%. 12. The oxo-aflibercept composition of claim 11, wherein N-glycosylation of the F(ab′)2 portion of said oxo-aflibercept at Asn196 is between 55.1% and 98.6%. 13. A prefilled syringe comprising aflibercept produced in a cell culture media wherein chemically defined media (CDM) is added to cell culture media and wherein said aflibercept includes oxidized variants that have at least one oxidized amino acid residue selected from the group consisting of His86, His110, His145, His209, His95, His19, His203, Trp58, Trp138 and a combination thereof. 14. The prefilled syringe of claim 13, wherein said aflibercept in said prefilled syringe has about 40% to about 50% total fucosylated glycans. 15. The prefilled syringe of claim 13, wherein said aflibercept in said prefilled syringe has about 30% to about 55% total sialylated glycans. 16. The prefilled syringe of claim 13, wherein said aflibercept in said prefilled syringe has about 2% to about 15% mannose-5. 17. The prefilled syringe of claim 13, wherein said aflibercept in said prefilled syringe has about 60% to about 79% galactosylated glycans. 18. The prefilled syringe of claim 16, wherein said aflibercept in said prefilled syringe has a b* value between 0.5 and 5, when the concentration of said aflibercept is normalized to 5.0 g/L. 19. The prefilled syringe of claim 17, wherein said aflibercept in said prefilled syringe has a BY value of at least 6 when the concentration of aflibercept is normalized to 5 g/L protein concentration. 20. The prefilled syringe of claim 16, wherein said aflibercept in said prefilled syringe has between 0.1% and 1% oxidized amino acid residue selected from the group consisting of His86, His110, His145, His209, His95, His19, His203, Trp58, Trp138 and a combination thereof. 21. The prefilled syringe of claim 13, wherein said aflibercept in said prefilled syringe has between 0.2% and 1% oxidized amino acid residue selected from the group consisting of His86, His110, His145, His209, His95, His19, His203, Trp58, Trp138 and a combination thereof. 22. The prefilled syringe of claim 17, wherein said aflibercept loaded into said prefilled syringe is formulated with (a) 40 to 250 mg/ml of aflibercept (b) a pH between 5.5 and 7.5, and (c) one or more pharmaceutically acceptable excipients selected from the group of buffering agents, preservatives, detergents and combinations thereof. 23. The prefilled syringe of claim 17, wherein said one or more pharmaceutically acceptable excipients includes 5-40 mM of a buffer. 24. The prefilled syringe of claim 21, further comprising 0.01% to 5.0% of an organic co-solvent. 25. The prefilled syringe of claim 21, further comprising 30 mM to 150 mM of a tonicity agent. 26. The prefilled syringe of claim 20, wherein 90% of said aflibercept or more by weight is not present as an aggregate. 27. The prefilled syringe of claim 22, wherein said prefilled syringe is glass. 28. The prefilled syringe of claim 22, wherein said prefilled syringe is an auto injector. 29. The prefilled syringe of claim 13, wherein said aflibercept is glycosylated at one or more Asparagines as follows: GO-G1cNAc glycosylation; G1-G1cNAc glycosylation; G1S-G1cNAc glycosylation; GO glycosylation; G1 glycosylation; G15 glycosylation; G2 glycosylation; G2S glycosylation; G2S2 glycosylation; GOF glycosylation; G2F2S glycosylation; G2F2S2 glycosylation; G1F glycosylation; G1FS glycosylation; G2F glycosylation; G2FS glycosylation; G2FS2 glycosylation; G3FS glycosylation; G3FS3 glycosylation; GO-2G1cNAc glycosylation; Man4 glycosylation; Man4 A1G1 glycosylation; Man4 A1 G151 glycosylation; ManS glycosylation; Man5 A1 G1 glycosylation; Man5 A1 G151 glycosylation; Man6 glycosylation; Man6 GO+Phosphate glycosylation; Man6+Phosphate glycosylation; and/or Man7 glycosylation. 30. The prefilled syringe of claim 13, wherein said aflibercept has a glycosylation profile based on molar percentage selected from the group consisting of about 40% to about 50% total fucosylated glycans, about 30% to about 55% total sialylated glycans, about 2% to about 15% mannose-5, and about 60% to about 79% galactosylated glycans.
An oxo-aflibercept composition produced in a cell culture media comprising a cell culture media wherein chemically defined media (CDM) is added to cell culture media and wherein one or more tryptophan amino acid residues of aflibercept is oxidized.
The oxo-aflibercept of claim 1, wherein said oxo-aflibercept has a glycosylation profile based on molar percentage selected from the group consisting of about 40% to about 50% total fucosylated glycans, about 30% to about 55% total sialylated glycans, about 2% to about 15% mannose-5, and about 60% to about 79% galactosylated glycans.
The oxo-aflibercept composition of claim 2, wherein said oxo-aflibercept has about 51.4% to about 52.4% total fucosylated glycans.
The oxo-aflibercept composition of claim 2, wherein said oxo-aflibercept has about 58.2% to about 59.2% total sialylated glycans.
The oxo-aflibercept composition of claim 2, wherein said oxo-aflibercept has about 5.19% to about 5.24% mannose-5.
The oxo-aflibercept composition of claim 2, wherein said oxo-aflibercept has about 79.6% to about 80.6% galactosylated glycans.
The oxo-aflibercept composition of claim 1, wherein said oxo-aflibercept is glycosylated at one or more Asparagines as follows: GO-G1cNAc glycosylation; G1-G1cNAc glycosylation; G1S-G1cNAc glycosylation; GO glycosylation; G1 glycosylation; GIS glycosylation; G2 glycosylation; G2S glycosylation; G2S2 glycosylation; GOF glycosylation; G2F2S glycosylation; G2F2S2 glycosylation; G1F glycosylation; G1FS glycosylation; G2F glycosylation; G2FS glycosylation; G2FS2 glycosylation; G3FS glycosylation; G3FS3 glycosylation; GO-2G1cNAc glycosylation; Man4 glycosylation; Man4 A1 G1 glycosylation; Man4 A1 G1S1 glycosylation; ManS glycosylation; Man5 A1 G1 glycosylation; Man5 A1 G1S1 glycosylation; Man6 glycosylation; Man6 GO+Phosphate glycosylation; Man6+Phosphate glycosylation; and/or Man7 glycosylation.
An oxo-aflibercept composition produced in a cell culture media comprising a cell culture media wherein chemically defined media (CDM) is added to cell culture media and wherein one or more amino acid residues of aflibercept is oxidized and wherein said one or more amino acid residues is histidine and/or tryptophan.
The oxo-aflibercept composition of claim 8, wherein N-glycosylation of the F(ab′)2 portion of said oxo-aflibercept at Asn36 is between 98.3% and 99.4%.
The oxo-aflibercept composition of claim 8, wherein N-glycosylation of the F(ab′)2 portion of said oxo-aflibercept at Asn68 is between 51.9% and 64.9%.
The oxo-aflibercept composition of claim 8, wherein N-glycosylation of the F(ab′)2 portion of said oxo-aflibercept at Asn123 is between 98.4% and 99.9%.
The oxo-aflibercept composition of claim 11, wherein N-glycosylation of the F(ab′)2 portion of said oxo-aflibercept at Asn196 is between 55.1% and 98.6%.
A prefilled syringe comprising aflibercept produced in a cell culture media wherein chemically defined media (CDM) is added to cell culture media and wherein said aflibercept includes oxidized variants that have at least one oxidized amino acid residue selected from the group consisting of His86, His110, His145, His209, His95, His19, His203, Trp58, Trp138 and a combination thereof.
The prefilled syringe of claim 13, wherein said aflibercept in said prefilled syringe has about 40% to about 50% total fucosylated glycans.
The prefilled syringe of claim 13, wherein said aflibercept in said prefilled syringe has about 30% to about 55% total sialylated glycans.
The prefilled syringe of claim 13, wherein said aflibercept in said prefilled syringe has about 2% to about 15% mannose-5.
The prefilled syringe of claim 13, wherein said aflibercept in said prefilled syringe has about 60% to about 79% galactosylated glycans.
The prefilled syringe of claim 16, wherein said aflibercept in said prefilled syringe has a b* value between 0.5 and 5, when the concentration of said aflibercept is normalized to 5.0 g/L.
The prefilled syringe of claim 17, wherein said aflibercept in said prefilled syringe has a BY value of at least 6 when the concentration of aflibercept is normalized to 5 g/L protein concentration.
The prefilled syringe of claim 16, wherein said aflibercept in said prefilled syringe has between 0.1% and 1% oxidized amino acid residue selected from the group consisting of His86, His110, His145, His209, His95, His19, His203, Trp58, Trp138 and a combination thereof.
The prefilled syringe of claim 13, wherein said aflibercept in said prefilled syringe has between 0.2% and 1% oxidized amino acid residue selected from the group consisting of His86, His110, His145, His209, His95, His19, His203, Trp58, Trp138 and a combination thereof.
The prefilled syringe of claim 17, wherein said aflibercept loaded into said prefilled syringe is formulated with (a) 40 to 250 mg/ml of aflibercept (b) a pH between 5.5 and 7.5, and (c) one or more pharmaceutically acceptable excipients selected from the group of buffering agents, preservatives, detergents and combinations thereof.
The prefilled syringe of claim 17, wherein said one or more pharmaceutically acceptable excipients includes 5-40 mM of a buffer.
The prefilled syringe of claim 21, further comprising 0.01% to 5.0% of an organic co-solvent.
The prefilled syringe of claim 21, further comprising 30 mM to 150 mM of a tonicity agent.
The prefilled syringe of claim 20, wherein 90% of said aflibercept or more by weight is not present as an aggregate.
The prefilled syringe of claim 22, wherein said prefilled syringe is glass.
The prefilled syringe of claim 22, wherein said prefilled syringe is an auto injector.
The prefilled syringe of claim 13, wherein said aflibercept is glycosylated at one or more Asparagines as follows: GO-G1cNAc glycosylation; G1-G1cNAc glycosylation; G1S-G1cNAc glycosylation; GO glycosylation; G1 glycosylation; G15 glycosylation; G2 glycosylation; G2S glycosylation; G2S2 glycosylation; GOF glycosylation; G2F2S glycosylation; G2F2S2 glycosylation; G1F glycosylation; G1FS glycosylation; G2F glycosylation; G2FS glycosylation; G2FS2 glycosylation; G3FS glycosylation; G3FS3 glycosylation; GO-2G1cNAc glycosylation; Man4 glycosylation; Man4 A1G1 glycosylation; Man4 A1 G151 glycosylation; ManS glycosylation; Man5 A1 G1 glycosylation; Man5 A1 G151 glycosylation; Man6 glycosylation; Man6 GO+Phosphate glycosylation; Man6+Phosphate glycosylation; and/or Man7 glycosylation.
The prefilled syringe of claim 13, wherein said aflibercept has a glycosylation profile based on molar percentage selected from the group consisting of about 40% to about 50% total fucosylated glycans, about 30% to about 55% total sialylated glycans, about 2% to about 15% mannose-5, and about 60% to about 79% galactosylated glycans.
Ref US12012444B2: Claims:
What is claimed is: 1. A culture media composition comprising chemically defined media (CDM) and aflibercept, wherein said aflibercept includes about 0.02% to about 1% oxidized aflibercept and wherein said oxidized aflibercept is oxidized at one or more amino acid residues selected from the group consisting of tryptophan, histidine and a combination thereof. 2. The culture media composition of claim 1, wherein said aflibercept includes between about 0.02% and about 0.5% oxidized aflibercept. 3. The culture media composition of claim 1, wherein said oxidized aflibercept includes His19 residue oxidation. 4. The culture media composition of claim 3, wherein a relative abundance of the oxidized His19 residue is at least about 0.02%. 5. The culture media composition of claim 1, wherein said oxidized aflibercept includes His86 residue oxidation. 6. The culture media composition of claim 5, wherein a relative abundance of the oxidized His86 residue is at least about 0.02%. 7. The culture media composition of claim 1, wherein said oxidized aflibercept includes His95 residue oxidation. 8. The culture media composition of claim 7, wherein a relative abundance of the oxidized His95 residue is at least about 0.03%. 9. The culture media composition of claim 1, wherein said oxidized aflibercept includes His110 residue oxidation. 10. The culture media composition of claim 9, wherein a relative abundance of the oxidized His110 residue is at least about 0.04%. 11. The culture media composition of claim 1, wherein said oxidized aflibercept includes His145 residue oxidation. 12. The culture media composition of claim 11, wherein a relative abundance of the oxidized His145 residue is at least about 0.19%. 13. The culture media composition of claim 1, wherein said oxidized aflibercept includes His203 residue oxidation. 14. The culture media composition of claim 1, wherein said oxidized aflibercept includes His209 residue oxidation. 15. The culture media composition of claim 14, wherein a relative abundance of the oxidized His209 residue is at least about 0.11%. 16. The culture media composition of claim 1, wherein said oxidized aflibercept includes Trp58 residue oxidation. 17. The culture media composition of claim 16, wherein a relative abundance of the oxidized Trp58 residue is at least about 0.03%. 18. The culture media composition of claim 1, wherein said oxidized aflibercept includes Trp138 residue oxidation. 19. The culture media composition of claim 18, wherein a relative abundance of the oxidized Trp138 residue is at least about 0.02%.
A culture media composition comprising chemically defined media (CDM) and aflibercept, wherein said aflibercept includes about 0.02% to about 1% oxidized aflibercept and wherein said oxidized aflibercept is oxidized at one or more amino acid residues selected from the group consisting of tryptophan, histidine and a combination thereof.
The culture media composition of claim 1, wherein said aflibercept includes between about 0.02% and about 0.5% oxidized aflibercept.
The culture media composition of claim 1, wherein said oxidized aflibercept includes His19 residue oxidation.
The culture media composition of claim 3, wherein a relative abundance of the oxidized His19 residue is at least about 0.02%.
The culture media composition of claim 1, wherein said oxidized aflibercept includes His86 residue oxidation.
The culture media composition of claim 5, wherein a relative abundance of the oxidized His86 residue is at least about 0.02%.
The culture media composition of claim 1, wherein said oxidized aflibercept includes His95 residue oxidation.
The culture media composition of claim 7, wherein a relative abundance of the oxidized His95 residue is at least about 0.03%.
The culture media composition of claim 1, wherein said oxidized aflibercept includes His110 residue oxidation.
The culture media composition of claim 9, wherein a relative abundance of the oxidized His110 residue is at least about 0.04%.
The culture media composition of claim 1, wherein said oxidized aflibercept includes His145 residue oxidation.
The culture media composition of claim 11, wherein a relative abundance of the oxidized His145 residue is at least about 0.19%.
The culture media composition of claim 1, wherein said oxidized aflibercept includes His203 residue oxidation.
The culture media composition of claim 1, wherein said oxidized aflibercept includes His209 residue oxidation.
The culture media composition of claim 14, wherein a relative abundance of the oxidized His209 residue is at least about 0.11%.
The culture media composition of claim 1, wherein said oxidized aflibercept includes Trp58 residue oxidation.
The culture media composition of claim 16, wherein a relative abundance of the oxidized Trp58 residue is at least about 0.03%.
The culture media composition of claim 1, wherein said oxidized aflibercept includes Trp138 residue oxidation.
The culture media composition of claim 18, wherein a relative abundance of the oxidized Trp138 residue is at least about 0.02%.
Ref US11753459B2: Claims:
What is claimed is: 1. An oxo-aflibercept composition produced in a cell culture media comprising a chemically defined media (CDM), wherein one or more amino acid residues of aflibercept is oxidized and wherein said one or more amino acid residues is histidine and/or tryptophan, and wherein said oxo-aflibercept has a glycosylation profile based on molar percentage selected from the group consisting of about 40% to about 50% total fucosylated glycans, about 30% to about 55% total sialylated glycans, about 2% to about 15% mannose-5, and about 60% to about 79% galactosylated glycans. 2. The oxo-aflibercept composition of claim 1, wherein said oxo-aflibercept has about 40% to about 50% total fucosylated glycans. 3. The oxo-aflibercept composition of claim 1, wherein said oxo-aflibercept has about 30% to about 55% total sialylated glycans. 4. The oxo-aflibercept composition of claim 1, wherein said oxo-aflibercept has about 2% to about 15% mannose-5. 5. The oxo-aflibercept composition of claim 1, wherein said oxo-aflibercept has about 60% to about 79% galactosylated glycans. 6. The oxo-aflibercept composition of claim 1, wherein said oxo-aflibercept is glycosylated at one or more Asparagines as follows: G0-GlcNAc glycosylation; G1-GlcNAc glycosylation; G1S-GlcNAc glycosylation
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