Office Action 2: Notice of Allowance (2025-03-10)

CLAIMS:
Listing of Claims:

The following claim amendments will replace all prior versions in this application.

What is claimed is:

1\. (Original) 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\. (Original) 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\. (Original) The composition of claim 1, further comprising a pharmaceutically acceptable carrier.

4\. (Original) The composition of claim 3, wherein said oxo-aflibercept is freeze-dried.

5\. (Original) The composition of claim 4, wherein said composition is sterile.

6\. (Original) 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\. (Original) The composition of claim 6, wherein said enzymatic digestion is performed using trypsin.

8\. (Original) 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 aflibercept is oxidized and wherein said one or more amino acid residues is phenylalanine and/or tyrosine.

9\. (Original) 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\. (Original) The oxo-aflibercept composition of claim 9, wherein soy hydrolysate media is added to said cell culture media.

11\. (Original) The oxo-aflibercept composition of claim 8, wherein components derived from soy hydrolysate are added to said cell culture media.

12\. (Original) The oxo-aflibercept composition of claim 8, wherein plant or animal-derived components are added to said cell culture media.

13\. (Original) The composition of claim 8, 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.

14\. (Original) The composition of claim 13, wherein said enzymatic digestion is performed using trypsin.

15\. (Original) 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\. (Original) 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\. (Original) The oxo-aflibercept composition of claim 16, wherein said cell culture media is supplemented with soy hydrolysate media.

18\. (Original) The oxo-aflibercept composition of claim 15, wherein components derived from soy hydrolysate are added to said cell culture media.

19\. (Original) The oxo-aflibercept composition of claim 15, wherein plant or animal-derived components are added to cell culture media.

20\. (Original) The 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\. (Original) The composition of claim 20, wherein said enzymatic digestion is performed using trypsin.

22\. (Original) The composition of claim 15, further comprising a pharmaceutically acceptable carrier.

23\. (Original) 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\. (Original) 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\. (Original) The oxo-aflibercept composition of claim 23, wherein said cell culture media is supplemented with soy hydrolysate media.

26\. (Original) The oxo-aflibercept composition of claim 23, wherein components derived from soy hydrolysate are added to said cell culture media.

27\. (Original) The oxo-aflibercept composition of claim 23, wherein plant or animal-derived :omponents are added to cell culture media.

28\. (Original) The composition of claim 23, wherein said oxo-aflibercept is enzymatically ligested resulting in one or more oligopeptides, and wherein said one or more oligopeptides s selected from the group consisting of: SEQ ID NO. 69, SEQ ID NO. 70, SEQ ID NO. 32 ind combinations thereof.

29\. (Original) The composition of claim 28, wherein said enzymatic digestion is performed using trypsin.

30\. (Original) The composition of claim 23, further comprising a pharmaceutically acceptable :arrier.

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

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


CITED REFERENCE SUMMARIES: Ref US20120010025A1: [content unavailable]
Ref US20180326126A1: Claims:
A pre-filled syringe containing a liquid formulation of a VEGF antagonist and comprising a syringe barrel, wherein the syringe barrel is made of plastic and is silicone-free, and further comprising a non-retractable stopper.
A pre-filled syringe containing a liquid formulation of a VEGF antagonist and comprising a syringe barrel, wherein the syringe barrel is made of plastic, is silicone-free, and has a length of 45 mm to 65 mm.
The pre-filled syringe according to claim 1 , wherein the VEGF antagonist is an anti-VEGF antibody or an antigen-binding fragment of such antibody or a VEGF receptor fusion protein.
The pre-filled syringe according to claim 3 , anti-VEGF antagonist is ranibizumab or aflibercept.
The pre-filled syringe according to claim 1 , wherein the antagonist concentration is 1 to 100 mg/ml.
The pre-filled syringe according to claim 1 , containing less than 50 particles per ml of the liquid formulation having a diameter of 10 Î¼m or greater.
The pre-filled syringe according to claim 1 , containing less than 5 particles per ml of the liquid formulation having a diameter of 25 Î¼m or greater.
The pre-filled syringe according to claim 1 , having a sliding force of less than or equal to 10N.
The pre-filled syringe according to claim 1 , further comprising a silicone-free stopper.
The pre-filled syringe according to claim 1 , wherein the syringe barrel is made of cycloolefin polymer or cycloolefin copolymer.
The pre-filled syringe according to claim 1 , wherein the syringe barrel comprises an internal coating other than a silicone coating.
The pre-filled syringe according to claim 1 , comprising a staked needle.
A kit comprising one or more pre-filled syringes of claim 1 .
The pre-filled syringe according to claim 1 for use in administering a liquid formulation of a VEGF antagonist to a patient having an ocular disease.
The pre-filled syringe for the use according to claim 13 , wherein the ocular disease is selected from the group consisting of age-related macular degeneration (AMD), visual impairment due to diabetic macular oedema (DME), visual impairment due to macular oedema secondary to retinal vein occlusion (branch RVO or central RVO), diabetic retinopathy in patients with diabetic macular edema, or visual impairment due to choroidal neovascularisation (CNV) secondary to pathologic myopia.
The pre-filled syringe for the use according to claim 14 or 15 , wherein a volume of 30 to 100 Î¼l of the liquid formulation is administered to the patient.
Ref WO2020229584A1: Claims:
Method for reducing the percentage of oxidized methionine residues in a recombinant protein, said method comprising culturing cells expressing said recombinant protein in a suitable cell culture medium and feeding the cells with glutamine.
Method according to claim 1, comprising feeding the cells with 0.2 mM to 5 mM glutamine.
Method according to claim 1 or 2, comprising feeding the cells with 0.5 mM to 4 mM glutamine on day 3 to 5 of the culture.
Method according to any one of the preceding claims, comprising feeding the cells with 0.2 mM to 2 mM glutamine on day 6 to 12 of the culture.
Method according to any one of the preceding claims, further comprising feeding the cells with methionine.
Method according to claim 5, comprising feeding the cells with 250 to 1000 mg/1 methionine.
Method according to any one of the preceding claims, further comprising reducing the culture temperature.
Method according to claim 7, wherein the culture temperature is reduced from 37Â°C to a temperature within the range of 30Â°C to 35Â°C.
Method according to claim 7 or 8, wherein the temperature is reduced in a first step from a first temperature of 37Â°C to a second temperature within the range of 33Â°C to 35Â°C and in a second step from the second temperature of 33Â°C to 35Â°C to a third temperature within the range of 31Â°C to 33Â°C.
Method according to any one of the preceding claims, wherein the recombinant protein is a recombinant antibody or a fusion protein of a receptor and the Fc portion of an immunoglobulin.
Method according to any one of the preceding claims, wherein the recombinant protein is aflibercept.
Method according to any one of the preceding claims, wherein the cells are CHO cells.
Use of glutamine for reducing the percentage of oxidized methionine residues in a composition comprising a recombinant protein.
Method for producing a recombinant protein, comprising
(a) culturing cells expressing the recombinant protein in a suitable cell culture medium;
(b) feeding the cells with glutamine, wherein the cells are fed with 0.5 mM to 4 mM glutamine on day 3 to 5 of the culture and with 0.2 mM to 2 mM glutamine on day 6 to 12 of the culture; and
(c) obtaining the recombinant protein.
Method for producing aflibercept, comprising:
(a) culturing cells expressing aflibercept in a suitable cell culture medium;
(b) feeding the cells with glutamine; and
(c) obtaining the aflibercept.
Ref US20120010025: Claims:
1. A golf ball comprising:
a core; and a cover layer substantially surrounding the core; the cover layer including
a plurality of dimples thereon, and at least one land area separating the dimples;
a total surface area;
a first portion, the first portion of the cover layer having a first hardness;
a second portion, the second portion of the cover layer having a second hardness, the second hardness being different from the first hardness;
 wherein the first portion consists of multiple non-contiguous zones each surrounded by the second portion; and wherein the first portion encompasses at least 20% of the total surface area of the cover layer; and the first portion encompasses at most 60% of the total surface area of the cover layer.
2. The golf ball according to claim 1, wherein each zone comprising the first portion has a perimeter shape, and the perimeter shape is selected from the group consisting of a circle, a triangle, a rectangle, a polygon having five or more sides, a graphic, and a logo.
3. The golf ball according to claim 1, wherein each zone comprising the first portion has a cross sectional shape, and the cross sectional shape is selected from the group consisting of a triangle, a hemisphere, a rectangle, and an incrementally stepped triangle.
4. The golf ball according to claim 1, wherein each of the multiple zones is associated with one of the plurality of dimples.
5. The golf ball according to claim 4, wherein the first portion of the cover layer includes all of the plurality of dimples thereon, and the second portion of the cover layer includes an entirety of all of the land area(s) thereon.
6. The golf ball according to claim 1, wherein the first portion encompasses at least 30% of the total surface area of the cover layer.
7. The golf ball according to claim 1, wherein the first portion encompasses at most 50% of the total surface area of the cover layer.
8. The golf ball according to claim 1, wherein the first hardness is harder than the second hardness.
9. The golf ball according to claim 1, wherein the first hardness is at least about 5 units on the Shore D scale different from the second hardness.
10. The golf ball according to claim 1, wherein the first hardness and second hardness are each from 30 to 75 on the Shore D scale.
11. The golf ball according to claim 1, wherein the zones are sized and arranged on the cover layer such that the golf ball is spherically symmetric.
12. The golf ball according to claim 1, wherein the first portion and the second portion consist of different materials.
13. A golf ball comprising:
a core; and a cover layer substantially surrounding the core; the cover layer including
a plurality of dimples thereon, and at least one land area separating the dimples;
a total surface area;
a first portion, the first portion of the cover layer having a first hardness;
a second portion, the second portion of the cover layer having a second hardness, the second hardness being at least 5 units on the Shore D scale different from the first hardness;
 wherein the first portion consists of multiple non-contiguous zones each surrounded by the second portion, and each of the multiple zones is associated with one of the plurality of dimples; and wherein the first portion encompasses at least 30% of the total surface area of the cover layer; and the first portion encompasses at most 50% of the total surface area of the cover layer.
14. The golf ball according to claim 13, wherein the first portion is harder than the second portion.
15. The golf ball according to claim 13, wherein the second portion is harder than the first portion.
16. The golf ball according to claim 13, wherein the first portion of the cover layer includes all of the plurality of dimples thereon, and the second portion of the cover layer includes an entirety of all of the land area(s) thereon.
17. The golf ball according to claim 13, wherein the zones are sized and arranged on the cover layer such that the golf ball is spherically symmetric.
18. The golf ball according to claim 13, wherein the first portion and the second portion consist of different materials.
19. A method of manufacturing a golf ball, the method comprising the steps of:
(1) receiving a golf ball having a core and a pre-cover layer substantially surrounding the core, the pre-cover layer being formed of a first material and having multiple non-contiguous depressions arranged in a pattern corresponding to a desired pattern of zones; (2) molding a second material on top of the pre-cover layer, such that the second material substantially surrounds the pre-cover layer and fills the depressions; (3) grinding the second material away, such that the second material overlaps the pre-cover layer only in the depressions, thereby forming a cover layer having multiple zones of second material; wherein the first material has a first hardness, the second material has a second hardness, the second hardness being different from the first hardness; and wherein the multiple zones of second material encompass at least 20% of a total surface area of the cover layer; and the multiple zones of second material encompass at most 60% of the total surface area of the cover layer.
20. The method of claim 19, wherein the cover layer includes a plurality of dimples thereon, and each of the multiple zones is associated with one of the plurality of dimples.