Office Action 2: Notice of Allowance (2024-09-09)

CLAIMS:
AMENDMENTS TO THE CLAIMS

Please amend the claims as follows. This listing of claims will replace all prior versions and listings of claims in the application.

1\. (Currently Amended) A pharmaceutical formulation comprising:
16-22 mg/mL of an anti-LAG3 antibody ; 3-7 mg/mL of an anti-PD-1 antibod; about 30-120 mg/mL of a non- reducing disaccharide; about 0.02-2.0 mg/mL polysorbate 80 or polysorbate 20; a buffer that maintains the pH of the pharmaceutical formulation at \[\[pH\]\] about \[\[4.5\]\]5\_0- 6.5; and about 40- 150 mM L-arginine or a pharmaceutically acceptable salt thereof, wherein the anti-LAG3 antibody comprises a variable light chain region comprising CDRL1 of SEQ ID NO: 39, CDRL2 of SEQ ID NO: 40, and CDRL3 of SEQ ID NO: 41, and a variable heavy chain region comprising CDRH1 of SEQ ID NO: 42, CDRH2 of SEQ ID NO: 59, and CDRH3 of SEQ ID NO: 44, and the anti-PD-1 antibody comprises a variable light chain region comprising CDRL1 of SEQ ID NO: 1, CDRL2 of SEQ ID NO: 2, and CDRL3 of SEQ ID NO: 3, and a variable heavy chain region comprising CDRH1 of SEQ ID NO: 6, CDRH2 of SEQ ID NO: 7, and CDRH3 of SEQ ID NO: 8; wherein the molar ratio of the anti-LAG3 antibody to anti-PD-1 antibody is 4:1.

2\. (Currently Amended) The pharmaceutical formulation of claim 1 comprising 18- 22 mg/mL of the anti-LAG3 antibody; 4-7 mg/mL of the anti-PD-1 antibody; about 50-90 mg/mL sucrose or trehalose; about 0.05-1.0 mg/mL polysorbate 80 or polysorbate 20; about 3-30 mM histidine buffer that maintains the pH of the pharmaceutical formulation at \[\[pH\]\] about 5.0 - 6.5; and about 40-100 mM L-arginine or a pharmaceutically acceptable salt thereof.

3\. (Currently Amended) The pharmaceutical formulation of claim 1 comprising 18- 20 mg/mL of the anti-LAG3 antibody; 4-7 mg/mL of the anti-PD-1 antibody; about 50-60 mg/mL sucrose or trehalose; about 0.05-1.0 mg/mL polysorbate 80 or polysorbate 20; about 8-12 mM histidine buffer that maintains the pH of the pharmaceutical formulation at \[\[pH\]\] about 5.0 - 6.5; and about 40-70 mM L-arginine or a pharmaceutically acceptable salt thereof.

4\. (Original) The formulation of any one of claims 1 to 3, further comprising about 5-15 mM L-methionine.

5\. (Previously presented) The formulation of claim 2, further comprising about 5-10 mM L-methionine.

6\. Cancelled.

7\. (Currently Amended) \[\[The\]\] A pharmaceutical formulation comprising about 20 mg/mL of the anti-LAG3 antibody; about 5 mg/mL of the anti-PD-1 antibody; about 54 mg/mL sucrose; about 0.2 mg/mL polysorbate 80; about 10 mM histidine buffer that maintains the pH of the pharmaceutical formulation at \[\[pH\]\] about 5.8; and about 56 mM L-arginine or a pharmaceutically acceptable salt thereof; and further comprising about 8 mM L-methionine.

8\. Cancelled.

9\. (Currently Amended) \[\[The\]\]A pharmaceutical formulation comprising about 18.02 mg/mL of the anti-LAG3 antibody; about 4.505 mg/mL of the anti-PD-1 antibody;
about 50 mg/mL sucrose; about 0.2 mg/mL polysorbate 80; about 10 mM histidine buffer that maintains the pH of the pharmaceutical formulation at \[\[pH\]\] about 5.8; and about 70 mM L- arginine or a pharmaceutically acceptable salt thereof; and further comprising about 10 mM L- methionine.

10\. (Currently Amended) A pharmaceutical formulation comprising: about 18-22 mg/mL of an anti-LAG3 antibody and about 3-7 mg/mL of an anti-PD-1 antibody at a molar ratio of 4:1 anti-LAG3 antibody to anti-PD-1 antibody, an excipient selected from istidine, aspartate, glutamine, glycine, proline,

methionine, arginine or a pharmaceutically acceptable salt thereof, NaCI, and KCl, or a combination thereof, at a total excipient concentration of about 25-250 mM, and a buffer that maintains the pH of the pharmaceutical formulation at \[\[pH\]\] about 4.5-8, wherein
8the anti-LAG3 antibody comprises a light chain sequence of SEQ ID NO: 35 and a heavy chain sequence of SEQ ID NO: 57, and the anti-PD-1 antibody comprises a heavy chain sequence of SEQ ID NO: 10 and a light chain sequence of SEQ ID NO: 5.

11\. Cancelled.

12\. (Currently Amended) The pharmaceutical formulation of claim 10, wherein the excipient is L-arginine or a pharmaceutically acceptable salt thereof at a concentration of about 25-250 mM.

13\. (Currently Amended) The pharmaceutical formulation of claim 10, wherein the excipient is L-arginine or a pharmaceutically acceptable salt thereof at a concentration of about 40-100 mM.

14\. (Currently Amended) The pharmaceutical formulation of claim 10, wherein the excipient\[\[s are\]\] is NaCl and L-arginine or a pharmaceutically acceptable salt thereof with a total excipient concentration of about 25-250 mM.

15\. (Currently Amended) The pharmaceutical formulation of claim 14, wherein the NaCl to L-arginine concentration ratio is 1:1.

16\. (Currently Amended) The pharmaceutical formulation of claim 15, wherein the NaCI concentration is about 35 mM and the L-arginine concentration is about 35 mM.

17\. (Currently Amended) The pharmaceutical formulation of claim 15, wherein the NaCI concentration is about 50 mM and the L-arginine concentration is about 50 mM.

18-21. Cancelled.1920

22\. (Currently Amended) The pharmaceutical formulation of claim 10, further comprising a non-ionic surfactant that is a polysorbate.

23\. (Currently Amended) The pharmaceutical formulation of claim 22, wherein the non-ionic surfactant is polysorbate 80 or polysorbate 20.

24\. (Currently Amended) The pharmaceutical formulation of claim 10, further comprising a sugar that is a non-reducing disaccharide.

25\. (Currently Amended) The pharmaceutical formulation of claim 24, wherein the sugar is trehalose or sucrose, or a combination thereof.

26\. (Currently Amended) The pharmaceutical formulation of claim 25, wherein the sugar is at a concentration of about 10-200 mg/ml.

27\. (Currently Amended) The pharmaceutical formulation of claim 10, further comprising a polyol selected from the group consisting of mannitol, sorbitol, glycerol and polyethylene glycol.

28\. (Currently Amended) The pharmaceutical formulation of claim 27, wherein the polyol is at a concentration of about 10-200 mg/ml.

29\. (Currently Amended) The pharmaceutical formulation of claim 10, further comprising about 10-250 mg/mL sucrose, trehalose, mannitol, sorbitol, polyethylene glycol or glycerol; about 0.005-2.0 mg/mL polysorbate 80 or polysorbate 20; and wherein the buffer is about 3-300 mM L-histidine, acetate or citrate buffer that maintains the pH of the pharmaceutical formulation at \[\[pH\]\] about 5.0 -6.5.

30\. (Currently Amended) The pharmaceutical formulation of claim \[\[10\]\]12 or 14, further comprising about 30-120 mg/mL sucrose or trehalose\[\[;\]\]and about 0.05-1.5 mg/mL polysorbate 80 or polysorbate 20; and wherein the buffer is about 3-150 mM L-histidine, acetate or citrate buffer that maintains the pH of the pharmaceutical formulation at \[\[pH\]\] about 5.0 -6.5.

31\. (Currently Amended) The pharmaceutical formulation of claim\[\[s\]\] 10, further comprising about 50-90 mg/mL sucrose or trehalose\[\[;\]\]and about 0.05-1.0 mg/mL polysorbate 80; and wherein the buffer is about 5-30 mM L-histidine, acetate or citrate buffer that maintains the pH of the pharmaceutical formulation at \[\[pH\]\] about 5.0 -6.5.

32\. (Currently Amended) The pharmaceutical formulation of claim 10 comprising about 20 mg/mL of the anti-LAG3 antibody ;and further comprising about 50-90 mg/mL sucrose or trehaloseand\[\[;\]\] about 0.05-1.0 mg/mL polysorbate 80 or polysorbate 20; wherein the buffer is about 5-20 mM L-histidine, acetate or citrate buffer that maintains the pH of the pharmaceutical formulation at \[\[pH\]\] about 5.0 - 6.5; and wherein the excipient is about 40-150 mM L-arginine or a pharmaceutically acceptable salt thereof.

33\. (Currently Amended) The pharmaceutical formulation of claim 10 comprising about 20 mg/mL of the anti-LAG3 antibody ; and further comprising about 20-200 mg/mL glycerol, sorbitol or PEG400\_and\[\[;\]\] about 0.05-1.0 mg/mL polysorbate 80 or polysorbate 20; wherein the buffer is about 3-150 mM L-histidine, acetate or citrate buffer that maintains the pH of the pharmaceutical formulation at \[\[pH\]\] about 5.0 - 6.5;

and wherein the excipient is about 40-150 mM L-arginine or a pharmaceutically acceptable salt thereof.

34\. (Currently Amended) The pharmaceutical formulation of claim 10 comprising about 20 mg/mL of the anti-LAG3 antibody ; and further comprising\[\[;\]\] about 0.05- 1.0 mg/mL polysorbate 80 or polysorbate 20; wherein the buffer is about 3-150 mM L-histidine, acetate or citrate buffer that maintains the pH of the pharmaceutical formulation at \[\[pH\]\] about 5.0 - 6.5; and wherein the excipient is about 40-150 mM L-arginine or a pharmaceutically acceptable salt thereofand about 40-100 mM L-glutamine, L-glycine, L-proline or L-methionine.

35\. Cancelled.

36\. (Currently Amended) The pharmaceutical formulation of claim 32, further comprising about 5-15 mM L-methionine.

37\. (Currently Amended) The pharmaceutical formulation of claim 31\[\[ 10\]\], further comprising about 5-\[\[70\]\]15 mM L-methionine.

38\. Cancelled.

39\. (Currently Amended) The pharmaceutical formulation of claim 10 or 37 comprising about 20 mg/mL of the anti-LAG3 antibody ;
further comprising about 50 mg/mL sucroseand\[\[;\]\] about 0.2 mg/mL polysorbate 80; wherein the buffer is about 10 mM L-histidine buffer that maintains the pH of the pharmaceutical formulation at \[\[pH\]\] about 5.8-6.0; and wherein the excipient is about 70 mM L-arginine or L- arginine-HCl.

40\. (Currently Amended) The pharmaceutical formulation of claim 1 that is a liquid formulation.

41\. (Currently Amended) The pharmaceutical formulation of claim 1 that is frozen to at least below -70°C.

42\. (Currently Amended) The pharmaceutical formulation of claim 1 that is a reconstituted solution from a lyophilized formulation.

43-44. Cancelled.

45\. (Currently Amended) The pharmaceutical formulation of claim\[\[s\]\] 1 , wherein the anti-LAG3 antibody comprises: a light chain variable region sequence of SEQ ID NO: 37 and a heavy chain variable region sequence of SEQ ID NO: 58, and the anti-PD-1 antibody comprises a heavy chain variable region of SEQ ID NO: 9 and a light chain variable region of SEQ ID NO: 4.

46\. (Currently Amended) The pharmaceutical formulation of claim 45, wherein the anti-LAG3 antibody comprises a light chain sequence of SEQ ID NO: 35 and a heavy chain sequence of SEQ ID NO: 57, and the anti-PD-1 antibody comprises a heavy chain sequence of SEQ ID NO: 10 and a light chain sequence of SEQ ID NO: 5.

47\. (Currently Amended) The pharmaceutical formulation of claim\[\[s\]\] 1 , wherein the anti-LAG3 antibody is Ab6 variant, and the anti-PD-1 antibody is pembrolizumab or pembrolizumab variant.

48\. Cancelled.

49\. (New) The pharmaceutical formulation of claim 2, wherein the anti-LAG3 antibody comprises a light chain sequence of SEQ ID NO: 35 and a heavy chain sequence of SEQ ID NO: 57, and the anti-PD-1 antibody comprises a heavy chain sequence of SEQ ID NO:
10 and a light chain sequence of SEQ ID NO: 5.

50\. (New) The pharmaceutical formulation of claim 3, wherein the anti-LAG3 antibody comprises a light chain sequence of SEQ ID NO: 35 and a heavy chain sequence of SEQ ID NO: 57, and the anti-PD-1 antibody comprises a heavy chain sequence of SEQ ID NO:
10 and a light chain sequence of SEQ ID NO: 5.

51\. (New) The pharmaceutical formulation of claim 4, wherein the anti-LAG3 antibody comprises a light chain sequence of SEQ ID NO: 35 and a heavy chain sequence of SEQ ID NO: 57, and the anti-PD-1 antibody comprises a heavy chain sequence of SEQ ID NO:
10 and a light chain sequence of SEQ ID NO: 5.

52\. (New) The pharmaceutical formulation of claim 5, wherein the anti-LAG3 antibody comprises a light chain sequence of SEQ ID NO: 35 and a heavy chain sequence of SEQ ID NO: 57, and the anti-PD-1 antibody comprises a heavy chain sequence of SEQ ID NO:
10 and a light chain sequence of SEQ ID NO: 5.

53\. (New) The pharmaceutical formulation of claim 7, wherein the anti-LAG3 antibody comprises a light chain sequence of SEQ ID NO: 35 and a heavy chain sequence of SEQ ID NO: 57, and the anti-PD-1 antibody comprises a heavy chain sequence of SEQ ID NO:
10 and a light chain sequence of SEQ ID NO: 5.

54\. (New) The pharmaceutical formulation of claim 9, wherein the anti-LAG3 antibody comprises a light chain sequence of SEQ ID NO: 35 and a heavy chain sequence of SEQ ID NO: 57, and the anti-PD-1 antibody comprises a heavy chain sequence of SEQ ID NO:
10 and a light chain sequence of SEQ ID NO: 5.

55\. (New) The pharmaceutical formulation of claim 49 that is a liquid formulation.

56\. (New) The pharmaceutical formulation of claim 50 that is a liquid formulation.

57\. (New) The pharmaceutical formulation of claim 51 that is a liquid formulation.

58\. (New) The pharmaceutical formulation of claim 52 that is a liquid formulation.

59\. (New) The pharmaceutical formulation of claim 53 that is a liquid formulation.

60\. (New) The pharmaceutical formulation of claim 54 that is a liquid formulation.

61\. (New) The pharmaceutical formulation of claim 10 that is a liquid formulation.

62\. (New) The pharmaceutical formulation of claim 29 that is a liquid formulation.

63\. (New) The pharmaceutical formulation of claim 30 that is a liquid formulation.

64\. (New) The pharmaceutical formulation of claim 31 that is a liquid formulation.

65\. (New) The pharmaceutical formulation of claim 32 that is a liquid formulation.

66\. (New) The pharmaceutical formulation of claim 33 that is a liquid formulation.

67\. (New) The pharmaceutical formulation of claim 34 that is a liquid formulation.

68\. (New) The pharmaceutical formulation of claim 39 that is a liquid formulation.

69\. (New) The pharmaceutical formulation of claim 10, wherein the excipient is selected from a) histidine, aspartate, glutamine, glycine, proline, methionine, or a combination thereof, at a total concentration of about 40-100 mM; b) arginine or a pharmaceutically acceptable salt thereof, NaCI, KCl, or a combination thereof at a total concentration of about 40- 150 mM; or a combination of a) and b).

70\. (New) The pharmaceutical formulation of claim 29, wherein the excipient is selected from a) histidine, aspartate, glutamine, glycine, proline, methionine, or a combination thereof, at a total concentration of about 40-100 mM; b) arginine or a pharmaceutically acceptable salt thereof, NaCI, KCl, or a combination thereof at a total concentration of about 40- 150 mM; or a combination of a) and b).

71\. (New) The pharmaceutical formulation of claim 31, wherein the excipient is selected from a) histidine, aspartate, glutamine, glycine, proline, methionine, or a combination thereof, at a total concentration of about 40-100 mM; b) arginine or a pharmaceutically acceptable salt thereof, NaCI, KCl, or a combination thereof at a total concentration of about 40- 150 mM; or a combination of a) and b).

OFFICE 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 .
Application Status
The amendment filed July 15, 2024, is acknowledged and filed.
Claims 1-3, 7, 9-10, 12-17, 22-34, 36-37, 39-42, and 45-47 have been amended.
Claims 6, 8, 11, 18-21, 35, 38, 43-44, and 48 have been canceled.
Claims 49-71 have been added.
Claims 1-5, 7, 9-10, 12-17, 22-34, 36-37, 39-42, 45-47, and 49-71 are pending.
Claims 1-5, 7, 9-10, 12-17, 22-34, 36-37, 39-42, 45-47, and 49-71 are examined on the merits herein.
Grounds of Rejection Withdrawn
Unless specifically reiterated below, Applicant’s amendments have obviated or rendered moot the grounds of objection and rejection set forth in the previous Office action mailed.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on May 2, 2023 and July 16, 2024 are in compliance with the provisions of 37 CFR 1.97.  Accordingly, the information disclosure statement has been considered by the examiner.
EXAMINER’S AMENDMENT
An examiner’s amendment to the record appears below. Should the changes and/or additions be unacceptable to applicant, an amendment may be filed as provided by 37 CFR 1.312. To ensure consideration of such an amendment, it MUST be submitted no later than the payment of the issue fee.
Authorization for this examiner’s amendment was given in an interview with Li Su, attorney of record on August 26, 2024.
The application has been amended as follows:
IN THE CLAIMS:
Claim 7:  line 2, replace both “the” with “an”
At the end of line 6 insert : “, wherein the anti-LAG3 antibody comprises a variable light chain region comprising CDRL1 of SEQ ID NO: 39, CDRL2 of SEQ ID NO: 40, and CDRL3 of SEQ ID NO: 41, and a variable heavy chain region comprising CDRH1 of SEQ ID NO: 42, CDRH2 of SEQ ID NO: 59, and CDRH3 of SEQ ID NO: 44, and the anti-PD-1 antibody comprises a variable light chain region comprising CDRL1 of SEQ ID NO: 1, CDRL2 of SEQ ID NO: 2, and CDRL3 of SEQ ID NO: 3, and a variable heavy chain region comprising CDRH1 of SEQ ID NO: 6, CDRH2 of SEQ ID NO: 7, and CDRH3 of SEQ ID NO: 8”.
After amendment claim 7 reads: A pharmaceutical formulation comprising about 20 mg/mL of an anti-LAG3 antibody; about 5 mg/mL of an anti-PD-1 antibody; about 54 mg/mL sucrose; about 0.2 mg/mL polysorbate 80; about 10 mM histidine buffer that maintains the pH of the pharmaceutical formulation at about 5.8; and about 56 mM L-arginine or a pharmaceutically acceptable salt thereof; and further comprising about 8 mM L-methionine, wherein the anti-LAG3 antibody comprises a variable light chain region comprising CDRL1 of SEQ ID NO: 39, CDRL2 of SEQ ID NO: 40, and CDRL3 of SEQ ID NO: 41, and a variable heavy chain region comprising CDRH1 of SEQ ID NO: 42, CDRH2 of SEQ ID NO: 59, and CDRH3 of SEQ ID NO: 44, and the anti-PD-1 antibody comprises a variable light chain region comprising CDRL1 of SEQ ID NO: 1, CDRL2 of SEQ ID NO: 2, and CDRL3 of SEQ ID NO: 3, and a variable heavy chain region comprising CDRH1 of SEQ ID NO: 6, CDRH2 of SEQ ID NO: 7, and CDRH3 of SEQ ID NO: 8.
Claim 9: line 2, replace both “the” with “an”
At the end of line 6 insert : “, wherein the anti-LAG3 antibody comprises a variable light chain region comprising CDRL1 of SEQ ID NO: 39, CDRL2 of SEQ ID NO: 40, and CDRL3 of SEQ ID NO: 41, and a variable heavy chain region comprising CDRH1 of SEQ ID NO: 42, CDRH2 of SEQ ID NO: 59, and CDRH3 of SEQ ID NO: 44, and the anti-PD-1 antibody comprises a variable light chain region comprising CDRL1 of SEQ ID NO: 1, CDRL2 of SEQ ID NO: 2, and CDRL3 of SEQ ID NO: 3, and a variable heavy chain region comprising CDRH1 of SEQ ID NO: 6, CDRH2 of SEQ ID NO: 7, and CDRH3 of SEQ ID NO: 8”.
After amendment claim 9 reads: A pharmaceutical formulation comprising about 18.02 mg/mL of an anti-LAG3 antibody; about 4.505 mg/mL of an anti-PD-1 antibody; about 50 mg/mL sucrose; about 0.2 mg/mL polysorbate 80; about 10 mM histidine buffer that maintains the pH of the pharmaceutical formulation at about 5.8; and about 70 mM L- arginine or a pharmaceutically acceptable salt thereof; and further comprising about 10 mM L- methionine, wherein the anti-LAG3 antibody comprises a variable light chain region comprising CDRL1 of SEQ ID NO: 39, CDRL2 of SEQ ID NO: 40, and CDRL3 of SEQ ID NO: 41, and a variable heavy chain region comprising CDRH1 of SEQ ID NO: 42, CDRH2 of SEQ ID NO: 59, and CDRH3 of SEQ ID NO: 44, and the anti-PD-1 antibody comprises a variable light chain region comprising CDRL1 of SEQ ID NO: 1, CDRL2 of SEQ ID NO: 2, and CDRL3 of SEQ ID NO: 3, and a variable heavy chain region comprising CDRH1 of SEQ ID NO: 6, CDRH2 of SEQ ID NO: 7, and CDRH3 of SEQ ID NO: 8.
Allowable Subject Matter
Claims 1-5, 7, 9-10, 12-17, 22-34, 36-37, 39-42, 45-47, and 49-71 are allowed.
The following is an examiner’s statement of reasons for allowance:
There is no prior art that teaches or suggests a molar ratio of 4:1 of LAG3: PD-1 antibody. The applicant’s unexpected results of increased clearance makes the instant application a non-obvious formulation.
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
Applicants have amended the specification to correct a typographical error. Support for this correction can be found on page 20 of the application as filed, which refers to the light chain of antibody Ab6 as SEQ ID NO: 35.
Claims 1-10, 12-17, 22-34, 36-37 and 39-47 are pending in this application. Claims 1-3, 7, 9-10, 12-17, 22-34, 36-37, 39-42, 45-47 are amended, and claims 6, 8, and 43-44 are cancelled, without prejudice to pursuing the subject matter thereof in a continuing or divisional application. Applicants have added claims 49-71. No new matter is added by these amendments.
Exemplary support for these amendments can be found on page 11, line 14, page 13, lines 15-20 and page 31, lines 14-17 in the application and the original claims as filed. Exemplary support for added claims 69-71 can be found on page 30, lines 21-23, page 31, lines 5 and 12-21 of the application as filed. After entry of the foregoing amendments, claims 1-5, 7, 9-10, 12-17, 22-34, 36-37, 39-42, 45-47, and 49-71 will remain pending.
Reconsideration of this application, as amended, is respectfully requested.
Co-Pending Applications
Applicants direct the Examiner to the file history of U.S. Patent No. 11,845,798 and co- pending Application No. 18/485,688 and Application No. 17/289,810.
Information Disclosure Statement
Applicants submit herewith copies of the references not included in the May 2, 2023
submission. Applicants request that the Examiner consider these references, and initial the May 2, 2023 PTO-1449 forms and provide to Applicants.
Rejections under 35 U.S.C. § 112
Claims 43 and 44 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th
paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Applicants have cancelled claims 43-44, thereby overcoming the rejection.
Rejections under 35 U.S.C. § 103
Claims 1-10, 12-17, 22-34, 36-37, 39, 40, and 42-47 are rejected under 35 U.S.C. 103 as being unpatentable over Liang (W02016/028672 Al), in view of Korman (US2016/0222116A1), the FDA insert for KEYTRUDA (May 2017; hereinafter "the KEYTRUDA FDA insert") and Lucas (US2012/0183531).
The Examiner contends that it would have been obvious to one of ordinary skill in the art before the filing date of the claimed invention to have combined the teachings of Liang, Korman, the KEYTRUDA FDA insert, and Lucas to arrive at the claimed invention for the following stated reasons: (i) Liang teaches the sequences of pembrolizumab and anti-LAG3 antibody and the combination therapy; (ii) Korman teaches that combining anti-PD-1 and anti-LAG3 antibodies for treatment produces a comparable clinical benefit rate better than that achieved by an anti-LAG3 or anti-PD-1 antibody alone; (iii) It would have been obvious to use the primary formulation components from the KEYTRUDA FDA insert as the starting point for formulation development for a combination treatment having KEYTRUDA as one of the components; (iv) As Korman teach various dosing of both the anti-LAG3 and anti-PD-1 antibodies and the KEYTRUDA FDA insert teaches that the efficacy is not significantly clinically different between 2 and 200 mg/kg, changing the ratio and/ or final formulation concentration of the antibodies would have been an obvious step of development of the combination treatment based on optimization; (v) Liang further teaches that dosing of the combination therapy can be determined by standard pharmaceutical procedure and that determination of the dose is made by the treating physician; (vi) Lucas teaches the various antioxidants of the claims, and (vii) Chelating agents added to a protein formulation can prevent or retard yellow color formation or oxidation, as these can be a result of excipients and buffers used to stabilize the protein against degradation.
Claim 41 is rejected under 35 U.S.C. 103 as being unpatentable over Liang in view of
Korman, the KEYTRUDA FDA insert and Lucas as applied to claims 1-10, 12-17, 22-34, 36-37, 39, 40, and 42-47 above, and further in view of Telikepalli (Telikepalli et al. J Pharm Sci. 2013. 103(3):796-809).
Amended claims 1 and 10 recite "wherein the molar ratio of the anti-LAG3 antibody to anti-PD-1 antibody is 4:1". Claims 7 and 9 are also directed to an anti-LAG3 antibody to anti- PD-1 antibody concentration ratio of 4:1. The Examiner cites to the human therapeutic dose of 200 mg of pembrolizumab in the KEYTRUDA FDA insert. However, prior to the effective filing date of the instant application, there was no teaching or suggestion in the cited references of the human therapeutic dose of the claimed anti-LAG3 antibody.
Instead, in example 10 Table 2, Korman teaches ratios of the anti-LAG3 antibody
(BMS986016) to anti-PD1 antibody (BMS936558) of 1:26, 1:80, 1:12, 1:3 and 1:1 for human clinical trials. In addition, one skilled in the art would also understand that antibody clearance pathways are complex, and the clearance properties of one antibody cannot be applied to a different antibody with different CDR regions. Therefore, there was no specific teaching or suggestion of the 4:1 ratio of the claimed anti-LAG3 antibody to anti-PD-1 antibody in Korman.
The inventors discovered that the claimed anti-LAG3 antibody had unexpectedly faster than anticipated clearance compared to typical monoclonal antibodies in human patients, and discovered the clinical dose of 800 mg. See US Publication 20210347889, Example 2.
"Compared to the antibody half-life predicted based on cynomolgus monkey PK
parameters, Ab6 unexpectedly has a shorter half-life due to approximately three-fold faster clearance than predicted from cynomolgus monkey (predicted CLhuman = 0.168 L/day) or faster than anticipated clearance compared to typical monoclonal antibodies (Ryman, J. T., & Meibohm, B. (2017). Pharmacokinetics of Monoclonal Antibodies. CPT pharmacometrics & systems pharmacology, 6(9), 576-588)".
Furthermore, Applicants submit that antibody formulation development is unpredictable. Physical instability of antibodies through aggregation is the main challenge of antibody formulation, as immunoglobulin aggregates can cause immunogenicity issues. Antibodies with different CDR regions present surface-exposed amino acid differences that stipulate antigen specificity. Thus, the interfacial surface of each antibody drug is unique and thus requires specific formulation components to provide maximal stability and retention of activity. This is discussed in the patent application, for example, on the beginning of page 15 of the application as originally filed.
The claimed anti-LAG3 antibody was found to have the inherent property of the molecule to self-associate (see Example 1). The inventors discovered that the presence of histidine, aspartate, glutamine, glycine, proline, methionine, arginine or a pharmaceutically acceptable salt thereof, or monovalent metal ions, or a combination thereof increased the diffusion interaction parameter (KD) or reduced self-interaction, and improved relative solubility. See Examples 1-2 and 7. In the presence of these excipients, the % change in High Molecular Weight species was within acceptable ranges, and there was minimal impact on physical stability of the antibody. See Tables 3-5 and 9, Figures 13, 15, 18, 24, 35 and 38 of the present application.
The teachings of Lucas are directed to a
different
antibody and a
different problem to be solved
(inhibit yellow color formation caused by oxidative pathways). In paragraph 67 of Lucas, it describes that in histidine buffer, the specific protein, polysorbate 80, glycine and glycerol contribute to yellowing of the solution. In paragraph 75 of Lucas, it concludes that the yellow color in histidine buffer formulation is caused by oxidative pathways. Whereas the problem solved in the claimed anti-LAG3 antibody formulation was self-association. Therefore, amended claims 1 and 10, and dependent claims, and amended claims 7 and 9, and dependent claims are not obvious over the cited references.
Claims 1-10, 12-17, 22-34, 36-37, 39-47 are rejected under 35 U.S.C. 103 as being obvious over U.S. Patent No. 11,845,798 ("the '798 patent") in view of the FDA insert for KEYTRUDA (May 2017; hereinafter "the KEYTRUDA FDA insert"). The Examiner contends that the '798 patent constitutes prior art under 35 U.S.C. 102(a)(2).
Applicants submit herewith a statement pursuant to 35 U.S.C. 102(b)(2)(C), thereby overcoming the rejection.
Double Patenting
Claims 1-10, 12-17, 22-34, 36-37, and 39-47, are rejected on the ground of non-statutory double patenting as being unpatentable over claims 1, 2, 18, 19, 26, 28, 31-32, 34, 36, 46, 47, 49, and 57-58 of U.S. Patent No. 11,845,798 in view of the FDA insert for KEYTRUDA (May 2017; hereinafter "the KEYTRUDA FDA insert").
The Examiner states that the '798 patent claims are silent on the concentration of the anti PD-1 antibody in the formulation and a molar ratio of 4:1 of anti-LAG3: anti-PD-1.
The Examiner contends that it would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to combine the teachings of the recited '798 patent claims to formulate anti-PD-1 and anti-LAG3 antibodies in a pharmaceutical composition. The Examiner contends that as the FDA insert for KEYTRUDA teaches various dosing and concentrations of the anti-PD-1 antibody and that efficacy of the anti-PD-1 antibody is not significantly clinically different between 200 mg and 2 mg/kg, changing the final formulation concentration of the antibody would have been an obvious step of development of the combination treatment based on optimization.
Amended claims 1 and 10 recite "wherein the molar ratio of the anti-LAG3 antibody to anti-PD-1 antibody is 4:1". Claims 7 and 9 are also directed to an anti-LAG3 antibody to anti- PD-1 antibody concentration ratio of 4:1. The Examiner cites to the human therapeutic dose of 200 mg of pembrolizumab in the FDA insert for KEYTRUDA. However, prior to the effective filing date of the instant application, there was no teaching or suggestion in the KEYTRUDA FDA insert of the human therapeutic dose of the claimed anti-LAG3 antibody.
The inventors discovered that the claimed anti-LAG3 antibody had unexpectedly faster than anticipated clearance compared to typical monoclonal antibodies in human patients, and discovered the clinical dose of 800 mg. See US Publication 20210347889 Example 2.
"Compared to the antibody half-life predicted based on cynomolgus monkey PK
parameters, Ab6 unexpectedly has a shorter half-life due to approximately three-fold faster clearance than predicted from cynomolgus monkey (predicted CLhuman = 0.168 L/day) or faster than anticipated clearance compared to typical monoclonal antibodies (Ryman, J. T., & Meibohm, B. (2017). Pharmacokinetics of Monoclonal Antibodies. CPT pharmacometrics & systems pharmacology, 6(9), 576-588)".
Therefore, amended Claims 1, 10 and claims dependent thereon, and claims 7 and 9 and claims dependent thereon are not obvious over the recited claims of U.S. Patent No. 11,845,798 in view of the KEYTRUDA FDA insert.
Claims 1-10, 12-17, 22-34, 36-37, 39-44 and 46-47 are provisionally rejected on the
ground of non-statutory double patenting as being unpatentable over claims 1-49 of co-pending
Application No. 18/485,688 ("the '688 application) in view of the FDA insert for KEYTRUDA (May 2017; hereinafter "the KEYTRUDA FDA insert").
The Examiner states that the '688 application does not teach a formulation of the anti- PD1 antibody at 3-7 mg/ml or a molar ratio of 4:1 of anti-LAG3: anti-PD1 antibodies. The Examiner states that the '688 application does not teach arginine and NaCI in the same formulation or a ratio of 1:1 arginine to NaCI.
The Examiner contends that the KEYTRUDA FDA insert teaches a formulation of
pembrolizumab with a final concentration of 1-10 mg/ml; and that the KEYTRUDA FDA insert further teaches there are no clinically significant differences in efficacy and safety between pembrolizumab doses of 200 mg or 2 mg/kg in patients. The Examiner contends that the molar ratios taught are very close to the instant claimed ratio; and that the dosing range of the '688 application could encompass a 4:1 ratio of anti-LAG3:anti-PD1 if the guidance of the KEYTRUDA FDA insert were incorporated. The Examiner contends that one of ordinary skill in the art would recognize antibody concentration, pH, and the concentrations of buffer, sucrose, polysorbate 80, polyol, and anti-oxidant as result-effective variables and optimize them by routine experimentation in order to minimize peroxide formation for the stability of antibody formulation as well as to generate the best efficacy of therapy.
Applicants have amended the claims of the '688 application to cancel claims that recite a molar ratio of anti-LAG3 antibody to anti-PD-1 antibody, or an anti-PD-1 antibody concentration. In view of the arguments presented above, amended Claims 1, 10, and claims dependent thereon, and claims 7 and 9, and claims dependent thereon, are not obvious over the pending claims of the '688 application in view of the KEYTRUDA FDA insert.
Applicants respectfully request reconsideration and withdrawal of the above rejections.
CONCLUSION