Office Action 1: Non-Final Rejection (2024-03-13)
Rejection types: 103 - Obviousness, 112 - Written Description/Enablement, Double Patenting

CLAIMS:
AMENDMENTS TO THE CLAIMS:The following listing of claims will replace all prior versions, and listings, of claims in the application:
(Original) A formulation comprising: 16-22 mg/mL of an anti-LAG3 antibody or antigen binding fragment thereof; 3-7 mg/mL of an anti-PD-1 antibody or antigen binding fragment thereof, about 30-120 mg/mL of a nonreducing disaccharide; about 0.02-2.0 mg/mL polysorbate 80 or polysorbate 20; a buffer at pH about 4.5-6.5; and about 40-150 mM L-arginine or a pharmaceutically acceptable salt thereof, wherein the anti-LAG3 antibody or antigen-binding fragment thereof 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 or antigen-binding fragment thereof 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.
(Original) The 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 at pH about 5.0 - 6.5; and about 40-100 mM L-arginine or a pharmaceutically acceptable salt thereof.
(Original) The 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 at pH about 5.0 - 6.5; and about 40-70 mM L-arginine or a pharmaceutically acceptable salt thereof.
Serial No.: To be assigned Attorney Docket No. 24667-US-PCT Page 44. (Original) The formulation of any one of claims 1 to 3, further comprising about 5-15 mM L-methionine.5. (Currently Amended) The formulation of claim 2 to 3, further comprising about 5-10 mM L-methionine.6. (Original) The formulation of claim 1 comprising about 18.75 mg/mL of the anti-LAG3 antibody; about 6.25 mg/mL of the anti-PD-1 antibody; about 55 mg/mL sucrose; about 0.2 mg/mL polysorbate 80; about 10 mM histidine buffer at pH about 5.8; and about 52.5 mM L-arginine or a pharmaceutically acceptable salt thereof, and further comprising about 7.5 mM L-methionine.7. (Original) The formulation of claim 1 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 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. (Original) The formulation of claim 1 comprising about 20.83 mg/mL of the anti-LAG3 antibody; about 4.17 mg/mL of the anti-PD-1 antibody; about 53 mg/mL sucrose; about 0.2 mg/mL polysorbate 80; about 10 mM histidine buffer at pH about 5.8; and about 58.3 mM L-arginine or a pharmaceutically acceptable salt thereof, and further comprising about 8.3 mM L-methionine.9. (Original) The formulation of claim 1 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 at pH about
Serial No.: To be assigned Attorney Docket No. 24667-US-PCT Page 55.8; and about 70 mM L-arginine or a pharmaceutically acceptable salt thereof; and further comprising about 10 mM L-methionine.10. (Currently Amended) A formulation comprising: about 18-22 mg/mL of an anti-LAG3 antibody or antigen-binding fragment thereof and about 3-7 mg/mL of an anti-PD-1 antibody or antigen-binding fragment thereof at a molar ratio of 4:1 antiLAG3 antibody to anti-PD-1 antibody, or antigen binding fragments thereof, one or more of an excipient selected from the group consisting of histidine, aspartate, glutamine, glycine, proline, methionine, arginine or a pharmaceutically acceptable salt thereof, NaCl, and KCl, at a total excipient concentration of about 25-250 mM, and a buffer at pH about 4.5-8, wherein the anti-LAG3 antibody or antigen-binding fragment thereof 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 or antigen-binding fragment thereof 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: 8.11. Cancelled.12. (Original) The 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. (Original) The 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. (Original) The formulation of claim 10, wherein the excipients are
Serial No.: To be assigned Attorney Docket No. 24667-US-PCT Page 6NaCl and L-arginine or a pharmaceutically acceptable salt thereof with a total excipient concentration of about 25-250 mM.15. (Original) The formulation of claim 14, wherein the NaCl to L-arginine concentration ratio is 1:1.16. (Original) The formulation of claim 15, wherein the NaCl concentration is about 35 mM and the L-arginine concentration is about 35 mM.17. (Original) The formulation of claim 15, wherein the NaCl concentration is about 50 mM and the L-arginine concentration is about 50 mM.18. Cancelled.19. Cancelled.20. Cancelled.21. Cancelled.22. (Currently Amended) The formulation of claim 10, further comprising a non-ionic surfactant that is a polysorbate.23. (Original) The formulation of claim 22, wherein the non-ionic surfactant is polysorbate 80 or polysorbate 20.24. (Currently Amended) The formulation of claim 10 to 23, further comprising a sugar that is a non-reducing disaccharide.
Serial No.: To be assigned Attorney Docket No. 24667-US-PCT Page 725. (Original) The formulation of claim 24, wherein the sugar is trehalose or sucrose, or a combination thereof.26. (Original) The formulation of claim 25, wherein the sugar is at a concentration of about 10-200 mg/ml.27. (Currently Amended) The formulation of claim 10, further comprising a polyol selected from the group consisting of mannitol, sorbitol, glycerol and polyethylene glycol.28. (Original) The formulation of claim 27, wherein the polyol is at a concentration of about 10-200 mg/ml.29. (Currently Amended) The formulation of claim 10 to 18, 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 about 3-300 mM L-histidine, acetate or citrate buffer at pH about 5.0 -6.5.30. (Currently Amended) The formulation of claim 10 to 18, further comprising about 30-120 mg/mL sucrose or trehalose; about 0.05-1.5 mg/mL polysorbate 80 or polysorbate 20; and about 3-150 mM L-histidine, acetate or citrate buffer at pH about 5.0 -6.5.31. (Currently Amended) The formulation of claim 10 to 20, further comprising about 50-90 mg/mL sucrose or trehalose; about 0.05-1.0 mg/mL polysorbate 80; and about 5-30 mM L-histidine, acetate or citrate buffer at pH about 5.0 - 6.5.
Serial No.: To be assigned Attorney Docket No. 24667-US-PCT Page 832. (Currently Amended) The formulation of claim 10 comprising about 20 mg/mL of the anti-LAG3 antibody or antigen-binding fragment thereof; about 50-90 mg/mL sucrose or trehalose; about 0.05-1.0 mg/mL polysorbate 80 or polysorbate 20; about 5-20 mM L-histidine, acetate or citrate buffer at pH about 5.0 - 6.5; and about 40-150 mM L-arginine or a pharmaceutically acceptable salt thereof.33. (Currently Amended) The formulation of claim 10 comprising about 20 mg/mL of the anti-LAG3 antibody or antigen-binding fragment thereof; about 20-200 mg/mL glycerol, sorbitol or PEG400; about 0.05-1.0 mg/mL polysorbate 80 or polysorbate 20; about 3-150 mM L-histidine, acetate or citrate buffer at pH about 5.0 -6.5; and about 40-150 mM L-arginine or a pharmaceutically acceptable salt thereof.34. (Currently Amended) The formulation of claim 10 comprising about 20 mg/mL of the anti-LAG3 antibody or antigen-binding fragment thereof; about 40-150 mM L-glutamine, L-glycine, L-proline or L-methionine; about 0.05-1.0 mg/mL polysorbate 80 or polysorbate 20; about 3-150 mM L-histidine, acetate or citrate buffer at pH about 5.0 - 6.5; and about 40-150 mM L-arginine or a pharmaceutically acceptable salt thereof.35. Cancelled.36. (Currently Amended) The formulation of claim 10 to 35, further comprising about 3-150 mM L-methionine.37. (Currently Amended) The formulation of claim 10 to 35, further comprising about 5-70 mM L-methionine.38. Cancelled.
Serial No.: To be assigned Attorney Docket No. 24667-US-PCT Page 939. (Original) The formulation of claim 10 or 37 comprising about 20 mg/mL of the anti-LAG3 antibody or antigen-binding fragment thereof; about 50 mg/mL sucrose; about 0.2 mg/mL polysorbate 80; about 10 mM L-histidine buffer at pH about 5.8-6.0; and about 70 mM L-arginine or L-arginine-HCI.40. (Currently Amended) The formulation of claim 1 that is a liquid formulation.41. (Currently Amended) The formulation of claim 1 that is frozen to at least below -70°C.42. (Currently Amended) The formulation of claim 1 that is a reconstituted solution from a lyophilized formulation.43. (Currently Amended) The formulation of claim 1, wherein at 40 °C, the percent (%) monomer of the anti-LAG3 antibody or antigen-binding fragment thereof and anti-PD-1 antibody or antigen-binding fragment thereof is ≥98 % after 3 months as measured by size exclusion chromatography.44. (Currently Amended) The formulation of claim 1, wherein at 5 °C, the % acidic variants of the anti-LAG3 antibody or antigen-binding fragment thereof is less than 15% after 3 months as measured by ion exchange chromatography, the % acidic variants of the anti-PD-1 antibody or antigen-binding fragment thereof is less than 20% after 3 months as measured by ion exchange chromatography.45. (Currently Amended) The formulation of any one of claims 1 and 10, wherein the anti-LAG3 antibody or antigen binding fragment 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 or antigen binding fragment thereof comprises a heavy chain variable region of SEQ ID NO: 9 and a light chain variable region of SEQ ID NO: 4.46. (Original) The 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 formulation of any one of claims 1 and 10, wherein the anti-LAG3 antibody is Ab6 or Ab6 variant, and the anti-PD-1 antibody is pembrolizumab or pembrolizumab variant.48. Cancelled.

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 .
Application Status
The amendment filed May 6, 2021 has been filed and entered. Claims 5, 10, 22, 24, 27, 29-34, 36-37, 40-45, and 47 have been amended. Claims 11, 18-21, 35, 38,  and 48 have been cancelled.
Claims 1-10, 12-17, 22-34, 36-37, and 39-47 are pending.
Claims 1-10, 12-17, 22-34, 36-37, and 39-47 are examined on the merits herein.
Information Disclosure Statement
The information disclosure statement filed May 2, 2023 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed.  A copy of AU2010/200784A1, WO1989/011297A1, WO1997/04801A1, WO2016/024228A1, Karagianni et al. (NPL 102), Liu et al. (NPL 117), Sharma et al (NPL 152), Sumit (NPL 161), Weber (NPL 181), and Yang et al (NPL 186) have not been included. It has been placed in the application file, but the information referred to therein has not been considered.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA  35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA  35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
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.
Claims 43 and 44 fail to further limit the scope of the claim from which they depend, by stating an intended result without any additional recited steps. Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure. Examples of claim language, although not exhaustive, that may raise a question as to the limiting effect of the language in a claim are: (A) adapted to or adapted for clauses; (B) wherein clauses; and (C) whereby clauses. The court noted that a ‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’ Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)).
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA  35 U.S.C. 102 and 103 (or as subject to pre-AIA  35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA  to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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 (WO2016/028672 A1 (PTO-892)), in view of Korman (US2016/0222116A1, IDS entered May 2, 2023), KEYTRUDA (FDA insert May 2017 (PTO-892)) and Lucas (US2012/0183531, IDS entered May 2, 2023).
Regarding claims 1 and 10, Liang teaches the sequences of the anti-LAG3 antibody clone Ab6 with light chain CDR SEQ ID NO: 38-40 and heavy chain CDR SEQ ID NO: 33, 457 and 35 (claim 2 (3)) which are 100% identical to the instant claimed light chain CDR SEQ ID NO: 39-41 and heavy chain CDR SEQ ID NO: 41, 42 and 59. Liang further teaches combining the  LAG3 antibody with pembrolizumab (claim 19/ 11). Liang further teaches SEQ ID NO: 41 and 42 are pembrolizumab (page 109, lines 21-35) which have 100% sequence identity to the anti-PD-1 antibody CDR SEQ ID NO: 1-3 and 6-8 of the instant application. Liang further teaches that dosing of antibodies administered in combination can be determined by standard pharmaceutical procedures (page 168, lines 22-24) and determination of appropriate dose is made by the clinician (page 172, line 1).
Liang does not teach the formulation of the PD-1 and LAG3 antibodies, or the concentration of the antibodies in the formulation.
Korman teaches a formulation of a combination of LAG3 and PD1 antibodies with a dose of 20mg of the LAG3 antibody (paragraph 0078). Korman further teaches various molar ratios of the LAG3 and PD-1 antibodies in the formulation (paragraphs 75-80). Korman further teaches that dosage regimes can be adjusted to provide the optimum desired response (0068). Korman further teaches that the combination therapy with LAG3 and PD1 antibody produces a comparable clinical benefit rate better than that achieved by an anti-LAG3 or anti-PD-1 antibody alone by 20-80% (paragraph 0099).
KEYTRUDA teaches formulation of pembrolizumab (anti PD-1 antibody) at a final concentration of 1-10 mg/ml (page 6) in 70 mg/ml sucrose (page 26), 0.2 mg/ml polysorbate 80, and 10mM L-histidine (calculated from 3.1 mg in 2ml) at pH 5.5 (page 30) that has been reconstituted from a lyophilized solution. KEYTRUDA further teaches there are no clinically significant differences in efficacy and safety between pembrolizumab doses of 200mg or 2 mg/kg in patients (page 26). The instant specification defines the term “about” as up to 10% variation.
Lucas teaches pharmaceutical protein formulations (paragraph 002) and the use of 150mM arginine and 10mM methionine (table 1) for preventing or retarding yellow color or peroxide formation in a composition (abstract). Lucas further teaches that histidine has excellent buffer capacity in the pH range typically used for biopharmaceuticals, pH 5.5-7.4, and has been found to stabilize some proteins against degradation (paragraph 004). A drawback to the use of histidine as a buffer in liquid formulations is its propensity to change color from clear to yellow during storage. Lucas teaches that a method for preventing or retarding (i.e., inhibiting) yellow color formation in a composition, wherein the method comprises use of an antioxidant, oxygen scavenger, and/or chelating agent (paragraph 008) and that the antioxidant is methionine (paragraph 10) and the chelating agent is arginine (claim 10). Lucas further teaches the concentration of the antioxidant, oxygen scavenger, and/or chelating agent depends upon the particular antioxidant, oxygen scavenger and/ or chelating agent chose but can otherwise be readily determined by those of skill in the art and that the concentration can range 0.01mM to 1000mM (paragraph 0053).
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, KEYTRUDA, and Lucas to arrive at the claimed invention for the following reasons. Liang teaches the sequences of pembrolizumab and anti-LAG3 antibody and the combination therapy of the two. Korman teaches that combining PD1 and LAG3 antibodies for treatment produces a comparable clinical benefit rate better than that achieved by an anti-LAG3 or anti-PD-1 antibody alone by 20-80%. Combining the antibodies into a single formulation makes dilution and administration of the treatment easier on providers and patients. As KEYTRUDA is recognized as an FDA approved antibody formulation, using the primary formulation components from this antibody as the starting point for formulation development would have been obvious for a combination treatment with KEYTRUDA as one of the components. As KEYTRUDA and Korman teach various dosing of both the LAG3 and PD1 antibodies and KEYTRUDA teaches that efficacy of the PD1 antibody is not significantly clinically different between 2 and 200mg/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. 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. As Lucas teaches the various antioxidants, and 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.
Regarding claims 4-5, 12, 14, 15, 22-33, and 36-37, Lucas further teaches use of various excipients such as polysorbate 20 or 80, NaCl, sucrose, glycerol, polyethylene glycol, mannitol, or sorbitol (paragraph 0050). Lucas further teaches a specific formulation with 1:1 NaCl and arginine, both at 150mM, as well as 100mM glycine, 10mM methionine and 150mM glycerol (Table 1). Lucas further teaches the concentration of the antioxidant, oxygen scavenger, and/or chelating agent depends upon the particular antioxidant, oxygen scavenger and/ or chelating agent chose but can otherwise be readily determined by those of skill in the art and that the concentration can range 0.01mM to 1000mM (paragraph 0053).
Regarding claims 2-3, 6-9, 12-13, 16-17, 34 and 39, the claims are drawn to further permutations of formulation and dosing of the same anti-LAG3 and PD-1 antibodies. As detailed above one of ordinary skill in the art would recognize antibody concentration, pH, 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. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention.
Regarding claims 40 and 42, Liang, Korman, KEYTRUDA and Lucas teach formulation of anti-PD-1 and anti-LAG3 antibodies as detailed above.
KEYTRUDA further teaches that the formulation can be liquid (solution) or reconstituted from lyophilization (page 6).
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 KEYTRUDA, Liang, Korman and Lucas to arrive at the claimed invention for the following reasons. The ordinary artisan would have been motivated to provide both a liquid and lyophilized formulation because a liquid formulation is ready to administer and requires less preparation by hospital personnel, while a lyophilized formulation has longer storage capability.
Regarding claims 43-44, as detailed above the claims do not further limit the scope of the independent claim 1 and are therefore included in this rejection.
Regarding claims 45-47, Liang, Korman, KEYTRUDA and Lucas teach formulation of anti-PD-1 and anti-LAG3 antibodies as detailed above.
Liang further teaches the sequences of the anti-LAG3 antibody clone Ab6 with light chain variable SEQ ID NO: 126 and heavy chain variable SEQ ID NO: 116 (claim 3 (6)) which are 100% identical to the instant claimed light chain variable SEQ ID NO: 37 and heavy chain variable SEQ ID NO: 58. Liang further teaches the sequences of the anti-LAG3 antibody clone Ab6 with light chain SEQ ID NO: 126 and heavy chain variable SEQ ID NO: 116 (claim 3 (6); page 38, line 17-34) which are 100% identical to the instant claimed light chain variable SEQ ID NO: 35 and heavy chain variable SEQ ID NO: 57. Liang further teaches SEQ ID NO: 41 and 42 are pembrolizumab (page 109, lines 21-35) which have 100% sequence identity to the anti-PD-1 antibody variable chain SEQ ID NO: 9 and 4 as well as the light and heavy chain SEQ ID NO: 5 and 10 of the instant application.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Claim 41 is rejected under 35 U.S.C. 103 as being unpatentable over Liang (WO2016/028672 A1 (PTO-892)), in view of Korman (US2016/0222116A1, IDS entered May 2, 2023), KEYTRUDA (FDA insert May 2017 (PTO-892)) and Lucas (US2012/0183531, IDS entered May 2, 2023) 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 (PTO-892)).
Liang, Korman, KEYTRUDA and Lucas teach formulation of monoclonal antibodies against LAG3 and PD-1 as detailed above.
Liang, Korman, KEYTRUDA and Lucas do not teach wherein the formulation is frozen to at least -70ºC.
Telikepalli teaches freezing antibodies to -80ºC to test aggregation formation on freeze-thaw (Generation of Aggregates, page 797). Telikepalli further teaches freeze thaw stress at this temperature is mild and does not change the overall higher order structure, showed no effect on turbidity and formed a very small amount of multimers and insoluble aggregates (Discussion and Figure 1g).
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 the formulation as taught by KEYTRUDA, Liang, Korman and Lucas with the freezing temperature as taught by Telikepalli. Th ordinary artisan would have been motivated to do so because as Telikepalli teaches freezing the antibody to -80ºC results in no increase in turbidity and only a small amount of aggregation providing an opportunity for long term storage of liquid formulations.
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 in view of KEYTRUDA (FDA insert May 2017).
The applied reference has a common assignee and inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
Regarding claim 1, the patented claims teach a formulation comprising about 15-50 mg/ml LAG3 antibody (claim 58) with light chain and heavy variable chain SEQ ID NO: 35 and 58 which are 100% identical to the instant claim 45 and 46 SEQ ID NO: 35 and 58 which contain the CDR sequences of claim 1 (claim 6/ 1), 10 mM histidine buffer at a pH of 5.8 (claim 18/ 1), 30-120 mg/ml sucralose (claim 2/ 1), 0.05-1.5 mg/ml polysorbate 80 or 20 (claim 2/ 1), 40-150 mM arginine (claim 1), and an anti-PD-1 antibody with light and heavy chain SEQ ID NO: 5 and 9 which are 100% identical to the instant claim 46 heavy and light chains SEQ ID NO: 5 and 10, which contain the CDR sequences of claim 1 (claim 36/ 34/ 26/ 19/ 1). The patented specification defines “about” as variation up to ±10%.
Regarding claims 2-5, the patented claims teach a formulation comprising about 15-50 mg/ml LAG3 antibody (claim 58), 10 mM histidine buffer at a pH of 5.8 (claim 18/ 1), 50 mg/ml sucralose (claim 18/ 1), 0.2 mg/ml polysorbate 80 or 20 (claim 18/ 1), 70 mM arginine (claim 18/ 1), 20-200 mg/ml glycerol (claim 25/ 19/ 1), 10 mM methionine (claim 18/ 1). The patented specification defines “about” as variation up to ±10%.
Regarding claims 6-9, the claims are drawn to further permutations of formulation and dosing of the same anti-LAG3 and PD-1 antibodies.
Regarding claim 10, the patented claims teach a formulation comprising 15-50 mg/ml LAG3 antibody (claim 58) with light chain and heavy variable chain SEQ ID NO: 35 and 58 which are 100% identical to the claimed SEQ ID NO: 35 and 58 which contain the CDR sequences of claim 1 (claim 6/ 1), 10 mM histidine buffer at a pH of 5.8 (claim 18/ 1), 30-120 mg/ml sucralose (claim 2/ 1), 0.05-1.5 mg/ml polysorbate 80 or 20 (claim 2/ 1), 40-150 mM arginine (claim 1), 20-200 mg/ml glycerol, 40-100 mM NaCl, 10 mM methionine and an anti-PD-1 antibody with light and heavy chain SEQ ID NO: 5 and 9 which are 100% identical to the instant claimed heavy and light chains SEQ ID NO: 5 and 10, which contain the CDR sequences of claim 1 (claim 36/ 34/ 26/ 19/ 1). The patented specification defines “about” as variation up to ±10%.
Regarding claims 12-17, 22-34, 36-37 and 39 the patented claims teach a formulation comprising 15-50 mg/ml LAG3 antibody (claim 58), 10 mM histidine buffer at a pH of 5.8 (claim 18/ 1), 50 mg/ml sucralose (claim 18/ 1), 0.2 mg/ml polysorbate 80 (claim 18/ 1), 70 mM arginine (claim 18/ 1), NaCl and arginine at 40-150mM (claim 49/ 47/ 46), 20-200 mg/ml glycerol (claim 25/ 19/ 1), 10 mM methionine (claim 18/ 1), 40-100mM L-glutamine (claim 57/ 47/ 46) and an anti-PD-1 antibody (claim 36/ 34/ 26/ 19/ 1). The patented specification defines “about” as variation up to ±10%.
Regarding claims 40-42, the patented claims 28 and 31-32 teach that the formulation is liquid, is frozen to at least below -70ºC and that it is reconstituted from a lyophilized formulation.
The patented claims are silent on the concentration of the anti PD-1 antibody in the formulation and a molar ratio of 4:1 of LAG3 : PD-1.
KEYTRUDA teaches a formulation of pembrolizumab with a final concentration of 1-10 mg/ml (page 6). KEYTRUDA further teaches there are no clinically significant differences in efficacy and safety between pembrolizumab doses of 200mg or 2 mg/kg in patients (page 26).
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 patented claims to formulate anti-PD-1 and LAG3 antibodies in a pharmaceutical composition. The ordinary artisan would have been motivated to do so as KEYTRUDA is recognized as an FDA approved antibody formulation, using the primary formulation concentration of this antibody as the starting point for formulation development would have been obvious for a combination treatment with KEYTRUDA as one of the components. As KEYTRUDA teaches various dosing and concentrations of the PD1 antibody and that efficacy of the PD1 antibody is not significantly clinically different between 2 and 200 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. One of ordinary skill in the art would recognize antibody concentration, pH, 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. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).  Therefore, the invention as a whole would have been obvious to one of ordinary skill in the art.
Regarding claims 43-44, as detailed above the claims do not further limit the scope of the independent claim 1 and are therefore included in this rejection.
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
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.
Claims 1-10, 12-17, 22-34, 36-37, and 39-47, are rejected on the ground of nonstatutory 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 KEYTRUDA (FDA insert May 2017).
Regarding claim 1, the patented claims teach a formulation comprising about 15-50 mg/ml LAG3 antibody (claim 58) with light chain and heavy variable chain SEQ ID NO: 35 and 58 which are 100% identical to the instant claim 45 and 46 SEQ ID NO: 35 and 58 which contain the CDR sequences of claim 1 (claim 6/ 1), 10 mM histidine buffer at a pH of 5.8 (claim 18/ 1), 30-120 mg/ml sucralose (claim 2/ 1), 0.05-1.5 mg/ml polysorbate 80 or 20 (claim 2/ 1), 40-150 mM arginine (claim 1), and an anti-PD-1 antibody with light and heavy chain SEQ ID NO: 5 and 9 which are 100% identical to the instant claim 46 heavy and light chains SEQ ID NO: 5 and 10, which contain the CDR sequences of claim 1 (claim 36/ 34/ 26/ 19/ 1). The patented specification defines “about” as variation up to ±10%.
Regarding claims 2-5, the patented claims teach a formulation comprising about 15-50 mg/ml LAG3 antibody (claim 58), 10 mM histidine buffer at a pH of 5.8 (claim 18/ 1), 50 mg/ml sucralose (claim 18/ 1), 0.2 mg/ml polysorbate 80 or 20 (claim 18/ 1), 70 mM arginine (claim 18/ 1), 20-200 mg/ml glycerol (claim 25/ 19/ 1), 10 mM methionine (claim 18/ 1). The patented specification defines “about” as variation up to ±10%.
Regarding claims 40-42, the patented claims 28 and 31-32 teach that the formulation is liquid, is frozen to at least below -70ºC and that it is reconstituted from a lyophilized formulation.
The patented claims are silent on the concentration of the anti PD-1 antibody in the formulation.
KEYTRUDA teaches a formulation of pembrolizumab with a final concentration of 1-10 mg/ml (page 6). KEYTRUDA further teaches there are no clinically significant differences in efficacy and safety between pembrolizumab doses of 200mg or 2 mg/kg in patients (page 26).
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 patented claims to formulate anti-PD-1 and LAG3 antibodies in a pharmaceutical composition. The ordinary artisan would have been motivated to do so as KEYTRUDA is recognized as an FDA approved antibody formulation, using the primary formulation concentration of this antibody as the starting point for formulation development would have been obvious for a combination treatment with KEYTRUDA as one of the components. As KEYTRUDA teaches various dosing and concentrations of the PD1 antibody and that efficacy of the PD1 antibody is not significantly clinically different between 2 and 200 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.
Regarding claims 6-9, the claims are drawn to further permutations of formulation and dosing of the same anti-LAG3 and PD-1 antibodies. One of ordinary skill in the art would recognize antibody concentration, pH, 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. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).  Therefore, the invention as a whole would be obvious to one of ordinary skill in the art.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Regarding claim 10, the patented claims teach a formulation comprising 15-50 mg/ml LAG3 antibody (claim 58) with light chain and heavy variable chain SEQ ID NO: 35 and 58 which are 100% identical to the claimed SEQ ID NO: 35 and 58 which contain the CDR sequences of claim 1 (claim 6/ 1), 10 mM histidine buffer at a pH of 5.8 (claim 18/ 1), 30-120 mg/ml sucralose (claim 2/ 1), 0.05-1.5 mg/ml polysorbate 80 or 20 (claim 2/ 1), 40-150 mM arginine (claim 1), 20-200 mg/ml glycerol, 40-100 mM NaCl, 10 mM methionine and an anti-PD-1 antibody with light and heavy chain SEQ ID NO: 5 and 9 which are 100% identical to the instant claimed heavy and light chains SEQ ID NO: 5 and 10, which contain the CDR sequences of claim 1 (claim 36/ 34/ 26/ 19/ 1). The patented specification defines “about” as variation up to ±10%.
Regarding claims 12-17, 22-34, 36-37 and 39 the patented claims teach a formulation comprising 15-50 mg/ml LAG3 antibody (claim 58), 10 mM histidine buffer at a pH of 5.8 (claim 18/ 1), 50 mg/ml sucralose (claim 18/ 1), 0.2 mg/ml polysorbate 80 (claim 18/ 1), 70 mM arginine (claim 18/ 1), NaCl and arginine at 40-150mM (claim 49/ 47/ 46), 20-200 mg/ml glycerol (claim 25/ 19/ 1), 10 mM methionine (claim 18/ 1), 40-100mM L-glutamine (claim 57/ 47/ 46) and an anti-PD-1 antibody (claim 36/ 34/ 26/ 19/ 1). The patented specification defines “about” as variation up to ±10%.
The patented claims are silent on the concentration of the anti PD-1 antibody in the formulation and a molar ratio of 4:1 of LAG3 : PD-1.
KEYTRUDA teaches a formulation of pembrolizumab with a final concentration of 1-10 mg/ml (page 6). KEYTRUDA further teaches there are no clinically significant differences in efficacy and safety between pembrolizumab doses of 200mg or 2 mg/kg in patients (page 26).
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 patented claims to formulate anti-PD-1 and LAG3 antibodies in a pharmaceutical composition. The ordinary artisan would have been motivated to do so as KEYTRUDA is recognized as an FDA approved antibody formulation, using the primary formulation concentration of this antibody as the starting point for formulation development would have been obvious for a combination treatment with KEYTRUDA as one of the components. As KEYTRUDA teaches various dosing and concentrations of the PD1 antibody and that efficacy of the PD1 antibody is not significantly clinically different between 2 and 200 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. One of ordinary skill in the art would recognize antibody concentration, pH, 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. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).  Regarding claims 43-44, as detailed above the claims do not further limit the scope of the independent claim 1 and are therefore included in this rejection.  Therefore, the invention as a whole would be obvious to one of ordinary skill in the art.
Claims 1-10, 12-17, 22-34, 36-37, 39-44 and 46-47, are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-49 of copending Application No. 18/485,688 in view of KEYTRUDA (FDA insert May 2017).
Regarding claim 1, the copending application claims teach a formulation comprising 10-120 mg/ml LAG3 antibody (claim 42/ 36-41/ 1-35) with CDRs comprising SEQ ID NO: 39-42, 44 and 59 (claim 43) which are 100% identical to the instant claimed CDRs of claim 1, 10-120 mg/ml PD1 antibody (claim 42/ 36-41/ 1-35) with CDRs comprising SEQ ID NO: 1-3 and 6-8 (claim 43) which are 100% identical to the instant claimed CDRs of claim 1, 10 mM histidine buffer at a pH about 5.8 (claim 27/ 1/ 2), 50 mg/ml sucralose (claim 27/ 1/ 2), 0.2 mg/ml polysorbate 80 (claim 27/ 1/ 2), and 70 mM arginine (claim 27/ 1/ 2).
Regarding claims 2-9, the copending application claims teach a formulation comprising 10-120 mg/ml LAG3 antibody (claim 42/ 36-41/ 1-35), 10-120 mg/ml PD1 antibody (claim 42/ 36-41/ 1-35), 10 mM histidine buffer at a pH about 5.8 (claim 27/ 1/ 2), 50 mg/ml sucralose (claim 27/ 1/ 2), 0.2 mg/ml polysorbate 80 (claim 27/ 1/ 2), and 70 mM arginine (claim 27/ 1/ 2), 70mM arginine (claim 27/ 1/ 2), 5-15 mM methionine (claim 49/ 43-47),  or specifically 10mM methionine (claim 27/ 1/ 2), NaCl 40-150mM (claim 6/ 1), 10-200 mg/ ml polyol or sugar (claim 15/ 11-14/ 1-10).
Regarding claims 40-42 the copending application claims 29-31 teach that the formulation is a liquid formulation, has been reconstituted from lyophilization and frozen to at least below -70ºC.
The copending application does not teach formulation of the anti PD1 antibody at 3-7 mg/ml.
KEYTRUDA teaches a formulation of pembrolizumab with a final concentration of 1-10 mg/ml (page 6). KEYTRUDA further teaches there are no clinically significant differences in efficacy and safety between pembrolizumab doses of 200mg or 2 mg/kg in patients (page 26).
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 patented claims to formulate anti-PD-1 and LAG3 antibodies in a pharmaceutical composition. The ordinary artisan would have been motivated to do so as KEYTRUDA is recognized as an FDA approved antibody formulation, using the primary formulation concentration of this antibody as the starting point for formulation development would have been obvious for a combination treatment with KEYTRUDA as one of the components. As KEYTRUDA teaches various dosing and concentrations of the PD1 antibody and that efficacy of the PD1 antibody is not significantly clinically different between 2 and 200 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. One of ordinary skill in the art would recognize antibody concentration, pH, 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. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).  Regarding claims 43-44, as detailed above the claims do not further limit the scope of the independent claim 1 and are therefore included in this rejection. Therefore, the invention as a whole would be obvious to one of ordinary skill in the art.
Regarding claim 10, the copending application claims teach a formulation comprising 10-120 mg/ml LAG3 antibody (claim 42/ 36-41/ 1-35) with CDRs comprising SEQ ID NO: 39-42, 44 and 59 (claim 43) which are 100% identical to the instant claimed CDRs of claim 1, 10-120 mg/ml PD1 antibody (claim 42/ 36-41/ 1-35) with CDRs comprising SEQ ID NO: 1-3 and 6-8 (claim 43) which are 100% identical to the instant claimed CDRs of claim 1, 10 mM histidine buffer at a pH about 5.8 (claim 27/ 1/ 2), 50 mg/ml sucralose (claim 27/ 1/ 2), 0.2 mg/ml polysorbate 80 (claim 27/ 1/ 2), 70 mM arginine (claim 27/ 1/ 2), and molar ratios of LAG3: PD-1 antibodies of 1:1, 2:1, 3:1 and 3.5 (claim 38/ 37/ 36/ 1-35).
Regarding claims 12-17, 22-34, 36-37, 39, and 46-47, the copending application claims teach a formulation comprising 10-120 mg/ml LAG3 antibody (claim 42/ 36-41/ 1-35), 10-120 mg/ml PD1 antibody (claim 42/ 36-41/ 1-35), 10 mM histidine buffer at a pH about 5.8 (claim 27/ 1/ 2), 50 mg/ml sucralose (claim 27/ 1/ 2), 0.2 mg/ml polysorbate 80 (claim 27/ 1/ 2), 70 mM arginine (claim 27/ 1/ 2), and molar ratios of LAG3: PD-1 antibodies of 1:1, 2:1, 3:1 and 3.5 (claim 38/ 37/ 36/ 1-35).
The copending application does not teach formulation of the anti PD1 antibody at 3-7 mg/ml or a molar ratio of 4:1 of LAG3: PD1 antibodies. The copending application does not teach arginine and NaCl in the same formulation or a ratio of 1:1 arginine to NaCl.
KEYTRUDA teaches a formulation of pembrolizumab with a final concentration of 1-10 mg/ml (page 6). KEYTRUDA further teaches there are no clinically significant differences in efficacy and safety between pembrolizumab doses of 200mg or 2 mg/kg in patients (page 26).
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 patented claims to formulate anti-PD-1 and LAG3 antibodies in a pharmaceutical composition. The taught molar ratios are very close to the instant claimed ratio and the dosing range of the copending application could encompass a 4:1 ratio of LAG3: PD1 if the guidance of KEYTRUDA were incorporated. The ordinary artisan would have been motivated to do so as KEYTRUDA is recognized as an FDA approved antibody formulation, using the primary formulation concentration of this antibody as the starting point for formulation development would have been obvious for a combination treatment with KEYTRUDA as one of the components. As KEYTRUDA teaches various dosing and concentrations of the PD1 antibody and that efficacy of the PD1 antibody is not significantly clinically different between 2 and 200 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. One of ordinary skill in the art would recognize antibody concentration, pH, 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. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).  Regarding claims 43-44, as detailed above the claims do not further limit the scope of the independent claim 1 and are therefore included in this rejection. Therefore, the invention as a whole would be obvious to one of ordinary skill in the art.
This is a provisional nonstatutory double patenting rejection.
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

NEXT 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

CITED REFERENCE SUMMARIES: Ref WO2016028672A1: Claims:
An antibody or antigen-binding fragment thereof that specifically binds human LAG3 comprising:
(a) the CDR1, CDR2, and CDR3 of a V L domain of an immunoglobulin chain that comprises the amino acid sequence set forth in SEQ ID NO: 7, 17, 27, 37, 57, 59, 61, 63, 65, 101, 126, 130, 132, 136, 138, 208, 210, 224, 226, 228, 230, 232, 241, 257, 259, 261, 263, 351, 369, 371, 373, 375, 401, 403, 405, 426, 427, 450-453 or 459-461 ; and/or
(b) the CDR1, CDR2, and CDR3 of a V H domain of an immunoglobulin chain that comprises the amino acid sequence set forth in SEQ ID NO: 2, 12, 22, 32, 45, 47, 49, 51, 53, 55, 67, 69, 71, 73, 75, 77, 79, 81, 83, 85, 87, 89, 91, 93, 95, 97, 99, 103, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 128, 134, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 212, 214, 216, 218, 220, 222, 234, 235, 237, 239, 243, 245, 247, 249, 251, 253, 255, 265, 267, 269, 271, 273, 275, 277, 279, 281, 283, 285, 287, 289, 291, 293, 295, 297, 299, 301, 303, 305, 307, 309, 311, 313, 315, 317, 319, 321, 323, 325, 327, 329, 331, 333, 335, 337, 339, 341, 343, 345, 347, 349, 353, 355, 357, 359, 361, 363, 365, 367, 377, 379, 381, 383, 385, 387, 389, 391, 393, 395, 397, 399, 406-419, 434-442, 448, 449, 462, 463 or 464.
The antibody or fragment of claim 1 which is an antibody comprising:
a light chain variable domain comprising:
CDR-L1 that comprises the amino acid sequence: KASQSLDYEGDSDMN (SEQ ID NO: 38);
CDR-L2 that comprises the amino acid sequence: GASNLES (SEQ ID NO: 39); and
CDR-L3 that comprises the amino acid sequence: QQSTEDPRT (SEQ ID NO: 40); and/or a heavy chain variable domain comprising:
CDR-H1 that comprises the amino acid sequence: DYNVD (SEQ ID NO: 33);
CDR-H2 that comprises the amino acid sequence: DINPNNGGT IYAQKFQE (SEQ ID NO: 458); and CDR-H3 that comprises the amino acid sequence: NYRWFGAMDH (SEQ ID NO: 35); or
CDR-L1 that comprises the amino acid sequence: KASQSLDYEGDSDMN (SEQ ID NO: 38); 

 CDR-L2 that comprises the amino acid sequence: GASNLES (SEQ ID NO: 39); and CDR-L3 that comprises the amino acid sequence: QQSTEDPRT (SEQ ID NO: 40); and/or a heavy chain variable domain comprising:
CDR-H2 that comprises the amino acid sequence: DINPNSGGTIYAQKFQE (SEQ ID NO: 456); and CDR-H3 that comprises the amino acid sequence: NYRWFGAMDH (SEQ ID NO: 35); or
CDR-H2 that comprises the amino acid sequence: DINPNDGGTIYAQKFQE (SEQ ID NO: 457); and CDR-H3 that comprises the amino acid sequence: NYRWFGAMDH (SEQ ID NO: 35); or
CDR-H2 that comprises the amino acid sequence: DINPNQGGTIYAQKFQE (SEQ ID NO: 455); and CDR-H3 that comprises the amino acid sequence: NYRWFGAMDH (SEQ ID NO: 35); or
CDR-H2 that comprises the amino acid sequence: DINPNGGGTIYAQKFQE (SEQ ID NO: 454); and
CDR-H3 that comprises the amino acid sequence: NYRWFGAMDH (SEQ ID NO: 35).
An antibody or antigen-binding fragment thereof that specifically binds human LAG3 comprising a light chain immunogoblin, a heavy chain immunogoblin, or both a light and heavy chain immunoglobulin, selected from the group consisting of:
a light chain immunoglobulin comprising an amino acid sequence having at least 90% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO: 126 or amino acids 21-131 thereof, and/or
a heavy chain immunoglobulin comprising an amino acid sequence having at least 90% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO: 106 or amino acids 1- 119 thereof;
a heavy chain immunoglobulin comprising an amino acid sequence having at least 90% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO: 108 or amino acids 1- 119 thereof;
a heavy chain immunoglobulin comprising an amino acid sequence having at least 90% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO: 110 or amino acids 1- 119 thereof;
a heavy chain immunoglobulin comprising an amino acid sequence having at least 90% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO: 112 or amino acids 1- 119 thereof;
(5) 

 a light chain immunoglobulin comprising an amino acid sequence having at least 90% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO: 126 or amino acids 21-131 thereof, and/or
a heavy chain immunoglobulin comprising an amino acid sequence having at least 90% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO: 114 or amino acids 1- 119 thereof;
a heavy chain immunoglobulin comprising an amino acid sequence having at least 90% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO: 116 or amino acids 1- 119 thereof;
a heavy chain immunoglobulin comprising an amino acid sequence having at least 90% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO: 118 or amino acids 1- 119 thereof;
a heavy chain immunoglobulin comprising an amino acid sequence having at least 90% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO: 120 or amino acids 1- 119 thereof; and
a heavy chain immunoglobulin comprising an amino acid sequence having at least 90% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO: 122 or amino acids 1- 119 thereof.
The antibody or antigen-binding fragment of claim 3 comprising:
a light chain immunoglobulin comprising CDR-L1, CDR-L2 and CDR-L3 of the
immunoglobulin comprising the amino acid sequence of SEQ ID NO: 126 or amino acids 21-131 thereof, and having at least 90% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO: 126 or amino acids 21-131 thereof, and/or
a heavy chain immunoglobulin comprising CDR-H1, CDR-H2 and CDR-H3 of the
immunoglobulin comprising the amino acid sequence of SEQ ID NO: 106 or amino acids 1-119 thereof, and having at least 90% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO: 106 or amino acids 1-119 thereof; or
immunoglobulin comprising the amino acid sequence of SEQ ID NO: 108 or amino acids 1-119 thereof, and having at least 90% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO : 108 or amino acids 1-119 thereof; or
immunoglobulin comprising the amino acid sequence of SEQ ID NO: 110 or amino acids 1-119 thereof, and having at least 90% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO: 110 or amino acids 1-119 thereof; or
immunoglobulin comprising the amino acid sequence of SEQ ID NO: 126 or amino acids 21-131 thereof, and having at least 90% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO: 126 or amino acids 21-131 thereof, and/or 

 a heavy chain immunoglobulin comprising CDR-H1, CDR-H2 and CDR-H3 of the immunoglobulin comprising the amino acid sequence of SEQ ID NO: 112 or amino acids 1-119 thereof, and having at least 90% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO: 112 or amino acids 1-119 thereof; or
immunoglobulin comprising the amino acid sequence of SEQ ID NO: 114 or amino acids 1-119 thereof, and having at least 90% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO: 114 or amino acids 1-119 thereof; or
immunoglobulin comprising the amino acid sequence of SEQ ID NO: 116 or amino acids 1-119 thereof, and having at least 90% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO: 116 or amino acids 1-119 thereof; or
immunoglobulin comprising the amino acid sequence of SEQ ID NO: 118 or amino acids 1-119 thereof, and having at least 90% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO: 118 or amino acids 1-119 thereof; or
immunoglobulin comprising the amino acid sequence of SEQ ID NO: 126 or amino acids 21-131 

 thereof, and having at least 90% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO: 126 or amino acids 21-131 thereof, and/or
immunoglobulin comprising the amino acid sequence of SEQ ID NO: 120 or amino acids 1-119 thereof, and having at least 90% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO: 120 or amino acids 1-119 thereof; or
immunoglobulin comprising the amino acid sequence of SEQ ID NO: 122 or amino acids 1-119 thereof, and having at least 90% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO : 122 or amino acids 1-119 thereof.
The antibody or antigen-binding fragment of any one of claims 3-4 wherein said sequence identity is at least 95%, 96%, 97%, 98%, 99% or 100%.
The antibody or antigen-binding fragment of claim 5 comprising:
a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 126 or amino acids 21-131 thereof, and/or
a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 106 or amino acids 1-119 thereof; or
a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 108 or amino acids 1-119 thereof; or
a light chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 126 or amino acids 21-131 thereof, and/or 

 a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 110 or amino acids 1-119 thereof; or
a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 112 or amino acids 1-119 thereof; or
a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 114 or amino acids 1-119 thereof; or
a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 116 or amino acids 1-119 thereof; or
a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 118 or amino acids 1-119 thereof; or
a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 120 or amino acids 1-119 thereof; or
a heavy chain immunoglobulin comprising the amino acid sequence set forth in SEQ ID NO: 122 or amino acids 1-119 thereof.
The antibody or antigen-binding fragment thereof of claim 1 comprising: 

 a mature or unprocessed V L domain or light chain immunoglobulin of SEQ ID NO: 7, 17, 27, 37, 57, 59, 61, 63, 65, 101, 126, 130, 132, 136, 138, 208, 210, 224, 226, 228, 230, 232, 241, 257, 259, 261, 263, 351, 369, 371, 373, 375, 401, 403, 405 or 422-430; and/or
a mature or unprocessed V R domain or heavy chain immunoglobulin of SEQ ID NO: 2, 12, 22, 32, 45, 47, 49, 51, 53, 55, 67, 69, 71, 73, 75, 77, 79, 81, 83, 85, 87, 89, 91, 93, 95, 97, 99, 103, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 128, 134, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 212, 214, 216, 218, 220, 222, 234, 235, 237, 239, 243, 245, 247, 249, 251, 253, 255, 265, 267, 269, 271, 273, 275, 277, 279, 281, 283, 285, 287, 289, 291, 293, 295, 297, 299, 301, 303, 305, 307, 309, 311, 313, 315, 317, 319, 321, 323, 325, 327, 329, 331, 333, 335, 337, 339, 341, 343, 345, 347, 349, 353, 355, 357, 359, 361, 363, 365, 367, 377, 379, 381, 383, 385, 387, 389, 391, 393, 395, 397, 399, 406-421 or 431-442.
An antibody or antigen-binding fragment thereof that specifically binds human LAG3 that: (i) binds to human LAG3 by contacting residues QEGAPAQL (amino acids 35-42 of SEQ ID NO: 443) and RPARRADAGEYRAAVH (amino acids 137-152 of SEQ ID NO: 443) and, optionally, residues DERGRQRGDFSLW (amino acids 123-135 of SEQ ID NO: 443) of LAG3; or residues S PT i PLQDL (amino acids 45-53 of SEQ ID NO: 443) and, optionally DERGRQRGDFSL (amino acids 123-134 of SEQ ID NO: 443); or residues HPLAPGPHPAAPS SWGPRPRRYTVL (amino acids 78-102 of SEQ ID NO: 443); and/or
(ii) specifically binds to human LAG3 and comprises a heavy chain immunoglobulin variable region having at least 78.99% amino acid sequence identity to amino acids 1-1 19 of SEQ ID NO: 106; and/or a light chain immunoglobulin variable region having at least 78.38% amino acid sequence identity to amino acids 1-111 of SEQ ID NO: 224;
wherein the antibody or fragment optionally cross-blocks or is cross-blocked by an antibody or fragment of any one of claims 1-7.
The antibody or fragment of any one of claims 1-8 which is glycosylated with engineered yeast N-linked glycans or CHO N-linked glycans.
The antibody or fragment of any one of claims 1 and 3-8 which is an antibody.
A composition or kit comprising the antibody or fragment of any of claims 1-10 in association with a further therapeutic agent.
A polypeptide comprising an amino acid sequence selected from the group consisting of 2, 3, 4, 5, 7, 8, 9, 10, 12, 13, 14, 15, 17, 18, 19, 20, 22, 23, 24, 25, 27, 28, 29, 30, 32, 33, 34, 35, 37, 38, 39, 40, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 81, 83, 85, 87, 89, 91, 93, 95, 97, 99, 101, 103, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210, 212, 214, 216, 218, 220, 222, 224, 226, 228, 230, 232, 234, 235, 237, 239, 241, 243, 245, 247, 249, 251, 253, 255, 257, 259, 261, 263, 265, 267, 269, 271, 273, 275, 277, 279, 281, 283, 285, 287, 289, 291, 293, 295, 297, 299, 301, 303, 305, 307, 309, 311, 313, 315, 317, 319, 321, 323, 325, 327, 329, 331, 333, 335, 337, 339, 341, 343, 345, 347, 349, 351, 353, 355, 357, 359, 361, 363, 365, 367, 369, 371, 373, 375, 377, 379, 381, 383, 385, 387, 389, 391, 393, 395, 397, 399, 401, 403, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 426, 427, 434, 435, 436, 437, 438, 439, 440, 441, 442, 446, 448, 449, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463 and 464; or a mature fragment and/or variable
immunoglobulin domain thereof.
A polynucleotide encoding the polypeptide of claim 12.
A vector comprising the polynucleotide of claim 13.
A host cell comprising the antibody, fragment, polypeptide, polynucleotide or vector of any of claims 1-10, 12, 13 or 14.
A composition comprising the antibody, antigen-binding fragment, polypeptide,
polynucleotide or vector of any one of claims 1-10, 12, 13 or 14 and a pharmaceutically acceptable carrier or diluent; optionally in association with a further therapeutic agent .
A vaccine comprising an antigen and a pharmaceutically acceptable carrier in association with an antibody or fragment or composition of any of claims 1-11.
A vessel or injection device comprising the antibody, antigen-binding fragment,
composition, polypeptide, polynucleotide or vector of any one of claims 1-10, 12, 13 or 14;
optionally, wherein the vessel or device includes a pharmaceutically acceptable carrier or diluent.
The composition or kit of claim 11 wherein the further therapeutic agent is a member selected from the group consisting of:
an anti-cancer therapeutic agent, an inhibitor of an immunomodulatory receptor, an anti-emetic, an MTOR (mammalian target of rapamycin) inhibitor, a cytotoxic agent, a platinum agent, an EGFR inhibitor, a VEGF inhibitor, a microtubule stabilizer, a taxane, a CD20 inhibitor, a CD52 inhibitor, a CD30 inhibitor, a RANK (Receptor activator of nuclear factor kappa-B) inhibitor, a RANKL (Receptor activator of nuclear factor kappa-B ligand) inhibitor, an ERK inhibitor, a MAP Kinase inhibitor, an AKT inhibitor, a MEK inhibitor, a PI3K inhibitor, a HERl inhibitor, a HER2 inhibitor, a HER3 inhibitor, a HER4 inhibitor, a Bcl2 inhibitor, a CD22 inhibitor, a CD79b inhibitor, an ErbB2 inhibitor, a farnesyl protein transferase inhibitor, an anti-PDl antibody or an antigen-binding fragment thereof, pembrolizumab, nivolumab, CT-011, anti- CTLA4 antibody or an antigen-binding fragment thereof, anti-TIM3 antibody or an antigen- binding fragment thereof, anti-CSl antibody or an antigen-binding fragment thereof,
elotuzumab, anti-KIR2DLl/2/3 antibody or an antigen-binding fragment thereof, lirilumab, anti- CD 137 antibody or an antigen-binding fragment thereof, urelumab, anti-GITR antibody or an antigen-binding fragment thereof, TRX518, anti-PD-Ll antibody or an antigen-binding fragment thereof, BMS-936559, MSB0010718C, MPDL3280A, anti-PD-L2 antibody or an antigen- binding fragment thereof, anti-ILTl antibody or an antigen-binding fragment thereof, anti-ILT2 antibody or an antigen-binding fragment thereof, anti-ILT3 antibody or an antigen-binding fragment thereof, anti-ILT4 antibody or an antigen-binding fragment thereof, anti-ILT5 antibody or an antigen-binding fragment thereof, anti-ILT6 antibody or an antigen-binding fragment thereof, anti-ILT7 antibody or an antigen-binding fragment thereof, anti-ILT8 antibody or an antigen-binding fragment thereof, anti-CD40 antibody or an antigen-binding fragment thereof, anti-OX40 antibody or an antigen-binding fragment thereof, anti-CD 137 antibody or an antigen- binding fragment thereof, anti-KIR2DLl antibody or an antigen-binding fragment thereof, anti- KIR2DL2/3 antibody or an antigen-binding fragment thereof, anti-KIR2DL4 antibody or an antigen-binding fragment thereof, anti-KIR2DL5 A antibody or an antigen-binding fragment thereof, anti-KIR2DL5B antibody or an antigen-binding fragment thereof, anti-KIR3DLl antibody or an antigen-binding fragment thereof, anti-KIR3DL2 antibody or an antigen-binding fragment thereof, anti-KIR3DL3 antibody or an antigen-binding fragment thereof, anti-NKG2A antibody or an antigen-binding fragment thereof, anti-NKG2C antibody or an antigen-binding fragment thereof, anti-NKG2E antibody or an antigen-binding fragment thereof, IL-10, anti- IL10, anti-TSLP, PEGylated IL-10, 13-cis-retinoic acid, 3-[5-(methylsulfonylpiperadinemethyl)- 

 indolyl]-quinolone, 4-hydroxytamoxifen, 5-deooxyuridine, 5'-deoxy-5-fluorouridine, 5- fluorouracil, 6-mecaptopurine, 7-hydroxystaurosporine, A-443654, abirateroneacetate, abraxane, ABT-578, acolbifene, ADS-100380, aflibercept, ALT-110, altretamine, amifostine,
aminoglutethimide, amrubicin, Amsacrine, anagrelide, anastrozole, angiostatin, AP-23573, ARQ-197, arzoxifene, AS-252424, AS-605240, asparaginase, AT-9263, ATI3387, atrasentan, axitinib, AZD1152, Bacillus Calmette-Guerin (BCG) vaccine, batabulin, BC-210, BGJ398, besodutox, bevacizumab, bicalutamide, Biol 11, BIO 140, BKM120, bleomycin, BMS-214662, BMS-247550, BMS-275291, BMS-310705, bortezimib, buserelin, busulfan, calcitriol, camptothecin, canertinib, capecitabine, carboplatin, carmustine, CC8490, CEA vaccine, cediranib, CG-1521, CG-781, chlamydocin, chlorambucil, chlorotoxin, cilengitide, cimitidine, cisplatin, cladribine, clodronate, cobimetnib, COL-3, CP-724714, cyclophosphamide, cyproterone, cyproteroneacetate, cytarabine, cytosinearabinoside, dabrafenib, dacarbazine, dacinostat, dactinomycin, dalotuzumab, danusertib, dasatanib, daunorubicin, decatanib, deguelin, denileukin, deoxycoformycin, depsipeptide, diarylpropionitrile, diethylstilbestrol, diftitox, DNE03, docetaxel, dovitinib, doxorubicin, droloxifene, edotecarin, yttrium-90 labeled- edotreotide, edotreotide, EKB-569, EMD121974, encorafenib, endostatin, enzalutamide, enzastaurin, epirubicin, epithilone B, ERA-923, erbitux, erlotinib, estradiol, estramustine, etoposide, everolimus, exemestane, ficlatuzumab, finasteride, flavopiridol, floxuridine, fludarabine, fludrocortisone, f uoxymesterone, f utamide, FOLFOX regimen, fulvestrant, galeterone, ganetespib, gefitinib, gemcitabine, gimatecan, glucopyranosyl lipid A, goserelin, goserelin acetate, gossypol, GSK461364, GSK690693, HMR-3339,
hydroxyprogesteronecaproate, hydroxyurea, IC87114, idarubicin, idoxyfene, ifosfamide, IM862, imatinib, imiquimod, IMC-1C11, INCB24360, INC280, INO1001, interferon, interleukin-2, interleukin-12, ipilimumab, irinotecan, JNJ- 16241199, ketoc
[Truncated to input limit]