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 .
Claims Status
Claims 2-5, 10-15, and 56-57 are canceled. Claims 1, 6-9, 16-30, 32-33, 35-55 and 58 are pending and are examined on the merits.
Rejections Withdrawn
Claims 2-5, 10-15, and 56-57 are canceled, rendering all rejections thereof moot.
Rejections of Claims 16-19, 38-55, and 58 made under 35 U.S.C. 112(a) are withdrawn in view of applicant’s amendments removing the “antigen fragment thereof” language.
Provisional double patenting rejections made over copending application 18/317,241 are withdrawn in view of amended claims of ‘241 filed 09/12/2025 which no longer encompass a method of treating cancer by combined administration of LAG3 and PD-1 antibodies.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 6-9, 16-30, 32-33, 35-55 and 58 are rejected under 35 U.S.C. 103 as being unpatentable over Ullman et al. 2017 (US 2017/0101472 A1; of record), herein “Ullman”, and further in view of Lowy et al. 2017 (US 2017/0327590 A1; of record), herein “Lowy”, and Hendrikx et al. 2017 (The oncologist, 22(10), 1212-1221.; of record), herein “Hendrikx”.
Ullman teaches a method of treating cancer comprising administering a combination of anti-LAG3 antibody and anti-PD-1 antibody (Example 19; ¶0342; Ullman claims 28-39).
Regarding instant Claims 1, 32-33, and 46 Ullman teaches the anti-PD-1 antibody is “REGN2810”, which comprises the instantly claimed sequences as evidenced by the instant specification (¶0073).
Regarding instant Claims 1, 35-36, and 46 Ullman teaches the anti-LAG3 is an antibody termed “mAb1” that is identical to the “REGN3767” antibody described in the instant application and comprises the same sequences. See sequence alignments below (CDRs are highlighted):
REGN3767 HC – Instant SEQ ID NO: 19 (SEQ19); Ullman SEQ ID 577 (U577)
SEQ19 1 QVQLVESGGGVVQPGRSLRLSCVASGFTFSSYGMHWVRQAPGKGLEWVAIIWYDGSNKYY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
U577 1 QVQLVESGGGVVQPGRSLRLSCVASGFTFSSYGMHWVRQAPGKGLEWVAIIWYDGSNKYY 60
SEQ19 61 ADSVKGRFTISRDNSKNTQYLQMNSLRAEDTAVYYCASVATSGDFDYYGMDVWGQGTTVT 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
U577 61 ADSVKGRFTISRDNSKNTQYLQMNSLRAEDTAVYYCASVATSGDFDYYGMDVWGQGTTVT 120
SEQ19 121 VSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
U577 121 VSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL 180
SEQ19 181 QSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPPVAGP 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
U577 181 QSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPPVAGP 240
SEQ19 241 SVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNS 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
U577 241 SVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNS 300
SEQ19 301 TYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEM 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
U577 301 TYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEM 360
SEQ19 361 TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQ 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
U577 361 TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQ 420
SEQ19 421 EGNVFSCSVMHEALHNHYTQKSLSLSLGK 449
|||||||||||||||||||||||||||||
U577 421 EGNVFSCSVMHEALHNHYTQKSLSLSLGK 449
REGN3767 LC – Instant SEQ ID NO: 20 (SEQ20); Ullman SEQ ID 578 (U578)
SEQ20 1 EIVLTQSPATLSLSPGERTTLSCRASQRISTYLAWYQQKPGQAPRLLIYDASKRATGIPA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
U578 1 EIVLTQSPATLSLSPGERTTLSCRASQRISTYLAWYQQKPGQAPRLLIYDASKRATGIPA 60
SEQ20 61 RFSGSGSGTGFTLTISSLEPEDFAVYYCQQRSNWPLTFGGGTKVEIKRTVAAPSVFIFPP 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
U578 61 RFSGSGSGTGFTLTISSLEPEDFAVYYCQQRSNWPLTFGGGTKVEIKRTVAAPSVFIFPP 120
SEQ20 121 SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
U578 121 SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT 180
SEQ20 181 LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 214
||||||||||||||||||||||||||||||||||
U578 181 LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 214
Regarding instant claims 9, 16-19, and 46-49 Ullman teaches that multiple doses of the combined anti-PD-1/anti-LAG3 therapy (i.e. secondary and tertiary doses) are administered after an initial dose (i.e. loading dose) every 3 weeks (¶0189; ¶0353), wherein each secondary and tertiary dose can be administered multiple times at the same frequency after the “immediately preceding dose” (¶0234). Specifically, Ullman teaches “each patient receives mAb1 (+/- REGN2810) every 21 days” and “patients receive up to seventeen 21-day treatment cycles” ¶0354.
Regarding instant Claims 6-8, Ullman teaches “the sequence of study drug administration is mAb1 [i.e. REGN3767] first followed by REGN2810 on the same day” (¶0412).
Regarding instant Claim 20, Ullman teaches the antibodies are administered intravenously (IV; ¶0412).
Regarding instant Claims 21 and 58, Ullman teaches the combination anti-LAG3/anti-PD-1 therapy is applicable to a variety of cancers including, for example, breast cancer, melanoma, and non-small cell lung cancer (Table 19).
Regarding instant Claims 22-25, Ullman teaches the patient population for a clinical trial studying the combination of mAb1/REGN3767 and REGN2810. Among the patients selected are those that have received prior anti-PD-1 therapy but have subsequently progressed (¶0378), those with a histologically confirmed diagnosis of a tumor (¶0384), those for whom no available therapy is expected to convey clinical benefit (¶0374), those without prior therapy (¶0385), anti-PD-1 experienced and anti-PD-1 naïve patients matching the criteria of instant claims 40 and 43 (¶0385-0393).
Regarding instant Claims 26-29 and 37, Ullman teaches the combination of mAb1/REGN3767 and REGN2810 is effective in an in vivo humanized mouse model, and that the combination is more effective than either therapy alone (Example 13-14, Fig. 6-7). Ullman further teaches the combined treatment results in increased survival (Fig. 6C, Fig. 7C), reduces tumor volume (Fig. 6A-B, Fig 7A-B), delays tumor growth by at least 10 days (e.g., Table 16, compare “Day 17” to “Day 7”), and inhibits tumor growth by at least 50% compared to untreated mice (e.g., Table 17, compare # of “tumor-free mice”).
Regarding instant Claim 30, Ullman teaches the anti-LAG3 antibody can be combined with “any additional therapeutic agent” including “one or more” antibodies, as well as chemotherapeutics, cancer vaccines, and radiation, etc. (§ Combination Therapies, ¶0219-0223). In addition, Ullman teaches that patients enrolled in the planned trial and receiving the combination REGN3767 and REGN2810 therapy may additionally be treated with a corticosteroid (i.e. “anti-inflammatory drug”) (¶0403 “Patients who require a brief course of steroids are not excluded”).
Regarding Claims 44-45, Ullman teaches patients receiving anti-LAG3 monotherapy, after having received at least 4 doses of monotherapy (i.e. 1-12 months), can additionally receive anti-PD-1 therapy in combination (¶0371).
Regarding Claims 51-52, Ullman teaches the anti-LAG3 antibody mAb1/REGN3767 can be administered at a dose of, for example, 1, 3, or 10 mg/kg (¶0352; Ullman claim 33).
Ullman teaches that the 1, 3, and 10 mg/kg doses are used to determine a maximum tolerated dose (MTD) in a dose escalation study, but “if dose escalation is not stopped for [dose-limiting toxicities], it will be considered that the MTD has not been determined” (¶0369).
Ullman teaches a dose of 25 mg/kg of mAb1/REGN3767 in a preclinical mouse model (Example 13) and demonstrates that, in combination with an anti-PD-1 antibody, tumor reduction improved with increasing an increasing dose of anti-LAG3 antibody (¶0327; Fig. 8A).
Ullman teaches that Cynomolgus monkeys were administered increasing doses of mAb1/REGN3767 up to a final dose of 50 mg/kg, and that no toxic effects were observed: “mAb1 was well tolerated at all dose levels” and “there were no mAb1 related changes in any safety parameters evaluated”.
Ullman does not teach a dose of anti-PD-1 antibody (i.e. REGN2810/cemiplimab) of 350 mg or the a fixed dose of anti-LAG3 antibody (i.e. REGN3767/”mAb1”) of 1600mg. These deficiencies are cured by Lowy and Hendrikx.
Lowy teaches a method of treating skin cancer, such as melanoma, comprising administering anti-PD-1 antibody REGN2810 (Lowy claims 1, 4).
Lowy teaches REGN2810 is administered at a dose of 350 mg every 3 weeks (¶0475; Lowy claim 17), including multiple “secondary” and “tertiary” doses 3 weeks after the “immediately preceding dose” (¶0127).
Lowy teaches the method of treatment further comprises administering a LAG3 inhibitor (Lowy Claim 23), such as an anti-LAG3 antibody (¶0076).
Hendrikx teaches that although monoclonal antibodies are typically administered in body-size-based dosing schedules, body size has only a minimal effect on distribution and elimination of most antibodies – and the usually wide therapeutic window of such antibodies used in oncology do not support body-size-based dosing (Abstract; Table 1).
Hendrikx teaches that, for example, anti-PD-1 antibody nivolumab has a wide therapeutic window, with doses between 1-10 mg/kg all equally effective, which supported a recent FDA approval of a fixed-dose regimen (Pg. 1217, Col.2 ¶2). Hendrikx proposes fixed dosing regimens for a variety of existing monoclonal antibodies (Table 1) and suggests that pharmacokinetic and pharmacodynamic data supports a strong rationale for applying fixed dosing to “almost all monoclonal antibodies used in oncology”.
Hendrikx further teaches that shifting from body-size-based dosing to fixed dosing of monoclonal antibodies would simplify compounding, reduce spillage, decrease dosing errors, and lower cost of such expensive biologics (Introduction; Table 4).
Lowy teaches a method of treating skin cancer, such as melanoma, comprising administering anti-PD-1 antibody REGN2810 (Lowy claims 1, 4).
Lowy teaches REGN2810 is administered at a dose of 350 mg every 3 weeks (¶0475; Lowy claim 17), including multiple “secondary” and “tertiary” doses 3 weeks after the “immediately preceding dose” (¶0127).
Lowy teaches the method of treatment further comprises administering a LAG3 inhibitor (Lowy Claim 23), such as an anti-LAG3 antibody (¶0076).
Hendrikx teaches that although monoclonal antibodies are typically administered in body-size-based dosing schedules, body size has only a minimal effect on distribution and elimination of most antibodies – and the usually wide therapeutic window of such antibodies used in oncology do not support body-size-based dosing (Abstract; Table 1).
Hendrikx teaches that, for example, anti-PD-1 antibody nivolumab has a wide therapeutic window, with doses between 1-10 mg/kg all equally effective, which supported a recent FDA approval of a fixed-dose regimen (Pg. 1217, Col.2 ¶2). Hendrikx proposes fixed dosing regimens for a variety of existing monoclonal antibodies (Table 1) and suggests that pharmacokinetic and pharmacodynamic data supports a strong rationale for applying fixed dosing to “almost all monoclonal antibodies used in oncology”.
Hendrikx further teaches that shifting from body-size-based dosing to fixed dosing of monoclonal antibodies would simplify compounding, reduce spillage, decrease dosing errors, and lower cost of such expensive biologics (Introduction; Table 4).
Accordingly, it would have been obvious to one of ordinary skill in the art that the method of treating cancer comprising administering anti-LAG3 antibody REGN3767 in combination with anti-PD-1 antibody REGN2810 could be modified to incorporate a fixed dose of 350 mg REGN2810 as taught by Lowy. Moreover, in view of the teachings of Hendrikx, a fixed dose of REGN3767 according to the instant claims, in lieu of weight-tiered dosing taught by Ullman, would have been obvious.
One would have been motivated to employ the 350 mg dose of REGN2810 taught by Lowy and/or a fixed dose of REGN3767 according to the combined teaching of Hendrikx and Ullman, for example, because Hendrikx teaches fixed doses save money and reduce complexity and mistakes during therapeutic administration.
There would have been a reasonable expectation of success because Hendrikx teaches monoclonal antibodies used in oncology, such as immune checkpoint inhibitors, generally have a wide therapeutic window, Ullman teaches doses of REGN3767 overlapping in scope with the instant claims, and Lowy teaches the 350mg dose of REGN2810 can be combined with additional therapeutics, such as anti-LAG3 antibodies.
The skilled artisan would have further been motivated to employ a higher dose of mAb1/REGN3767 such as 1600 mg because Ullman teaches that increased doses of mAb1/REGN3767 resulted in improved anti-tumor efficacy when combined with anti-PD-1 antibody, and Ullman further suggests that the maximum tolerated dose of mAb1/REGN3767 may be in excess of the 10 mg/kg (i.e. 800 mg) dose. There would have been a reasonable expectation of success because Ullman teaches that mAb1/REGN3767 was effective at a dose of 25 mg/kg in a preclinical in vivo study and no toxic effects of mAb1/REGN3767 were observed in monkeys even at doses up to 50 mg/kg (equivalent to a fixed dose of 4000 mg).
Further, Regarding Claim 50, a dose of 400 mg of mAb1/REGN3767 lies between the fixed dose equivalents of the 3 mg/kg and 10 mg/kg doses taught by Ullman (240 mg and 800 mg, respectively, assuming a patient weight of 80 kg). Moreover, the courts have held “[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) (see MPEP §2144.05). It is well settled that “discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.” In re Boesch, 617 F.2d 272,276, 205 USPQ2d 1843, 1847-48 (Fed. Cir. 1989).
In the instant case, the prior art teaches doses both surrounding (3 mg/kg and 10 mg/kg) and in excess (25 mg/kg and 50 mg/kg) of the claimed anti-LAG3 doses of 400 mg (i.e. 5 mg/kg) or 1600 mg (i.e. 20 mg/kg). Accordingly, discovery of the “optimal” dose through routine optimization is conventional and well within the purview of one of ordinary skill in the art, and the courts, over a period of over 50 years, have consistently held that treatment (i.e. dosage and intervals) optimization is obvious.
Response to Arguments
Applicant's arguments filed 11/04/2025 have been fully considered but they are not persuasive because:
The limitation of an anti-LAG3 dose of either 400 mg or 1600 mg was omitted from the previous rejections. New rejections utilizing the same prior art are presented above addressing this limitation.
Further, regarding applicant’s assertion that the instant claims encompass unexpected results because “it is difficult to predict outcomes in humans based on mouse models”, it is first noted that the claims are not limited to treating human subjects. Moreover, Ullman teaches a dose escalation study in humans comprising doses that straddle and exceed the claimed 400 mg fixed dose, in addition to teaching a strong safety profile observed in monkeys (doses up to 50 mg/kg; a fixed dose equivalent of 4000 mg).
In addition, the efficacy observed in Exhibits B and C required administration of 1600 mg anti-LAG-3 antibody every 3 weeks – whereas the claims recite an alternative dose of 400 mg anti-LAG-3 and, for example, independent Claim 1 does not specify a treatment interval. Accordingly, the claims are not commensurate in scope with the purportedly unexpected results. Moreover, the provided exhibits do not compare or provide any unexpected benefit of the 1600 mg over the 10 mg/kg (800 mg) dose disclosed in Ullman, and the changes in CD4/CD8 T cell counts disclosed in the instant specification (Fig 3, copied below) between the 10 mg/kg and 20 mg/kg doses show modest and linear increases with increasing dose – which would not be surprising in view of Ullman’s disclosure of greater efficacy with increased anti-LAG-3 antibody.
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Conclusion
No claim is allowed.
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/BRYAN WILLIAM HECK/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643