The Examiner of your application in the USPTO has changed. To aid in correlating any papers for this application, all further correspondence regarding this application should be directed to Supervisory Patent Examiner Julie Wu.
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 1, 6-9, 20, 22-30, 32-33, 35-38, 40, 41, 43, 44, 46, 47, 49, 51, 52, 54 and 55 are pending and are examined on the merits.
Rejections Withdrawn
All previous rejection of claims 16-19, 21, 39, 42, 45, 50, 53 and 58 are moot in view of claim cancellation.
All previous rejections are withdrawn in view of claim amendments.
New rejections Necessitated by Claim Amendments
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, 20, 22-30, 32-33, 35-38, 40, 41, 43, 44, 46, 47, 49, 51, 52, 54 and 55 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 Skokos et al. 2017 (US 2017/0327567 A1; of record), herein “Skokos”, and Hendrikx et al. 2017 (The oncologist, 22(10), 1212-1221.; of record), herein “Hendrikx”.
Ullman teaches a method of treating cancer in a human comprising administering a combination of anti-LAG3 antibody and anti-PD-1 antibody (Example 19; ¶0008, 0342; Ullman claims 28-39), wherein the cancer is triple negative breast cancer or colorectal cancer (table 19; example 13-14, Fig. 6-7).
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 instant “REGN3767” antibody.
Ullman teaches administering the anti-LAG3 antibody with a flat dose of about 0.1 mg to about 800 mg (¶0189)
Regarding instant claims 9, 46, 47, and 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 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 with colorectal cancer, and that the combination is more effective than either therapy alone (Example 13-14, Fig. 6). 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 a fixed dose of anti-LAG3 antibody (i.e. REGN3767/”mAb1”) of 1600mg. These deficiencies are cured by Lowy and Hendrikx.
Skokos teaches a method of treating cancer, including colorectal or breast cancer, comprised of administering anti-PD-1 antibody every 3 weeks(¶0133; figure 1).
Skokos teaches REGN2810 is administered at a dose of 350 mg every 3 weeks (figure 1), including multiple “secondary” and “tertiary” doses 3 weeks after the “immediately preceding dose” to treat basal cell carcinoma (example 11).
Skokos teaches the method of treatment further comprises administering a LAG3 inhibitor, including an anti-LAG3 antibody (¶0085).
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 to modify the method of treating colorectal or triple negative breast cancer comprised of administering mAb1/REGN3767 and anti-PD-1 antibody REGN2810 of Ullman with 350 mg of anti-PD-1 antibody REGN2810 as taught by Skokos. 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.
Further, 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.
One would have been motivated to employ the 350 mg dose of REGN2810 taught by Lowy and/or a fixed dose of 1600 mg 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.
Further, 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.
Therefore, there would have been a reasonable expectation of success for treating colorectal cancer or triple negative breast cancer comprised of administering 350 mg REGN2810 every three weeks, and 1600 mg mAb1/REGN3767 once every three weeks, because Ullman teaches treating colorectal cancer or triple negative breast cancer comprised of administering mAb1/REGN3767, and 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), Skokos teaches the 350mg dose of REGN2810 can be combined with additional therapeutics, such as anti-LAG3 antibodies, and Hendrikx teaches monoclonal antibodies used in oncology, such as immune checkpoint inhibitors, generally have a wide therapeutic window.
Response to Arguments
Applicants’ arguments filed June 24, 2026 noted unpredictability in the claimed drug combination and treatment regimen. Applicants argued that based on the state of the art, it is unpredictable that the combination of REGN3767 and REGN2810 is effective at treating the claimed cancers.
PNG
media_image1.png
372
774
media_image1.png
Greyscale
Applicant's arguments have been fully considered but they are not persuasive. Contrary to Applicant’s arguments, as discussed above, Ullman and Skokos provided data that administering mAb1/REGN3767 and REGN2810 is effective in an in vivo humanized mouse model with colorectal cancer, and that the combination is more effective than either therapy alone (Example 13-14, Fig. 6). These data demonstrate that there is an expectation of success that administration of mAb1/REGN3767 and REGN2810 is effective at treating cancer.
Applicants’ arguments that the prior art does not teach the claimed dosage of REGN3767 and REGN2810 is administered.
Applicant's arguments have been fully considered but they are not persuasive. As stated above, 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), Skokos teaches the 350mg dose of REGN2810 can be combined with additional therapeutics, such as anti-LAG3 antibodies, and Hendrikx teaches monoclonal antibodies used in oncology, such as immune checkpoint inhibitors, generally have a wide therapeutic window. 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. Thus, through routine optimization it is obvious to modify the flat dose of 350 mg, 800 mg, or 4000mg mAb1/REGN3767 of Ullman to arrive at the instant claimed dose of 1600 mg.
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).
Applicants’ arguments filed June 24, 2026 noted unexpected results for the claimed drug combination to treat unpredictability in the claimed drug combination and treatment regimen to treat melanoma, NSCLC, small cell lung cancer, HNSCC, RCC, DLBCL, cutaneous squamous cell carcinoma, endometrial cancer, triple negative breast cancer, colorectal cancer, or cholangiocarcinoma.
Applicant's arguments have been fully considered but they are not persuasive. Unexpected results are persuasive for the claimed method of treating melanoma (Hamid et al., 2024, Journal of Clinical Oncology, 42:2928-2938). However, unexpected results have not been demonstrated for all the claimed cancers. MPEP 716.02d states “whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support”.
As argued by the Applicant on page 5 of the Applicant’s Remarks and Arguments entered on June 24, 2026, there is unpredictability in safety and responsiveness to immunotherapy:
PNG
media_image2.png
177
770
media_image2.png
Greyscale
Thus, without data demonstrating unexpected improvements for the claimed method of treating all the recited cancers of claim 1, the 103 obviousness rejection is maintained.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JULIE WU whose telephone number is (571)272-5205. The examiner can normally be reached M-F 9-5PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Bonnie Eyler can be reached at 571-272-1200. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
Prosecution Insights