DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Applicant’s reply filed on 8/4/2026 is acknowledged. New claims 22-24 have been added. Claims 4, 5, 7-9, 14 and 18-24 are pending. Claims 1-3, 6, 10-13 and 15-17 are canceled. Claims 4, 5, 7-9 and 18-20 have been amended.
3. Claims 4, 5, 7-9, 14 and 18-24 are under examination.
Information Disclosure Statement
4. The information disclosure statement (IDS) submitted on 6/18/2026 has been considered by the examiner.
Objections and Rejections Withdrawn
5. All objections and rejections in the office action mailed on 3/6/2026 except those maintained below are withdrawn in view of applicant’s amendments.
Rejections Maintained
Claim Rejections - 35 USC § 103
6. 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.
7. Claims 4, 5, 7-9, 14, 18 and 20-24 remain/are rejected under 35 U.S.C. 103 as being unpatentable over Sharma et al (WO 2018/204368A1, pub. date: 11/8/2018, IDS filed on 8/2/2022), in view of Desai al (WO 2018/204374A1, pub. date: 11/8/2018, IDS filed on 8/2/2022).
The rejection has been modified in view of applicant’s amendments.
Claim 19 is withdrawn from the rejection in view of applicant’s persuasive arguments of unexpected results.
Regarding claim 4, Sharma et al. teaches a liquid formulation comprising:
(a) perbrolizumab (an anti-human PD-1 antibody);
(b) sucrose
(c) polysorbate 80 (PS-80, a non-ionic surfactant), and
(d) 10 mM histidine buffer at pH 5.5
(page 60, Table 8, Formulation D1),
The formulation further comprises 20 mM sodium citrate (page 61, Table 9, Formulation E8).
Sharma et al. further teaches that either histidine or citrate buffer can be used as buffer to control pH at about 5.5 (page 28, lines 11-16), and the concentration of the buffer is 5-20 mM (page 28, lines 5-6, and page 61, Table 9),
Regarding claim 5, Sharma et al. teaches that the formulation comprises 20 mM sodium citrate (page 61, Table 9, Formulation E8).
Regarding claim 7, Sharma teaches that the formulation comprises 7% sucrose (corresponding to 205 mM sucrose) (page 60, Table 1, Formulation D1, and page 61, Table 9, Formulation E8).
Regarding claim 8, Sharma teaches that the formulation comprises polysorbate 80 (PS-80) (page 60, Table 1, Formulation D1, and page 61, Table 9, Formulation E8).
Regarding claim 9, Sharma teaches that the formulation comprises 0.02% PS-80 (corresponding to 0.2 mg/ml polysorbate 80) (page 60, Table 1, Formulation D1, and page 61, Table 9, Formulation E8).
Regarding claim 14, Sharma teaches that the formulation may comprise 75 to 200 mg/ml anti-human PD-1 antibody (claim 15) and the anti-human PD-1 antibody is pembrolizumab (claim 38).
Regarding claim 20-21 Sharma et al. further teaches treating cancer by administering the formulation to a subject having cancer, wherein the cancer is melanoma (page 7, line 9-10 and page 10, line 8).
Regarding claim 22, Sharma et al. teaches that the formulation may comprise 5-20 mM buffer, wherein the buffer is citrate buffer (page 28, lines 5-6, and line 15, and page 61, Table 9).
Regarding claim 23, Sharma et al. teaches that the formulation may comprise either polysorbate 20 or polysorbate 80 (page 29, lines 20-22, and page 30, lines 5-6).
Sharma et al. does not specifically teach that concentration of the citrate is 10 mM.
Desai et al. discloses that histidine or L-histidine or citrate can be used in making a coformulation comprising anti-LAG3 antibody and an anti-human PD-1 antibody including pembrolizumab, and a preferred buffer for antibody formulation contains about 10 mM histidine, acetate or citrate mM (page 30, lines 14-15 and page 32, lines 27-29).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used 10 mM citrate buffer in the formulation of Sharma in view of Desai. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success because Sharma et al. teaches that the buffer can be either histidine or citrate buffer (page 28, lines 13-16), and the concentration of the buffer is 5-20 mM (page 28, lines 5-6, and page 61, Table 9), and Desai et al. discloses that a preferred buffer for antibody formulation contains about 10 mM histidine, acetate or citrate (page 30, lines 14-15 and page 32, lines 27-29).
Regarding claim 18, Sharma et al. teaches a liquid formulation consisting of:
(a) perbrolizumab (an anti-human PD-1 antibody);
(b) sucrose
(c) polysorbate 80 (PS-80, a non-ionic surfactant), and
(d) 10 mM histidine buffer at pH 5.5
(page 60, Table 8, Formulation D1).
Sharma et al. further teaches that either histidine or citrate buffer can be used as buffer to control pH at about 5.5 (page 28, lines 11-16), and the concentration of the buffer is 5-20 mM (page 28, lines 5-6, and page 61, Table 9). Sharma et al. teaches that the formulation may be provided as a lyophilized powder and is reconstituted with water for injection (page 37, lines 22-26).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted citrate buffer for histidine buffer in the formulation of Sharma in view of Desai. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success because Sharma et al. teaches that the buffer can be either histidine or citrate buffer (page 28, lines 13-16), and the concentration of the buffer is 5-20 mM (page 28, lines 5-6, and page 61, Table 9), and Desai et al. discloses that a preferred buffer for antibody formulation contains about 10 mM histidine, acetate or citrate (page 30, lines 14-15 and page 32, lines 27-29).
When one substitutes 10 mM citrate buffer for 10 mM histidine buffer in the formulation of Sharma, one would have arrived the liquid formulation of claim 18.
Applicant’s Arguments
The response states that (i) none of the cited references disclose or suggest the
liquid pharmaceutical composition of amended claim 4 or of amended claim 18 and (ii) the claimed liquid pharmaceutical composition exhibits unexpected results.
Sharma et al. lists citrate buffer, but only as part of a longer list of possible buffers controlling the pH in the range of 5.0 to 6.4. The Examples of Sharma et al. only tested histidine-and acetate-based compositions. See Sharma et al., Examples 2-14. Desai et al. does not rectify the deficiencies of Sharma et al. The only formulations with an anti-PD1 antibody tested in Desai et al. are those listed in Table 10, which are all based on a histidine buffer. The only citrate-containing formulations investigated in Desai et al. are those in Table 9, which compares formulations containing an anti-LAG3 antibody (and not an anti-human PD 1 antibody) comprising either histidine, acetate or citrate. One of skill in the art would recognize that the results obtained for the anti-LAG3 antibody cannot be transferred to another antibody such as pembrolizumab. Further, the comparison of the three buffer systems shows that a histidine- based formulation is superior to a citrate-based formulation, as it had a lower amount of aggregates than the citrate-based formulation (see Figure 35). Consequently, it was concluded:
As seen in Figure 35, 10 mM L-histidine buffer in presence of 70 mM L-arginine hydrochloride is effective in reducing soluble aggregates levels compared to 10 mM L- acetate or 10 mM citrate buffer for high concentration of anti-LAG3 formulation (200 mg/mL). 5% (w/v) sucrose is effective as a stabilizer in reducing soluble aggregate levels further, followed by 5% (w/v) glycerol. The stabilizing effect of amino acids i.e., 70 mM L-glutamine, 70 mM L-glycine, 70 mM praline and 70 mM L-methionine is comparable. See Desai et al., page 78, lines 12-17. Hence, even if, contrary to the above, one of skill in the art had taken the results obtained with the anti-LAG3 antibody into account when developing a pembrolizumab formulation, they would not have been motivated to use a citrate buffer, but would have used a histidine buffer instead. It follows that amended claims 4 and 18 are patentable over Sharma et al. and/or Desai et al. The other rejected claims depend from amended claims 4 or 18 either directly or indirectly and are also patentable over Sharma et al. and/or Desai et al. for at least the same reasons.
The patentability of the liquid pharmaceutical composition of amended claims 4 and 18 is underscored by the fact that it exhibits unexpected results. These unexpected results include the fact that the combination of citrate buffer and sucrose has a surprising effect on the stability of the antibody. According to Table 5 of the present application, seven histidine-based formulations were compared with three citrate-based formulations, wherein formulation (h) has a composition as required by the claims, i.e., it contains citrate and sucrose and has a pH of 5.5. It was found that:
- In formulation (h) the content of high molecular weight species (HMWS) was more
or less constant during the full storage time. See WO2021/123202, page 35, lines 4-7 and Table 6.
- Formulation (h) had the lowest content of M105 oxidation. See WO2021/123202,
Table 7 and page 37, lines 7-8.
- The lowest content of N325 deamidation was observed when using formulation (h).
See WO2021/123202, page 39, lines 1-3 and Table 8.
It was therefore concluded:
Surprisingly it was found that a formulation comprising a citrate buffer stabilized
pembrolizumab against aggregation at target storage temperature 5°C, even better than
histidine based formulations. Formulation (h), comprising the combination of citrate
buffer with sucrose and polysorbate 80 led to promising results also in minimizing
deamidation and oxidation.
See WO2021/123202, page 43, lines 6-10.
Therefore, the application shows that the combination of citrate buffer and sucrose has unexpected effects on pembrolizumab stability.
Response to Arguments
Applicant’s arguments have been carefully considered but are not persuasive. Regarding claim 4, Sharma et al. teaches a liquid formulation comprising:
(a) perbrolizumab (an anti-human PD-1 antibody);
(b) sucrose
(c) polysorbate 80 (PS-80, a non-ionic surfactant), and
(d) 10 mM histidine buffer at pH 5.5
(page 60 Table 8, Formulation D1).
The formulation further comprises 20 mM sodium citrate (page 61, Table 9, Formulation E8).
Sharma et al. further teaches that either histidine or citrate buffer can be used as buffer to control pH at about 5.5 (page 28, lines 11-16), and the concentration of the buffer is 5-20 mM (page 28, lines 5-6, and page 61, Table 9),
Although Sharma et al. does not specifically teach that concentration of the citrate is 10 mM, Desai et al. teaches that a preferred buffer for antibody formulation contains about 10 mM histidine, acetate or citrate (page 30, lines 14-15 and page 32, lines 27-29).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used 10 mM citrate buffer in the formulation of Sharma in view of Desai. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success because Sharma et al. teaches that the buffer can be either histidine or citrate buffer (page 28, lines 13-16), and the concentration of the buffer is 5-20 mM (page 28, lines 5-6, and page 61, Table 9), and Desai et al. discloses that a preferred buffer for antibody formulation contains about 10 mM histidine, acetate or citrate (page 30, lines 14-15 and page 32, lines 27-29).
Applicant’s arguments of unexpected results are persuasive for claim 19. Accordingly, claim 19 is withdrawn from the rejection. However, the arguments are not persuasive for other claims.
MPEP 716.02(d) states: "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980)”.
As discussed above, Sharma et al. teaches a liquid formulation comprising:
(a) perbrolizumab (an anti-human PD-1 antibody);
(b) 205 mM sucrose
(c) 0.2 mg/ml of polysorbate 80 (PS-80, a non-ionic surfactant), and
(d) 10 mM histidine buffer at pH 5.5
(page 60 Table 8, Formulation D1).
The formulation further comprises 20 mM sodium citrate (page 61, Table 9, Formulation E8).
The instant specification only shows unexpected results for Formulation (h) which consists of 25 mg/ml perbrolizumab, 10 mM citrate buffer, 205 mM sucrose, and 0.2 mg/mml polysorbate 80 with a pH 5.5 (see Table 5 of the instant application). Claims 4, 5, 7-9, 14 and 20-24 recite the term “comprising”, as such the formulation does not preclude the presence of other ingredients. Furthermore, claims 4, 5, 7-9, 14 and 20-24 including claim 18 do not define the concentration of each ingredient. It is known in the art that the stability of the formulation depends on the concentration of each ingredient. Applicants have not shown unexpected results for all the claims.
Double Patenting
8. 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.
9. Claims 4, 5, 7-9, 14, 18 and 20-24 remain/are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 and 18-25 of copending Application No. 18/573,798 (reference application), in view of Sharma et al (WO 2018/204368A1, pub. date: 11/8/2018, IDS filed on 8/2/2022).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-12 and 18-25 of copending Application No. 18/573,798 (reference application) disclose a liquid pharmaceutical composition comprising: (a) an anti-human PD 1 antibody; (b) one or more amino acids other than histidine; (c) a non-ionic surfactant; and (d) citrate buffer, and water for injection and having a pH of 5.0 to 5.8,
wherein the citrate buffer is present in a concentration of 5 mM or 10 mM,
the non-ionic surfactant is polysorbate 20 or polysorbate 80 and is present in a concentration of 0.1 mg/ml to 0.4 mg/ml; preferably of 0.2 mg/ml,
the anti-human PD 1 antibody is pembrolizumab and is present in a concentration of 25 to 80 mg/ml; preferably of 25 mg/ml, and
wherein the one or more amino acids other than histidine is arginine and/or lysine.
The claims of copending application further disclose a method for treating a subject having cancer, comprising administering to the subject the pharmaceutical composition, wherein the cancer is melanoma, non-small cell lung carcinoma, classical Hodgkin lymphoma, urothelial carcinoma, head and neck squamous cell carcinoma, renal cell carcinoma, colorectal cancer, small cell lung cancer, microsatellite instability-high or mismatch repair deficient cancer, primary mediastinal large B-cell lymphoma, gastric or gastroesophageal junction adenocarcinoma, hepatocellular carcinoma, Merkel cell carcinoma, endometrial carcinoma, tumor mutational burden-high cancer, cutaneous squamous cell carcinoma, triple-negative breast cancer or cervical cancer.
The claims of copending application disclose use one or more amino acids other than histidine, such as arginine or lysine as a stabilizer. The claims of copending application do not disclose using sugar such as sucrose as stabilizer.
Sharma et al. teaches that sucrose or trehalose, mannitol, arginine or glycine can be used as stabilizer in the formulation of anti-human PD-1 antibody (page 18, lines 26-27). Sharma et al. teaches using 7% sucrose (205 mM) as a stabilizer (page 31, lines 14-16).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used sucrose as a stabilizer in the formulation of the copending application in view of Sharma. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success because Sharma et al. teaches that sucrose or trehalose, mannitol, arginine or glycine can be used as stabilizer in the formulation of anti-human PD-1 antibody (page 18, lines 26-27).
Applicant’s Arguments
The response states that the instant application is an application filed earlier than the reference Application, the '798 application. Thus, Applicant submits that the Examiner "should withdraw the rejection in the application having the earlier patent term filing date and permit that application to issue as a patent."
Response to Arguments
Applicant’s arguments have been carefully considered but are not persuasive as the instant rejection is not the only rejection remaining at this time.
Conclusion
10. No claims are allowed. Claims 4, 5, 7-9, 14, 18 and 20-24 are rejected. Claim 19 is objected to as being dependent from a rejected claim.
THIS ACTION IS MADE FINAL. 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.
11. Any inquiry concerning this communication or earlier communications from the examiner should be directed to HONG SANG whose telephone number is (571)272-8145. The examiner can normally be reached Monday-Friday 8am-5pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Gregory Emch can be reached at 571-272-8149. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/HONG SANG/Primary Examiner, Art Unit 1646
