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 .
Status of Application, Amendments and/or Claims
1. Claims 1, 23 and 28-30 have been amended and claims 5-7 have been canceled as requested in the amendment filed April 15, 2026. Following the amendment, claims 1-4 and 8-30 are pending in the present application.
2. Claims 1-4 and 8-30 are under examination in the current office action.
Information Disclosure Statement
3. The information disclosure statement (IDS) filed 04/15/2026 has been considered and the references therein are now of record.
Withdrawn Claim Rejections
4. Any objection or rejection of any of canceled claims 5-7 is rendered moot by applicant’s amendment.
5. The rejection of claims 28 and 30 under 35 U.S.C. 112(b) for being indefinite, as set forth at section 4 of the 01/15/2026 office action, is withdrawn in view of applicant’s clarifying amendments to the claims.
6. The rejection of claims 1-2, 4-12, 14-17 and 19-30 under 35 U.S.C. 103 as being unpatentable over Sharma et al. (US 9,220,776 B2) as evidenced by Wang et al. (Oncoimmunology, 2021, 10(1):1896643), and in view of Li et al. (WO 2017/054646) and Luisi et al. (US 2006/0210557 A1) and Hartl et al. (J Pharm Sci. 2013, 102:4121-4131), as set forth at section 8 of the 01/15/2026 office action, is withdrawn in view of applicant’s amendments to the claims to delete (2-hydroxypropyl)-b cyclodextrin from the claims.
7. The terminal disclaimer filed on April 15, 2026 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of U.S. Patent No. 11,633,476 and any patent granted on U.S. Patent Application Nos. 19/346,648, 19/346,638, 18/182,135 and 18/182,097 has been reviewed and is accepted. The terminal disclaimer has been recorded.
Accordingly, the non-statutory double patenting rejections over the claims of the aforementioned patent and patent applications have been overcome.
Maintained Claim Rejections
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.
8. Claim(s) 1-2, 4, 8-12, 14-17 and 19-30 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sharma et al. (US 9,220,776 B2) as evidenced by Wang et al. (Oncoimmunology, 2021, 10(1):1896643), and in view of Li et al. (WO 2017/054646 A11; Pub April 6, 2017 with priority to earlier filing date) and Luisi et al. (US 2006/0210557 A1) (all references listed on 10/01/2025 IDS). The rejection is maintained for reasons of record and as discussed below.
The basis for this rejection has been set forth previously (see section 5 of the 01/15/2026 office action) and therefore will not be reiterated here.
Response to Arguments
9. In the response filed 04/15/2026, applicant argues that the claimed invention is not rendered obvious by the cited references because there is not reason to combine the references “other than hindsight gained from the invention itself” (citing various case law). According to applicant, a person of skill in the art would not have been motivated to arrive at the claimed compositions based upon the combination of references, and further, the references do not provide a reasonable expectation of success.
Applicant further argues that formulation of claim 1 possesses improved properties that were not predicted by the cited references, and there would have been no motivation to combine the references because the claimed invention solves a problem not recognized in the art. In particular, “the claimed formulations have sufficiently low viscosity while minimizing aggregation and oxidation, and the claimed formulations provide a stable formulation in which the amount of oxidation of the methionine amino acid at position 105 (met105) within a heavy chain CDR of pembrolizumab is reduced.” It is asserted that the skilled artisan was unaware of the problem of Met105 oxidation in the pembrolizumab CDRs, and thus he/she would not have been motivated to combine the teachings of Li and Luisi with those of Sharma.
Applicant points to Example 2 of the specification, which tested the stability of five pembrolizumab formulations at three different temperatures over a period of 12 weeks, Example 8, which was performed with high concentration antibody formulations, and Example 12, which confirmed the beneficial effects of adding an antioxidant to the formulation, in arguing that the present claims are directed to formulations experimentally shown to reduce oxidation of a key amino acid in pembrolizumab. Thus, applicant again contends that because the problem of Met105 oxidation in CDR-H3 was not recognized in the art, the skilled person would neither have been motivated to combine the cited references nor would have had a reasonable expectation of success at the time of filing.
10. Applicant’s arguments have been considered but are not persuasive. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). In the instant case, the components of antibody formulations (i.e., buffer, stabilizer/cryoprotectant/bulking agent, surfactant, antioxidant) as well as their commonly used concentrations and/or w/v percentages were well-known in the art at the time of filing and were routinely used within the formulation of pharmaceutical antibody and protein compositions. Each of Sharma, Li and Luisi teach such components of antibody formulations; Sharma teaches formulations comprising pembrolizumab, Li teaches formulations comprising anti-PD-1 antibodies, and Luisi teaches formulations comprising therapeutic antibodies generally.
Further, Sharma provides an exemplary liquid antibody formulation comprising 10 mM histidine buffer, pH 5.5, 7% sucrose, 0.02% polysorbate 80, and 25 mg/ml h409A11 (i.e., pembrolizumab) (col. 20 lines 16-18), which differs from the instant formulation of claim 1 only in that sucrose is used instead of trehalose. Yet Sharma also teaches that trehalose and sucrose are equivalent stabilizing protectants, and thus their substitution would have been obvious and predictable. Similarly, Li discloses that sucrose and trehalose are both suitable stabilizing agents for anti-PD-1 antibody formulations, and both Li and Luisi collectively teach that arginine, proline and glycine may also be considered for such use. Therefore, one of ordinary skill in the art not only would have recognized that sucrose and trehalose (or arginine, glycine or proline) were functionally equivalent saccharide stabilizers, rendering their substitution obvious, but also would have had reasonable expectation that substituting trehalose for sucrose would be successful.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, the simple substitution of trehalose for sucrose in the formulation taught by Sharma would have been obvious and predictable because, as discussed above, these are known to be functionally equivalent stabilizers (also called tonicity agents or lyoprotectants, and include amino acids such as arginine, proline and glycine) in the art. As such, the recited formulation of claim 1 would have been obvious as well as predictable.
The prior art references also recognized that the addition of antioxidants, such as methionine or EDTA, can act to reduce oxidation and antibody aggregation as taught by both Li and Luisi. Li also teaches that stabilizers such as arginine are useful in anti-PD-1 antibody formulations. Thus, all elements of the presently claimed formulations are provided for in the prior art teachings, and the combination of these components into an antibody formulation comprising pembrolizumab would have been obvious and reasonably predictable.
And in response to applicant's argument that the claimed formulations provide a stable formulation in which the amount of oxidation at Met105 CDR-H3 of pembrolizumab is reduced, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). The prior art references clearly recognize that the stability of antibody products within formulations was a concern due to their tendency to form aggregates within solution. In particular, Luisi specifically discloses formulations for maintaining the stability of polypeptides, including therapeutic antibodies, wherein the formulations include an antioxidant in a sufficient amount so as to inhibit by-product formation, such as the formation of high molecular weight polypeptide aggregates, low molecular weight polypeptide degradation fragments, and mixtures thereof (see abstract). The prior art therefore provides both motivation to use the components of the claimed invention (buffer, stabilizer, surfactant, antioxidant) in an antibody formulation and a reasonable expectation that inclusion of such antioxidants would be successful in maintaining antibody stability.
Furthermore, the results provided in the instant specification are neither surprising nor unexpected. In particular, of the five formulations of Example 2 of the instant specification, four used sucrose as the stabilizer within the formulations, which is exactly what was exemplified by Sharma; the fifth formulation used sorbitol, which is no longer within the scope of the present invention. Similarly, Example 8 used sucrose as the stabilizer, and Example 12 had multiple formulations using a combination of sucrose and sorbitol or glycine. Thus, many of the examples pointed to by applicant do not fall within the scope of the claims and/or are the same as that used by Sharma, and therefore are not persuasive for the assertion of alleged unexpected results.
The rejection of claims 1-2, 4, 8-12, 14-17 and 19-30 is therefore maintained.
11. Claim(s) 1-2, 4, 8-12 and 14-30 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sharma et al. (US 9,220,776 B2) as evidenced by Wang et al. (Oncoimmunology, 2021, 10(1):1896643), and in view of Li et al. (WO 2017/054646 A12; Pub April 6, 2017 with priority to earlier filing date) and Luisi et al. (US 2006/0210557 A1) as applied to claims 1-2, 4, 6-12, 14-17 and 19-30 above, and further in view of Sadineni et al. (WO 2016/168716 A1) (all references listed on 10/01/2025 IDS). The rejection is maintained for reasons of record and as discussed below.
The basis for this rejection has been set forth previously (see section 6 of the 01/15/2026 office action) and therefore will not be reiterated here.
Response to Arguments
12. In the response filed 04/15/2026, applicant argues that Sadineni does not remedy the deficiency of Sharma, Li and Luisi as noted above.
13. Applicant’s argument has been considered but is not persuasive. The reasons why the teachings of Sharma, Li and Luisi render obvious the presently claimed invention is discussed above.
14. Claim(s) 1-4, 8-12, 14-17 and 19-30 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sharma et al. (US 9,220,776 B2) as evidenced by Wang et al. (Oncoimmunology, 2021, 10(1):1896643), and in view of Li et al. (WO 2017/054646 A13; Pub April 6, 2017 with priority to earlier filing date) and Luisi et al. (US 2006/0210557 A1) as applied to claims 1-2, 4, 6-12, 14-17 and 19-30 above, and further in view of Wang et al. (Mol. Pharmaceutics, 2015, 12, 4478-4487; hereinafter “Wang 2015”) and Barry et al. (US 2009/0060906 A1) (all references listed on 10/01/2025 IDS). The rejection is maintained for reasons of record and as discussed below.
The basis for this rejection has been set forth previously (see section 7 of the 01/15/2026 office action) and therefore will not be reiterated here.
Response to Arguments
15. In the response filed 04/15/2026, applicant argues that Wang and Barry do not remedy the deficiency of Sharma, Li and Luisi because one of skill in the art, being unaware of the Met105 oxidation in pembrolizumab, would not have been motivated to combine the references nor have a reasonable expectation of success.
16. Applicant’s argument has been considered but is not persuasive. The reasons why the teachings of Sharma, Li and Luisi render obvious the presently claimed invention is discussed above. Furthermore, the addition of arginine as an additional stabilizing agent is taught and suggested by Sharma, Li and Luisi, and further disclosed and exemplified by Wang and Barry. The addition of arginine to the pembrolizumab formulation functions exactly as the prior art teaches: to improve stability of the antibody formulation. Thus, the combination of components as taught by the prior art references amounts to simply combining prior art elements as they are taught to function to achieve a reasonably predictable outcome.
17. Claim(s) 1-2, 4, 8-17 and 19-30 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sharma et al. (US 9,220,776 B2) as evidenced by Wang et al. (Oncoimmunology, 2021, 10(1):1896643), and in view of Li et al. (WO 2017/054646 A14; Pub April 6, 2017 with priority to earlier filing date) and Luisi et al. (US 2006/0210557 A1) as applied to claims 1-2, 4, 6-12, 14-17 and 19-30 above, and further in view of Kang et al. (BioProcess Intl. 2016, 14(4): 40-45) (all references listed on 10/01/2025 IDS). ). The rejection is maintained for reasons of record and as discussed below.
The basis for this rejection has been set forth previously (see section 9 of the 01/15/2026 office action) and therefore will not be reiterated here.
Response to Arguments
18. In the response filed 04/15/2026, applicant argues that Kang does not remedy the deficiency of Sharma, Li and Luisi as noted above.
19. Applicant’s argument has been considered but is not persuasive. The reasons why the teachings of Sharma, Li and Luisi render obvious the presently claimed invention is discussed above.
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.
20. Claims 1-2, 4, 8-12, 14-17 and 19-30 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 and 13 of U.S. Patent No. 9,220,776 in view of Li et al. (US 2018/0339045 A1) and Luisi et al. (US 2006/0210557 A1). The rejection is maintained for reasons of record and as discussed below.
The basis of this rejection has been set forth previously (see section 10 of the previous office action) and therefore will not be reiterated here.
Response to Arguments
21. Applicant argues that one of skill in the art, being unaware of the Met105 oxidation in the pembrolizumab CDR, would not have been motivated to combine the cited claims with the cited references with a reasonable expectation of success. Applicant further asserts that Li does not provide direction as to which buffer, stabilizer, or non-ionic surfactant would be successful.
22. Applicant’s arguments have been considered but are not persuasive. The patented ‘776 claims recite an anti-human PD-1 antibody formulation that is directly on point to each of elements (a), (b) and (d) of present claim 1, and differ from the stabilizer of element (c) only in that the patented claims recite using 7% sucrose instead of the stabilizer(s) of the instant claims. However, as discussed above, the combination of Li and Luisi teach that sucrose, trehalose, glycine, arginine and proline can be used in the capacity of stabilizing agents (also called tonicity agents) within a therapeutic antibody formulation, and thus the substitution of these functionally equivalent stabilizers within the formulation of patented claim 1 would have been obvious and predictable. The rejection is therefore maintained.
23. Claim 3 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4, 8-12, 14-17 and 19-30 of U.S. Patent No. 9,220,776 in view of Li et al. (US 2018/0339045 A1) and Luisi et al. (US 2006/0210557 A1) as applied to claims 1-2, 4, 6-12, 14-17 and 19-30 above, and further in view of Wang et al. (Mol. Pharmaceutics, 2015, 12, 4478-4487; hereinafter “Wang 2015”) and Barry et al. (US 2009/0060906 A1). The rejection is maintained for reasons of record and as discussed below.
The basis of this rejection has been set forth previously (see section 11 of the previous office action) and therefore will not be reiterated here.
Response to Arguments
24. Applicant argues that neither Wang nor Barry remedies the deficiency of the ‘776 patent, Li and Luisi as discussed above with respect to claim 1.
25. Applicant’s arguments have been considered but are not persuasive as discussed above. Wang and Barry provide further teaching and motivation to include L-arginine in an antibody formulation, and therefore the patented ‘776 claims in combination with the teachings of the prior art references still render obvious the presently claimed invention of claim 3.
26. Claim 13 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4, 8-12, 14-17 and 19-30 of U.S. Patent No. 9,220,776 in view of Li et al. (US 2018/0339045 A1) and Luisi et al. (US 2006/0210557 A1) as applied to claims 1-2, 4, 6-12, 14-17 and 19-30 above, and further in view of Kang et al. (BioProcess Intl. 2016, 14(4): 40-45). The rejection is maintained for reasons of record and as discussed below.
The basis of this rejection has been set forth previously (see section 13 of the previous office action) and therefore will not be reiterated here.
Response to Arguments
27. Applicant argues that Kang does not remedy the deficiency of the ‘776 patent in view of Li and Luisi with respect to claim 1 as noted above.
28. Applicant’s arguments have been considered but are not persuasive as discussed above. Kang provides for the use of poloxamer 188 as a surfactant, teaching that it is functionally equivalent to PS80 and therefore its substitution would be obvious and predictable in the art. The rejection is therefore maintained.
29. Claim 18 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 and 13 of U.S. Patent No. 9,220,776 in view of Li et al. (US 2018/0339045 A1) and Luisi et al. (US 2006/0210557 A1) as applied to claims 1-2, 4, 6-12, 14-17 and 19-30 above, and further in view of Sadineni et al. (WO 2016/168716 A1). The rejection is maintained for reasons of record and as discussed below.
The basis of this rejection has been set forth previously (see section 14 of the previous office action) and therefore will not be reiterated here.
Response to Arguments
30. Applicant argues that Sadineni does not remedy the deficiency of the ‘776 patent in view of Li and Luisi with respect to claim 1 as noted above.
31. Applicant’s arguments have been considered but are not persuasive as discussed above. Sadineni provides both motivation for the use of the metal chelator DTPA in a formulation comprising pembrolizumab and a reasonable expectation that the inclusion of DTPA would be successful. The rejection is therefore maintained.
Conclusion
32. No claims are allowed.
33. 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.
Advisory Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Kimberly A. Ballard whose telephone number is (571)272-2150. The examiner can normally be reached Mon-Fri 8AM - 5PM EST.
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, Jeffrey Stucker can be reached at 571-272-0911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KIMBERLY BALLARD/Primary Examiner, Art Unit 1675
1 This document is in Chinese; however, US 2018/0339045 A1 is the English language equivalent of the WO document (PCT/CN2016/098982) and therefore reference and citations within this rejection will be made with respect to the ‘045 publication.
2 This document is in Chinese; however, US 2018/0339045 A1 is the English language equivalent of the WO document (PCT/CN2016/098982) and therefore reference and citations within this rejection will be made with respect to the ‘045 publication.
3 This document is in Chinese; however, US 2018/0339045 A1 is the English language equivalent of the WO document (PCT/CN2016/098982) and therefore reference and citations within this rejection will be made with respect to the ‘045 publication.
4 This document is in Chinese; however, US 2018/0339045 A1 is the English language equivalent of the WO document (PCT/CN2016/098982) and therefore reference and citations within this rejection will be made with respect to the ‘045 publication.
Prosecution Insights