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 .
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 86 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 86 recites that the ABP has a maximum percentage of fucosylation. This claims read on the percent fucosylation of a single ABP (“the ABP”). It is unclear how one would assess the percent fucosylation of a single ABP. From the description of Figure 24, it seems that Applicant has assessed the percent of a population, or production lot, of ABP which is fucosylated. The assessment of percent of a population of ABP is further supported in paragraphs 00365-00367. For the purpose of compact prosecution, the claims will be interpreted as reciting a percentage of a population of ABP which is fucosylated.
Examiner suggests mirroring the amended language of claim 1. Specifically, replace “ABP is” in claim 86 with “antibodies in the pharmaceutical composition are”.
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 66-69, 71, 75, 76, 85, 86, 105, and 109 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 and 7-13 of U.S. Patent No. 12,421,311 B2 in view of Dijk et al. (WO 2016/196237 A1: Published: December 8, 2016), Mishra et al. (Journal of Biotechnology. 324S: 100015; Published Online: February 20, 2020), and Misaghi et al. (WO 2017/079165 A1; Published: May 11, 2017).
Regarding instant claims 66 and 67, issued claims 1-3 recite an ABP with CDRs comprising SEQ ID NOs: 1014, 2014, 3014, 4014, 5014, and 6014, which are 100% identical to instant SEQ ID NOs: 1014, 2014, 3014, 4014, 5014, and 6014 and an ABP comprising a VL and VH at least 97% identical to SEQ ID NOs: 14 and 114, respectively, which are 100% identical to instant SEQ ID NOs: 14 and 114.
Regarding instant claims 68 and 69, issued claims 4 and 5 teach that the ABP is a scFv or full-length monoclonal antibody and comprises an immunoglobulin constant region.
Regarding instant claim 85, issued claim 7 teaches that a pharmaceutical composition comprising an excipient.
Regarding instant claims 105 and 109, issued claims 8-10 teach a method of treating cancer comprising administering the ABP and one or more additional therapeutic agents.
While the issued claims teach a method of producing the ABP comprising expression in a host cell and isolation, the issued claims do not teach that the ABP is afucosylated or means of producing an afucosylated antibody.
Regarding instant claim 75, Dijk et al. teaches an anti-CTLA-4 antibody which comprises an afucosylated Fc region; see claim 55. Regarding instant claim 86, Dijk et al. teaches that at least 70% of the antibodies will not be fucosylated; see paragraph 0094. Regarding claim 76, Dijk et al. teaches methods of producing afucosylated antibodies including culturing in the absence of fucose or expression in cells lacking α1,6-fucosyltransferase (Fut8); see paragraph 00230. Regarding claim 71, Dijk et al. teaches an afucosylated anti-CTLA4 antibody which is an IgG1 antibody; see antibody AGEN1884w N297A.
Dijk et al. does not teach the use of a fucosylation inhibitor (2FF) or the bacterial protein RMD.
Mishra et al. teaches engineering strageties to control fucosylation of monoclonal antibodies. Regarding claim 76, Mishra et al. teaches that treatment of cell cultures with either 2FF or RMD resulted in decreased fucosylation; see sections 3.1. and 3.2.
It would have been obvious to one of ordinary skill in the art to produce the anti-CTLA-4 antibody of U.S. Patent No. 12,421,311 B2 further comprising an afucosylated Fc region by the methods taught be Dijk et al. or Mishra et al. Given that Dijk et al. teaches producing an anti-CTLA-4 antibody comprising an afucosylated Fc region, one would have had a reasonable expectation of success producing the anti-CTLA-4 antibody of U.S. Patent No. 12,421,311 B2 further comprising an afucosylated Fc region. One would have been motivated to produce this afucosylated anti-CTLA-4 antibody because Mishra et al. teaches that the use of an antibody in cancer immunotherapy is dependent of the antibody’s antibody-dependent cell cytotoxicity (ADCC) response and that this response can be increased by afucosylation; see page 1 right column and page 2 left column.
Regarding claim 86 which recite minimum and maximum percent fucosylation in antibody populations of a pharmaceutical composition, it would have been obvious to one of ordinary skill in art and one would have been a reasonable expectation of success to optimize through routine optimization the percent fucosylation. Given that afucosylation increases the ADCC response, one of ordinary skill in the art would be motivated to optimize the percent fucosylation of the ABPs in the pharmaceutical composition such that the desired ADCC response necessary for treatment efficacy is achieved while minimizing the risks of adverse effects. The instant disclosure does not demonstrated that any of the minimum or maximum percent fucosylation are critical to the claimed invention. Indeed, Misaghi et al. demonstrated that almost 80% of the ADCC activity demonstrated by a fully afucosylated antibody species was maintained in a species comprising only 60% afucosylation; see paragraph 0318. Thus, “it is not necessary to have 100% fully afucosylated antibodies in order to achieve nearly maximum levels of ADCC activity.”
It would have been obvious to one of ordinary skill in the art to construct the anti-CTLA-4 ABP taught by U.S. Patent No. 12,421,311 B2 as an IgG1 antibody as taught by Dijk et al. Given that Dijk et al. has reduced an anti-CTLA-4 IgG1 antibody to practice (AGEN1884w N297A), one would have had a reasonable expectation of success. Further, one would have been motivated to construct such an anti-CTLA-4 IgG1 antibody based off the demonstration of increased IL-2 expression which would be beneficial when using the anti-CTLA-4 IgG1 antibody as an anti-cancer therapeutic; see Figure 14.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Claim 98 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 and 7-13 of U.S. Patent No. 12,421,311 B2 in view of Dijk et al. (WO 2016/196237 A1: Published: December 8, 2016), Mishra et al. (Journal of Biotechnology. 324S: 100015; Published Online: February 20, 2020), and Misaghi et al. (WO 2017/079165 A1; Published: May 11, 2017), as applied to claims 66-69, 71, 75, 76, 85, 86, 91, 105, and 109 above, and further in view of Sadineni et al. (EP 3,283,107 B1: Published: May 27, 2020).
The teachings of U.S. Patent No. 12,421,311 B2, Dijk et al., Mishra et al., and Misaghi et al. as related to claim(s) 66-69, 71, 75, 76, 85, 86, 91, 105, and 109, from which these claims depend are given previously in this Office action and are fully incorporated here.
While the issued claims teach that the ABP as a pharmaceutical composition, neither the issued claims, Dijk et al., Mishra et al., nor Misaghi et al.teach the formulation of the composition.
Sadineni et al. teaches a composition comprising ipilumumab, an anti-CTLA-4 antibody, comprising a pH of about 6, 20 mM histidine, 50 mM of NaCl, and about 6% sucrose. The instant disclosure paragraph 00600 evidences that 10% sucrose is about 290 mM; see paragraph 0025. A 6% sucrose formulation would contain about 170 mM sucrose.
Given that Sadineni et al. teaches this formulation for a pharmaceutical composition comprising an anti-CTLA-4 antibody, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to use the same formulation for the pharmaceutical composition comprising the anti-CTLA-4 ABP of U.S. Patent No. 12,421,311 B2.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Claim 73 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 and 7-13 of U.S. Patent No. 12,421,311 B2 in view of Dijk et al. (WO 2016/196237 A1: Published: December 8, 2016), Mishra et al. (Journal of Biotechnology. 324S: 100015; Published Online: February 20, 2020), and Misaghi et al. (WO 2017/079165 A1; Published: May 11, 2017), as applied to claims 66-69, 71, 75, 76, 85, 86, 105, and 109 above, and further in view of Navon et al. (WO 2020/058762 A1; Published: March 26, 2020).
The teachings of U.S. Patent No. 12,421,311 B2, Dijk et al., Mishra et al., and Misaghi et al. as related to claim(s) 66-69, 71, 75, 76, 85, 86, 105, and 109, from which these claims depend are given previously in this Office action and are fully incorporated here.
While issued claims 4 and 5 teach that the ABP is a full length antibody and comprises a constant region, neither the issued claims, Dijk et al., Mishra et al., nor Misaghi et al. teach the ABP constant region sequence wherein a lysine or an arginine occupy position 97 by IMGT numbering or position 214 by EU numbering.
Navon et al. teaches an anti-CTLA-4 antibody comprising a heavy chain constant region from human IgG1 and further comprising a K214R substitution; see page 23 lines 18-20 and claim 23. Claim 22, from which claim 23 reciting a K214R substitution depends, recites an afucosylated anti-CTLA-4 antibody. Navon et al. teaches that the constant regions may be modified to modulate the ADCC activity and the K214R substitution is one such modification.
Given that Navon et al. teaches an anti-CTLA-4 antibody comprising and afucosylated Fc region and a K214R substitution for modified ADCC, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to include the combined constant region modifications to the instant anti-CTLA-4 antibody comprising the instant CDRs.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Claims 66-69, 71, 73, 75, 76, 85, 86, 98, 105, and 109 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7, 27, 29, 36, 53, 65, 66, 70, and 81 of copending Application No. 18/573,408 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding instant claims 66 and 67, copending claims 1, 27, 65, and 66 recite an ABP with CDRs comprising SEQ ID NOs: 12078-12090 which are 100% identical to instant SEQ ID NOs: 12078-12080 and an ABP comprising a VL and VH at least 97% identical to SEQ ID NOs: 14 and 114, respectively, which are 100% identical to instant SEQ ID NOs: 14 and 114.
Regarding instant claims 68, 69, 71, 73, and 75, copending claim 29 teaches that the ABP is a scFv or full-length monoclonal antibody and the comprises a IGHG1*01 human heavy chain constant region, comprises an afucosylated Fc domain, or has a lysine at position 97. Regarding instant claim 76, copending claim 36 recites the ABP produces under the same conditions.
Regarding instant claim 85, copending claim 53 teaches that the ABP is administered as a pharmaceutical composition comprising sucrose, an excipient. Regarding instant claim 98, copending claim 70 teaches the same pharmaceutical composition pH, NaCl, sucrose, and histidine or citrate buffer concentrations. Regarding instant claims 86 and 91, copending claim 81 teaches that the ABP is less than 50% fucosylated, which encompasses more than 30% fucosylated in instant claim 91.
Regarding instant claims 105 and 109, copending claims 1 and 7 teach a method of treating cancer comprising administering the ABP and an additional therapeutic agent that binds PD-1 or PD-L1.
Thus, copending claims 1, 7, 27, 29, 36, 53, 65, 66, 70, and 81 read on instant claims 66-69, 71, 73, 75, 76, 85, 86, 91, 98, 105, and 109 in an anticipatory manner.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Allowable Subject Matter
It is noted that while no claim is currently allowed, the sequences of claims 66 and 67 are not taught by the prior art. The instant claims were examined with the effectively filed date of July 2, 2020.
Stone et al. (WO 2021/231648 A2; Published: November 18, 2021; Effectively Filed: May 12, 2020) is prior art under 35 U.S.C. 102(a)(2) and teaches the sequences of instant claims 66 and 67; see SEQ ID NOs: 5909 and 5910 of WO 2021/231648 A2. However, the priority document US Application No. 63/023,790 only teaches a sequence comprising the light chain CDRs. The heavy chain CDRs of claim 66 and the VH of claim 67 is not taught in US Application No. 63/023,790.
Response to Arguments
Applicant’s amendments filed February 19, 2026 are acknowledged. Any rejection not repeated above is resolved by amendment.
Applicant's arguments filed February 19, 2026 have been fully considered but they are not persuasive.
Regarding the nonstatutory double patenting rejections over the claims of U.S. 12,421,311 B2, Applicant asserts that Dijk et al. does not teach therapeutic effects of afucosylated anti-CTLA4 antibodies and, therefore, one would not have found it obvious to obvious to make a pharmaceutical composition comprising an afucosylated anti-CTLA4 antibody. Further, Applicant suggests that paragraph 0094 has been mischaracterized and is not related to a pharmaceutical composition comprising an afucosylated anti-CTLA4 antibody.
Dijk et al. claim 55 teaches an afucosylated anti-CTLA4 antibody. Paragraph 0094 defines the term “afucosylated” and states that “in a composition comprising a plurality of afucosylated antibodies, at least 70% of the antibodies will not be fucosylated, directly or indirectly (e.g., via intervening sugars) at residue 297 of the Fc region of the antibodies, and in some embodiments at least 80%, 85%, 90%, 95%, or 99% will not be fucosylated, directly or indirectly, at residue 297 of the FC region.” Claim 69 recites a pharmaceutical composition comprising the antibody of claims 1-68, which includes the afucosylated anti-CTLA4 antibody of claim 55. Thus, one would interpret a pharmaceutical composition comprising afucosylated anti-CTLA4 antibodies in line with the definition provided by Dijk et al. for a composition comprising afucosylated anti-CTLA4 antibodies. Further, regarding the assertion that Dijk et al. does not teach any therapeutic effect of afucoyslation, Figures 12A and 12B demonstrate that the afucosylated anti-CTLA4 antibody (i.e. AGEN1884w-105) effects a greater increase in IL-2 production compared to a residue 297 fucosylated anti-CTLA4 antibody (i.e. AGEN1884w-N297A) without any change in CTLA4 binding.
Applicant asserts the Mishra et al. does not support the use of a pharmaceutical composition comprising afucosylated anti-CTLA4 antibodies to treat cancer because “[a]lthough afucosylation may enhance an ADCC response, afucosylation also tends to increase immune-related Adverse Events (irAE). See subject application at paragraph [0516].”
Paragraph 0516 is reproduced below:
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It is unclear what data or paper supports Applicant’s statement regarding irAEs. Mishra et al., referenced in the same paragraph in Applicant’s arguments, does not teach away from treating cancer with afucosylated anti-CTLA4 antibodies due to immune-related AEs. Regardless, immune-related AEs are associated with checkpoint inhibitors, especially anti-CTLA4 antibodies; see Brahmer et al. (Journal of Clinical Oncology. 36(17): 1714-1768; Published: February 14, 2018) Figure A1. Brahmer et al., which was published prior to the effective filing date of the instant application, teaches that irAEs are managed on a case-by-case basis and the presence of an irAEs does not automatically result in discontinuation of the ICI; see whole document. Further, Brahmer et al. teaches that irAEs may positively correlate with clinical response; see page 18. Thus, Applicants’ interpretation of how the skilled artisan would have interpreted the presence of irAEs as a teaching away from treating cancer with afucosylated anti-CTLA4 antibodies is directly contradicted by Brahmer et al., who demonstrates that years before the instant disclosure, the art understood that irAEs were common with anti-CLTA4 antibodies, did not always necessitate discontinuation of treatment, and were often associated with better clinical response.
Applicant alleges unexpected results on pages 14-15 of the arguments. Regarding the reference to Example 9, the distinguishing limitation between the instant claims and the claims of U.S. 12,421,311 B2 is that the composition comprises anti-CTLA4 antibodies which comprise an afucosylated Fc region and wherein less than 50% of the antibodies are fucosylated. It is unclear which antibodies in Example 9 are afucosylated and to what extent. Further, Example 9 appears to assess the AEs following treatment with three anti-CTLA antibodies. The instant claims are to 7 anti-CTLA4 antibodies. Thus, the alleged unexpected result is not commensurate in scope. Finally, the disclosure teaches “that anti-CTLA4s with reduced blocking activity may limit induction of irAEs even when the ADCC is enhanced.” This statement suggests that the alleged unexpected result is due to the antigen binding of the anti-CTLA4 antibodies and not the afucosylation.
Regarding the reference to Figure 41 (not part of the instant application), similar to Example 9, Figure 41 includes data from two anti-CTLA4 antibodies having less than 50% fucosylation, which is not commensurate in scope with claims to 7 different anti-CTLA4 antibodies. Additionally, this finding of an inverse relationship between FcγRIIIa binding and fucosylation is not unexpected. Mishra et al. teaches “the presence of fucose on the core glycan structure has been shown to have an inverse relationship to binding of the antibody Fc region to the FcgRIIIa receptor.”; see page 2.
Further, MPEP 716.01(c), “[t]o be of probative value, any objection evidence should be supported by actual proof. Objective evidence which must be factually supported by an appropriate affidavit or declaration to be of probative value includes evidence of unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the inventor or at least one joint inventor. See, for example, In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984) (“It is well settled that unexpected results must be established by factual evidence.” “[A]ppellants have not presented any experimental data showing that prior heat-shrinkable articles split. Due to the absence of tests comparing appellant’s heat shrinkable articles with those of the closest prior art, we conclude that appellant’s assertions of unexpected results constitute mere argument.”).” The evidence, while allegedly probative, is not properly filed in an affidavit or declaration. Therefore, the veracity of the evidence is not supported by the manner of Applicant’s submission.
Regarding the nonstatutory double patenting rejection over the claims of Application 18/573,408, the instant application has the earlier patent term filing date and the rejection will be withdrawn only when it is the last remaining rejection of record; see MPEP 1490 VI.D.2.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Rosskopf et al. (Cancer Immunology, Immunotherapy. 68: 1359-1368; Published Online: July 22, 2019) teaches that ipilimumab, an anti-CTLA-4 antibody, reduced CD4+ T cell proliferation, a population which includes Tregs, and depleted intra-tumoral CTLA-4high Tregs via Fc-receptor dependent mechanisms; see page 1360 left column. Romano et al. (PNAS. 112(19): 6140-6145; Published: May 12, 2015) teaches the effect of ipilimumab treatment on Tregs using melanoma biopsy samples.
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 KATHERINE ANN HOLTZMAN whose telephone number is (571)270-0252. The examiner can normally be reached Monday - Friday 8:30am - 5:00pm MT.
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/KATHERINE ANN HOLTZMAN/Examiner, Art Unit 1646
/JULIET C SWITZER/Primary Examiner, Art Unit 1682
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