DETAILED ACTION
1. The present application is being examined under the pre-AIA first to invent provisions.
2. Applicant’s amendment filed on December 9, 2025 is acknowledged.
Claims 1-27 have been canceled.
Claims 28-55 are pending.
Claims 29-31, 34, 40-42, 46, and 51-55 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on July 30, 2025.
Claims 28, 32, 33, 35-39, 43-45, and 47-50 are currently under consideration as they read on the elected invention of a polypeptide comprising a human Fc region comprising Asp at EU position 238 (238D) and at least Lys at EU position 330 (330K).
3. In view of applicant’s amendment, following rejections are set forth.
4. Applicant’s submission of the English translation of the two foreign priority documents JAPAN 2011-040923 (02/25/2011) and JAPAN 2011-219835 (10/04/2011) is acknowledged.
However, these two foreign priority documents upon which priority is claimed fails to provide adequate support under 35 U.S.C. 112 for the instant claims of this application. Specifically, insufficient support was identified for the limitation of Asp at EU position 238 and Lys at EU position 330 (the elected species). Consequently, 28, 32, 33, 35-39, 43-45, and 47-51 have been accorded the priority of February 24, 2012 (the 371 date).
Should Applicant disagree with the Examiner’s factual determination above, it is incumbent upon Applicant to provide a showing that specifically supports the instant claim limitations.
5. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
6. The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
7. Claims 28, 32, 33, 35-39, 43-45, and 47-50 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Lazar (US 9,051,373) in view of D’Angelo et al. (WO 2011/120134) and Igawa et al. (US 2010/0298542) for the reasons of record.
The previous Office Action states:
“Lazar claims a polypeptide comprising a variant Fc region comprising an amino acid substitution D at position 238 (238D) (e.g. see claim 1). Lazar teaches examples of an anti-CD20 antibody with human IgG1 Fc region comprising amino acid substitution including P238D (variant 748), and show that the variant exhibits increased binding affinity to FcγRIIb compared to unmodified parent anti-CD20 antibody (e.g. see Figure 41, variant 748). The anti-CD20 antibody is also an Fc fusion protein with polypeptide (e.g. VH region of the antibody) operably linked to Fc. Lazar teaches Fc fusion protein comprising the Fc fused to a cytokine (e.g. see col. 53-54). Lazar further teaches pharmaceutical composition comprising the Fc variant (e.g. see paragraph col. 70). Lazar also teaches a variant polypeptide comprising the Fc variant comprising amino acid substitutions described above (e.g. see claim 4). Moreover, Lazar discloses that the Fc variants are produced in the human IgG1-4 naturally occurring Fc regions as listed in Figure 3 according to EU index (e.g. see Figure 3a-1 to Figure 3b-3).
Lazar teaches that "In some embodiments, Fc variants of the invention with enhanced affinity for Fc.gamma.RIIb can be used to promote anti-inflammatory activity” and or “to reduce autoimmunity” (e.g. see paragraph 102). Lazar teaches substitution A330 in the Fc region (e.g. see col. 20).
Lazar states in col. 41-42 that “(104) In one embodiment, Fc variants that provide enhanced binding to the inhibitory receptor Fc.gamma.RIIb provide an enhancement to the IVIg therapeutic approach. In particular, the Fc variants of the present invention that bind with greater affinity to the Fc.gamma.RIIb receptor than parent Fc polypeptide may be used. Such Fc variants would thus function as Fc.gamma.RIIb agonists, and would be expected to enhance the beneficial effects of IVIg as an autoimmune disease therapeutic and also as a modulator of B-cell proliferation. In addition, such Fc.gamma.RIIb-enhanced Fc variants may also be further modified to have the same or limited binding to other receptors. In additional embodiments, the Fc variants with enhanced Fc.gamma.RIIb affinity may be combined with mutations that reduce or ablate to other receptors, thereby potentially further minimizing side effects during therapeutic use.
(105) Such immunomodulatory applications of the Fc variants of the present invention may also be utilized in the treatment of oncological indications, especially those for which antibody therapy involves antibody-dependant cytotoxic mechanisms. For example, an Fc variant that enhances affinity to Fc.gamma.RIIb may be used to antagonize this inhibitory receptor, for example by binding to the Fc/Fc.gamma.RIIb binding site but failing to trigger, or reducing cell signaling, potentially enhancing the effect of antibody-based anti-cancer therapy. Such Fc variants, functioning as Fc.gamma.RIIb antagonists, may either block the inhibitory properties of Fc.gamma.RIIb, or induce its inhibitory function as in the case of IVIg. An Fc.gamma.RIIb antagonist may be used as co-therapy in combination with any other therapeutic, including but not limited to antibodies, acting on the basis of ADCC related cytotoxicity. Fc.gamma.RIIb antagonistic Fc variants of this type are preferably isolated Fc or Fc fragments, although in alternate embodiments antibodies and Fc fusions may be used”.
The reference teachings differ from the instant invention by not teaching A330K substitution and that C terminal amino acid is at position 445.
D’Angelo et al. teach that FcγRIIb is widely expressed and bears an immune receptor tyrosine-based inhibitory motif (ITIM) and enhanced affinity to FcγRIIb would suppress activation of B cells or macrophage and monocytes and would be useful to dampen immune response in autoimmune diseases (e.g. see [0013]). D’Angelo et al. teach human IgG1 antibody consisting amino acid substitutions D270K/Y300L/A330K exhibits increased binding to FcγRIIb and reduced binding to activating FcγRIIIa (e.g. see Table 2 in page 62).
Igawa et al. teach that it could be beneficial to abolish the binding between the Fc of a therapeutic IgG to activating Fcγ receptor by mutating at positions such as position 330 in the Fc region (e.g. see [0004]-[005]). Igawa et al. teach an antibody constant region of a human antibody constant region comprising deletion of the two C-terminal amino acid residues (e.g. see [0036]-[0037]). Igawa et al. teach that such antibody is superior in terms of safety, immunogenicity, physiochemical properties such as stability and homogeneity (e.g. see [0035]).
It would thus be obvious to one of ordinary skill in the art at the time the invention was filed to combine the teachings of the references to produce a polypeptide comprising and Fc variant comprises amino acid substitutions 238D and 330K and further delete the two amino acid residues at the C-terminal of the Fc region. An ordinary skill in the art would have been motivated to do so, and have a reasonable expectation of success because Lazar et al. teach substitution in position 238 with amino acid D resulted in an Fc variant with enhanced binding to FcγRIIb beneficial in treating autoimmune disease, D’Angelo et al. and Igawa et al. both teach substitution in position 330 (A330K by D’Angelo) is beneficial in abolishing Fc’s binding to activating Fcγ receptors. It was also known that deleting the two amino acids in the C-terminal of the IgG Fc region can produce a superior antibody as taught by Igawa. Therefore, an ordinary skill in the art would have been motivated to produce an Fc variant comprising 238D and 330K substitutions in the Fc region for the benefit of enhanced binding to the inhibitory FcγRIIb and reduced binding to the activating Fcγ receptors including FcγRIIIa for treating autoimmune disease with a reasonable expectation of success. An ordinary skill in the art would also be motivated to delete the C-terminal two amino acids in the Fc region as disclosed by Igawa for an antibody that is superior in safety, immunogenicity, stability and homogeneity.”
Applicant’s arguments have been fully considered but have not been found persuasive.
Applicant asserts that Lazar teaches 238D but does not teach 330K because Lazar in col. 19-20 discloses substitution in position 330 but not 238 in these cols. Applicant further argues Lazar proposed substitution in position 330 with Tyr, Leu or Ile. Thus, applicant asserts that Lazar does not provide motivation for 330K substitution. Applicant also argues that D’Angelo provides no data regarding the actual Fcγ receptor binding activities of any of the Table 2 variants and does not provide reasons to select the D270L/Y300L/A330K for enhanced FcγRIIb binding. Applicant asserts that there is no reason to select A330K but discard D270L and Y300L. Applicant asserts that the instant specification discloses that combining P238D with other variants with enhanced binding to FcγRIIb (e.g. L328E or S267E/L328F) was surprisingly an unexpectedly reduced binding to FcγRIIb.
Applicant states:
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Therefore, applicant asserts that the rejection should be withdrawn.
This is not found persuasive for following reasons:
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
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).
While some combinations of the substitutions with increased binding to FcγRIIb may not yielded additive increased binding activity, all that is required is a reasonable expectation of success, not absolute predictability of success. See In re O’Farrell, 853 F.2d 894,903 (Fed. Cir. 1988).
Further, contrary to applicant’s arguments that the instant claims recite two substitutions 238D and 330K but Lazar and De’Angelo teach 238D and D270K/Y300L/A330K, respectively, note that the instant claims are drawn to a polypeptide comprising a human Fc comprising 238D and 330K (the elected species). The transitional phrase “comprising” is opened-ended and does not exclude additional unrecited elements.
In this case, an ordinary skill in the art would have been motivated to do so, and have a reasonable expectation of success because Lazar et al. teach substitution in position 238 with amino acid D resulted in an Fc variant with enhanced binding to FcγRIIb beneficial in treating autoimmune disease, D’Angelo et al. and Igawa et al. both teach substitution in position 330 (A330K by D’Angelo) is beneficial in abolishing Fc’s binding to activating Fcγ receptors. It was also known that deleting the two amino acids in the C-terminal of the IgG Fc region can produce a superior antibody as taught by Igawa. Therefore, an ordinary skill in the art would have been motivated to produce an Fc variant comprising 238D and 330K substitutions in the Fc region for the benefit of enhanced binding to the inhibitory FcγRIIb and reduced binding to the activating Fcγ receptors including FcγRIIIa for treating autoimmune disease with a reasonable expectation of success.
As such, applicant’s arguments are not found persuasive.
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 28, 32, 33, 35-39, 43-45, and 47-50 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-27 of US 12,304,960 (the ‘960 Patent) for the reasons of record.
Applicant’s arguments have been fully considered but have not been found persuasive.
Applicant argues that the instant claims are read on the elected species 238D/330K but nothing else. As such, applicant asserts that the claims in the ‘960 Patent containing 238D/330K and additional substitutions would not render the instant claims obvious.
This is not found persuasive for following reasons:
The instant claims are drawn to a polypeptide comprising a human Fc comprising 238D and 330K (the elected species). The transitional phrase “comprising” is opened-ended and does not exclude additional unrecited elements. As such, the claims in the ‘960 patent encompassing 238D/330K substitutions and additional substitutions for the specific anti-CD137 antibody would anticipate the genus polypeptide recited in the instant claims.
10. Claims 28, 32, 33, 35-39, 43-45, and 47-50 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of US 10,919,953 (the ‘953 Patent) in view of Igawa et al. (US 2010/0298542) for the reasons of record.
Applicant admits that the claims in the ‘953 Patent encompass 238D and 330K in one of the combinations but argues that there are additional substitutions in the combination. Therefore, applicant argues the claims in the ‘953 Patent do not render the instant claims encompass only 238D/330K obvious.
This is not found persuasive for the reasons stated above.
11. Claims 28, 32, 33, 35-39, 43-45, and 47-50 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending USSN 17/798,686 (the ‘686 application) in view of Igawa et al. (US 2010/0298542) for the reasons of record.
Applicant’s arguments and the Examiner’s rebuttals are essentially the same as discussed above.
12. No claim is allowed.
13. 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.
14. Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHUN DAHLE whose telephone number is (571)272-8142. The examiner can normally be reached Mon-Fri 6:30am-4:00pm.
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, Misook Yu can be reached at 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CHUN W DAHLE/Primary Examiner, Art Unit 1641