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 Status
Claims 7-9 have been amended as requested in the amendment filed on 10/02/2025. Following the amendment, claims 1-10 are pending in the instant application.
Claims 1-10 are under examination in the instant office action.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 10/02/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Specification - Objections Withdrawn
Applicant has provided an abstract on a separate paper devoid of any other text. Applicant has also amended the specification to remove references to DOIs and/or web-based hyperlinks. As such, the objections to the specification are withdrawn.
Claim Objections - Withdrawn
Claims 7-9 were objected to as being of improper form as being multiple dependent claims. Applicant has amended the claims to recite “[t]he method of any one of claims 1-6”, and as such the claims refer to other claims in the alternative only. Thus, the objection to claims 7-9 is withdrawn.
Claim Rejections - 35 USC § 103 - Withdrawn
Claims 1-8 were rejected under 35 U.S.C. § 103, as being unpatentable over WO 2019/236739 (previously cited on PTO-892; hereinafter referred to as "Kuhns") in view of non-patent literature published by Liu in 2015 (previously cited on PTO-892; hereinafter referred to as "Liu").
Claims 9-10 were rejected under 35 U.S.C. § 103, as being unpatentable over
Kuhns and Liu as applied to claims 1-8, and further in view of non-patent literature published by
Derer et al. in 2013 (previously cited on PTO-892; hereinafter referred to as "Derer").
On Pages 8-9 of Remarks (10/02/2025), it is noted that pursuant to 35 U.S.C. § 102(a)(2), § 102(b)(2)(C), and 37 C.F.R. § 1.130, Applicant has disqualified WO 2019/236739 ("Kuhns") as prior art. The Kuhns reference is commonly owned or subject to an obligation of assignment to the same entity, Amgen Inc., as the instant application at the time of filing. Accordingly, under 35 U.S.C. § 102(b)(2)(C), Kuhns does not qualify as prior art against the instant application. As such, the above-listed claim rejections under 35 U.S.C. 103 utilizing the Kuhns reference have been withdrawn.
Double Patenting - Withdrawn
Claims 1-8 were provisionally rejected on the ground of nonstatutory double patenting as
allegedly being unpatentable over claims 3, 5-7, 13-17 of copending Application l7/275,140 (herein after referred to as “’140”) in view of WO 2019/236739 (previously cited on PTO-892; hereinafter referred to as "Kuhns") and non-patent literature published by Liu in 2015 (previously cited on PTO-892; hereinafter referred to as "Liu").
Claims 9-10 were provisionally rejected on the ground of nonstatutory double patenting
as allegedly being unpatentable over claims 3, 5-7, 13-15 and 17 of ‘140, Kuhns, and Liu as
applied to claims 1-8, and further in view of non-patent literature published by Derer et al. in 2013 (previously cited on PTO-892; hereinafter referred to as "Derer").
Claims 1-3 and 7-8 were provisionally rejected on the grounds of nonstatutory double
patenting as allegedly being unpatentable over claims 3, 5-7, 13-15 and 17 of '140 in view of Liu.
Claims 4-6 were provisionally rejected on the grounds of nonstatutory double patenting
as allegedly being unpatentable over claims 3, 5-7, 13-15 and 17 of '140 and Liu as applied to claims 1-3 and 7-8, and further in view of non-patent literature published by Thomann et al. in 2016 (previously cited on PTO-892; hereinafter referred to as "Thomann").
Claims 9-10 were provisionally rejected on the grounds of nonstatutory double patenting
as allegedly being unpatentable over claims 3, 5-7, 13-15 and 17 of '140, Liu and Thomann as applied to claims 1-8, and further in view of Derer.
Applicant indicates on Page 14 of Remarks that reference application l7/275,140 has since been abandoned. As such, the above-listed double patenting rejections are withdrawn.
Claims 1-8 were provisionally rejected on the grounds of nonstatutory double patenting
as allegedly being unpatentable over claims 1, 52, 57, 59, 60, 65, and 70 of copending
Application No. 18/698,098 (herein after referred to as “’098”) in view of Kuhns and Liu.
Claims 9-10 were provisionally rejected on the grounds of nonstatutory double patenting
as allegedly being unpatentable over claims 1, 52, 57, 59, 60, 65, and 70 of '098, Kuhn, and Liu
as applied to instant claims 1-8 above, and in further view of Derer.
As detailed above, Applicant has disqualified the Kuhns reference as prior art. As such, the above-listed provisional claim rejections under nonstatutory double patenting over ‘098 utilizing the Kuhns reference are withdrawn.
Claim Rejections - 35 USC § 103 - Maintained
Claims 1-3 and 7-8 stand as rejected under 35 U.S.C. § 103, as being unpatentable over non-patent literature published by Liu in 2015 (previously cited on PTO-892; hereinafter referred to as "Liu").
Claims 4-6 stand as rejected under 35 U.S.C. § 103, as being unpatentable over Liu
as applied to claims 1-3 and 7-8, and further in view of non-patent literature published by
Thomann et al. in 2016 (previously cited on PTO-892; hereinafter referred to as "Thomann").
Claims 9-10 as rejected under 35 U.S.C. § 103, as allegedly being unpatentable over Liu
and Thomann as applied to claims 1-8, and further in view of non-patent literature published by
Derer et al. in 2013 (previously cited on PTO-892; hereinafter referred to as "Derer").
On Pages 9-13 of Remarks, Applicant argues the following regarding the above-listed claim rejections under 35 U.S.C. 103:
Liu does not disclose modulating (i.e., increasing or decreasing) Fc gamma Receptor (FcyR)-mediated cytotoxicity of panitumumab, a specific IgG2 antibody nor increasing or decreasing specific product quality attributes, namely: amount of terminal β-galactose; amount of molecules that comprise GI, Gla, Glb and/or G2 galactosylated glycan; amount of molecules that comprise fucosylated glycan or afucosylated glycan; or amount of molecules that comprise a high-mannose glycan.
None of these studies of Liu refers to or suggests the particular combination of features of the amended claims, in particular the claimed methods of modulating FcyR-mediated cytotoxicity of panitumumab; Applicant argues that the outcomes of the scientific studies mentioned in Liu highlight the unpredictability in the field wherein, for example, Liu teaches (a) that complement-dependent cytotoxicity (CDC) activity behaves differently in different antibodies (sometimes a glycosylation attribute or modification influences the CDC activity and sometimes it does not) (Page 1876, First Column, Paragraph 4) and (b) the pharmacokinetic (PK) profile of an aglycosylated IgG1 mAb with an N-297 mutation was almost identical to that of the glycosylated form, while aglycosylated IgG3 molecules showed relatively faster clearance for unclear reasons (Page 1873, First Column, Paragraph 2).
The influence of product quality attributes of an IgG2 antibody, such as panitumumab, on immune mediated cytotoxicity activity was poorly understood as of the filing date of the present application, in part because IgG2 molecules were traditionally believed to not be capable of inducing effector functions; Liu teaches that, while IgG1 antibodies are often used in therapeutic applications that require Fc effector functions, IgG2 and IgG4 antibodies are generally used where the effector function is not required or desired. Applicant further argues that there are several differences exist between IgGl and IgG2 mediated cytotoxicity: (a) IgG2 molecules such as panitumumab can mediate cytotoxic effects similar to conventional ADCC by engaging FcyRIIa, but after evaluating product quality attributes that affect the FcyR-mediated cytotoxicity levels of panitumumab using sensitive cytotoxicity assays, the inventors of the present application found that the cytotoxic effects mediated by panitumumab are distinct from conventional ADCC mediated by IgG1 molecules wherein cytotoxic effects of IgG2 are mediated primarily through cells of the myeloid lineage (monocytes and neutrophils), in contrast to conventional ADCC, which is mediated by IgG1 antibodies through lymphoid-derived natural killer (NK) cells.
Applicant further cites WO 2020/006176, Niwa et. al., and Yang et. al. (Foreign Patent Document #3, NPL Document #10, and NPL Document #22, respectively, on 10/02/2025 IDS) to demonstrate the unpredictability in the art. WO 2020/006176 demonstrates the ADCC activities of Vectibix® (panitumumab) appeared to be undetectable (marked by a dash), which is consistent with the teachings of the present application, which teaches that IgG2 molecules were traditionally believed to not be capable of inducing effector functions. Niwa et. al. reports a failed attempt to increase the ADCC activity of IgG2 molecules wherein "significant FcyRIIIa binding was also observed of IgG2 (f+) and IgG4 (f+) both of which were incapable of mediating ADCC" (Page 157, Second Column, Paragraph 1). Yang et. al. discloses an approach to enhancing ADCC activity of panitumumab by grafting the variable regions of panitumumab to an IgGl backbone wherein the grafted antibody, with panitumumab variable regions but IgGl backbone, exhibited stronger ADCC activity in vitro and more potent antitumor effect in vivo.
Through glyco-engineering (i.e., modifying glycan profiles), the inventors discovered that "the impact of the different glycans on FcγRIIa-mediated cell killing can be substantial" (Paragraph 19 of the instant specification). The claimed method avoids extensive antibody engineering (i.e., changing the entire antibody backbone from IgG2 to IgG1) that was required by Yang et al.
Thomann states that the authors "analyze[d] a set of 54 batches of a monoclonal IgGl antibody (mAbl) derived from a standard CHO-based manufacturing process" and that "mAbs 1-4 of the IgG1 subclass were manufactured". Thomann does not disclose modulating Fc gamma Receptor (FcγR)-mediated cytotoxicity of an IgG2 molecule (panitumumab), which were traditionally believed to not be capable of inducing effector functions.
Applicant's arguments have been fully considered but they are deemed not persuasive.
With regard to arguments (i)-(v) above, it is first noted that obviousness does not require absolute predictability, only a reasonable expectation of success, i.e., a reasonable expectation of obtaining similar properties. See, e.g., In re O’Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir. 1988). A at least some degree of predictability is required (MPEP 2143.02(II)). Furthermore, Liu explicitly indicates that all antibodies of the IgG class have a canonical glycosylation site of Asn297, and with regard to IgG2 indicates that while antibody monomer does not bind any FcγRs, in immune complex form IgG2 antibodies most strongly bind FcγRIIaH131 while also binding FcγRIIaR131 and FcγRIIaV158 (see Page 1872 and Table 3). The mechanism of Fc effector functions were established, as Liu discloses that Fc effector functions include complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), and antibody-dependent cell-mediated phagocytosis (ADCP), wherein all three effector functions are triggered by the formation of immune complexes, which then recruit complement proteins and/or effector cells (Liu Page 1867, Column 1, First Full Paragraph; emphasis added). IgG Fc receptors (FcγRs) are a family of molecules consisting of three activating (FcγRI, FcγRIII, and FcγRIV in mice; FcγRIa, FcγRIIa, and FcγRIIIa in humans) and one inhibitory (FcγRIIb) receptor, and it is well established that the absence of glycosylation dramatically reduces the binding affinity to FcγRI and eliminates the binding to FcγRII and FcγRIII receptors (Id.). As such, while effector functions could be expected to be less compared to, for example, IgG1 antibodies, Liu specifically indicates that effector functions with IgG2 antibodies are possible through immune complex interactions with FcγRIIaH131, FcγRIIaR131, and FcγRIIIaV158. While most currently approved IgG are IgG1 (~75%), some IgG4 and IgG2 versions of IgG have been approved with more in development (e.g., IgG2 antibody panitumumab; see Table 1) (Page 1872, Column 1, Paragraph 1; emphasis added). Thus, Liu generally establishes that IgG2 therapeutic antibodies exists, and that IgG2 antibodies would, to some extent, be expected to have effector functions. Liu further suggests close control of glycosylation of biosimilar product candidates is required to ensure high similarity in safety and efficacy to the innovator molecules; modifying galactosylation, fucosylation, and high-mannose are implicated in FcγR binding and modulation of cytotoxic activity (Page 1879, Summary and Conclusions; Table 5). It is particularly noted that G1 galactosylated glycan at the N-297 site as instantly claimed would refer to attaching a single galactose residue to N-297 (G1a and G1b are states of G1 pertaining to the attachment of different isomers which are attached via different arms); such a modification is suggested by Liu Table 5 which indicates that increased galactose (addition of at least one galactose residue) enhances antibody CDC. Thus, Liu discloses the implications of glycan modification at Asn297, including galactosylation, fucosylation (or defucosylation), and high-mannose, wherein their modulation would reasonably be expected to modulate effector functions through the modulation of FcγR interactions. The mechanism by which the effector functions occur (IgG1 via NK cells and IgG2 via monocytes) does not render glycan modification and subsequent effects “unpredictable”, especially in view of Table 3 of Liu which suggests this difference. WO 2020/006176 establishes a baseline for unmodified panitumumab, but does not establish effector functions after glycan modification as “unpredictable”. With regard to Niwa et. al., Applicant points to a very specific section of paper disclosing a “failed” attempt to increase ADCC activity; it is particularly noted, however, that in a broader sense Niwa et. al. explicitly discloses that a fucose-negative variant of IgG2, IgG3, and IgG4 exhibited enhanced ADCC and FcgRIIIa binding compared with their highly fucosylated counterparts wherein fucose removal did not affect complement-dependent cytotoxicity (CDC) of any IgGs and fucose removal from IgG2 and IgG4 resulted in a unique effector function profile wherein they had potent ADCC and no CDC (Abstract). Niwa et. al. concludes that fucose depletion can provide a panel of IgGs with enhanced ADCC without an impact on other inherent properties specific for each IgG subclass, such as CDC (Id.); and this notion is further supported by Table 3 and 5 of Liu wherein it is explicitly indicated that defucosylation enhances ADCC activity of monoclonal antibodies. Yang et. al. is not commensurate in scope with the instant claims, as their approach to increasing effector functions of antibodies are not directed to glycan modification. In view of the above, it is considered that the suggestions of Liu regarding glycan modification (e.g., at Asn297 comprising galactosylation, fucosylation, and high-mannose content), which could be applied to IgG2 antibodies (e.g., therapeutic antibody panitumumab) would reasonably be expected to modulate antibody effector functions.
It is further noted that the only argument presented regarding secondary references are those of argument (vi) above directed at Thomann. Applicant argues Thomann does not remedy the deficiencies of Liu and does not disclose modulating FcγR-mediated cytotoxicity of IgG2 molecules (i.e., panitumumab). As detailed above, Liu is regarded as not having any deficiencies. Furthermore, it is particularly noted that Thomann is only relied upon for its teaching of matching FcγR-mediated toxicity (i.e., ADCC) of glycan-modified antibodies to a reference sample; the methodology of Thomann may be applied to investigate IgG2 antibody modification and subsequent cytotoxicity.
In view of the above, the claim rejections under 35 U.S.C. 103 in view of Liu, Thomann, and/or Derer are deemed proper and are maintained.
Double Patenting - Maintained
Claims 1-3 and 7-8 were provisionally rejected on the grounds of nonstatutory double
patenting as allegedly being unpatentable over claims 1, 52, 57, 59, 60, 65 and 70 of copending
Application No. 18/698,098 (herein after referred to as “’098”) in view of Liu.
Claims 4-6 were provisionally rejected on the grounds of nonstatutory double patenting
as allegedly being unpatentable over claims 1, 52, 57, 59, 60, 65, and 70 of '098 and Liu as
applied to claims 1-3 and 7-10 and further in view of Thomann.
Claims 9-10 were provisionally rejected on the grounds of nonstatutory double patenting as allegedly being unpatentable over claims 1, 52, 57, 59, 60, 65 and 70 of '098, Liu and Thomann as applied to claims 1-8 and further in view of Derer.
It is noted that on Page 15 of Remarks Applicant indicates that they disagree with the Examiner’s position and rationale underlying the rejection. No specific arguments with respect to the rejections are provided. Applicant has indicated that the instant application has an earlier effective U.S. filing date than the copending reference applications, i.e., U.S. Application No. 18/698,098. If a provisional nonstatutory double patenting rejection is the only rejection remaining in an application having the earliest effective U.S. filing date[ ... ] compared to the reference application(s), the examiner should withdraw the rejection in the application having the earliest effective U.S. filing date and permit that application to issue as a patent[ ... ]. See MPEP § 804. For this reason, Applicant has requested that the provisional nonstatutory double patenting rejections listed above be withdrawn. However, it is noted that the claim rejections under 35 U.S.C. 103 utilizing the cited prior art references have been maintained, as detailed above. As such, the above-listed claim rejections under provisional nonstatutory double patenting are not the only rejections remaining, and with no specific arguments presented regarding the Examiner’s position and rationale underlying the rejection, the above-listed claim rejections under provisional nonstatutory double patenting in view of ‘098 are maintained.
Conclusion
Claims 1-10 are pending. Claims 1-10 are rejected. No claims are allowed.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALYSSA RAE STONEBRAKER whose telephone number is (571)270-0863. The examiner can normally be reached Monday-Thursday 7:00 am - 5:00 pm.
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, Samira Jean-Louis can be reached at (571)270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ALYSSA RAE STONEBRAKER/Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642