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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 19MAR2026 has been entered.
Claim Status
Applicant’s amendments received 19MAR2026 are acknowledged.
Claims 4-6 and 15-16 have been canceled.
Claim 1 has been amended.
Claims 1-3, 7-14, and 17-23 are pending in the instant application (i.e., Claim(s) 1 and 14 is/are independent).
Claims 7-14 and 17-23 remain withdrawn.
Claims 1-3 are examined on the merits.
Priority
The present application is a 371 National Stage of PCT International Application No. PCT/JP2020/025135, filed 26JUN2020, which claims foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy of Japan 2019-120991 filed on 28JUN2019 has been received and is acknowledged.
Withdrawn Rejections
Written Description
Applicant’s arguments, see p 5, Rejections under 35 USC §112(a) section, filed 19MAR2026, with respect to the rejection(s) of claim(s) 1-3 and 15-16 (i.e., claim(s) 15-16 have been cancelled) under 35 USC §112(a) – written description have been fully considered and said rejections of claim(s) 1-3 have been withdrawn in view of the claim amendments filed as part of said response.
Claim Rejections - 35 USC § 103
Applicant’s arguments, see p 7-10, Claim rejections—35 USC §103 section, filed 19MAR2026, with respect to the rejection(s) of claim(s) 1-4 and 15-16 (i.e., claims(s) 15-16 have been cancelled) under 35 USC §103 have been fully considered and said rejections of claim(s) 1-3 have been withdrawn in view of the claim amendments filed as part of said response.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-3 are rejected under 35 U.S.C. 103 as being unpatentable over US 2005/0282233 A1 (Eriksson, et. al, 22DEC2005, included in IDS), herein referred to as “’233” and in view of Papadopoulos, et al., (Molecular Aspects of Med, 2018, 62, 75-88), herein referred to as “Papadopoulos,” US Patent 9,428,577 B2 (Arch, et al., 30AUG2016), herein referred to as “’577,” and WO 2007/146160 (Curagen Corporation, et al., 21DEC2007), herein referred to as “’160.”
‘233 teaches bispecific humanized antibodies (i.e., multispecific antigen-binding molecule) comprising a first antigen binding site that specifically binds to PDGF-A, -B, -C, or -D and a second antigen binding site that specifically binds to PDGF-A, -B, -C, or -D (¶0019, ¶0054, claim 1 and 27), and methods of inhibiting fibrosis by administering the bispecific antibodies to subjects in need (¶0076). ‘233 further teaches that the bispecific antibody inhibits the first and second growth factors to which it binds from stimulating phosphorylation of the receptor tyrosine kinases (i.e., PDGF receptors) (¶0061), inhibits dimerization between ligands of the family of growth factors that are able to dimerize (¶0059), inhibits PDGF binding to its PDGFR (¶0051), and the CDRs may be modified to provide increased specificity or affinity (¶0148). Additionally, ‘233 teaches that multivalent antibodies (i.e., multiple antigen binding sites) comprise multiple single chain variable fragments (scFv) (i.e., antibody fragment) that are assembled tandemly, linearly, or as larger globular fusion proteins and include an Fc region or other antibody portion (¶0177). Furthermore, ‘233 teaches claim 1, an antibody substance that specifically binds to a first and a second growth factor, selected from VEGFA,…PDGFA, PDGFB, PDGFC, and PDGFD, wherein each of said growth factors binds and stimulates phosphorylation of at least on RTK, and wherein the antibody substance inhibits the first and second growth factors to which it binds from stimulating phosphorylation of said RTK (i.e., inhibits growth factor mediated phosphorylation) and claim 27, wherein the bispecific antibody of claim 1, comprises a first antigen binding site that specifically binds to PDGF-A, -B, -C, or -D and a second antigen binding site that specifically binds to PDGF-A, -B, -C, or -D. Additionally, working examples 10-11 of ‘233 provides support for the production and use thereof for bispecific antibodies binding two different isoforms of PDGF.
However, they do not teach: the specific PDGFB x PDGFD bispecific construct, wherein the first antigen binding domain may comprise a VH and a VL comprising the amino acid sequences of SEQ ID NOs: 1 and 2, respectively, the second antigen binding domain may comprise a VH and a VL comprising the amino acid sequences of SEQ ID NOs: 3 and 4, respectively and an Fc region with reduced binding activity towards an Fc gamma receptor.
Nevertheless, Papadopoulos teaches targeting the PDGF/PDGFR pathway for fibrosis therapy and that PDGFB and PDGFD have a special role in the PDGFRß-mediated liver fibrosis (see abstract and section 1.2). Furthermore, Papadopoulos teaches that inhibition of the PDGF/PDGFR pathway may be accomplished by sequestering the ligand with antibodies (i.e., binding PDGF isoforms which blocks interaction with the PDGFRß receptor and therefore inhibits activation of the receptor); however, due to the functional redundancy in the activation of PDGFRs by their ligands, results in challenges in selective drugs for inhibiting PDGF function (i.e., the necessity to target the redundancy to achieve a therapeutic effect) (section 2, Fig 1). Papadopoulos further teaches known PDGF-isoform blocking antibodies of MOR8457 which binds to PDGFB and prevents PDGFB binding to PDGFRß and CR002 which was found to neutralize PDGFD (i.e., prevent PDGFD binding to PDGFRß) (section 2.1.1).
Furthermore, ‘577 teaches bispecific antibodies that have binding specificities for PDGF-B and at least another antigen (e.g., PDGF-D) (col 58, lines 14-16), wherein the antibodies are useful for treating diseases and disorders mediated by PDGF-B binding to PDGFRßß and PDGFRαß (col 1, lines 24-25), (i.e., treating fibrosis, which exacts a heavy toll on human mortality and morbidity) (col 3, lines 5-7) and PDGF-D is known to activate PDGFRßß (col 1, line 52). Specifically ‘577 teaches the MOR8457 antibody or any variant or fragment that retains the ability to bind PDGF-B, such as germline (i.e., GL) mutated MOR8457 (col 35, lines 52-55), which reduces immunogenicity upon administration (col 55, lines 20-26) wherein the GL-VH and GL-VL are set forth in SEQ ID NOs: 6 and 4 (i.e., 100% query match to SEQ ID NOs: 1 and 2 of the instant application, see OA.APPENDIX) and the full-length LC is set forth in SEQ ID NO: 16 and the full-length HC further comprising an effector function triple mutation in the constant domain is set forth in SEQ ID NO: 14 (i.e., 98.9% query match to the fusion of SEQ ID NOs: 1 and 19 of the instant application, wherein SEQ ID NO: 19 comprises the Fc region of the instant application, see OA.APPENDIX) (col 38, lines 40-52). Modification of the constant region of an antibody can reduce binding with the Fc gamma receptor and complement systems and therefore reduce immune system response (col 53, lines 65-68). ‘577 further teaches that the antibodies specifically bind to PDGF-B, but do not detectably bind to other molecules (col 28, lines 21-24), inhibit PDGF-B binding to PDGFRß, inhibit phosphorylation of PDGFRß (col 28, line 65 to col 29, line 6), and inhibit cell proliferation via mitogenesis (Example 9).
Additionally, ‘160 teaches humanized bispecific antibodies comprising one arm (i.e., VH/VL pair) specific to PDGF-DD (i.e., CR002) and a second arm specific to a second molecule (e.g., VH/VL pair specific to PDGF-B) for the treatment of fibrosis (¶00128, ¶0090, and abstract). Specifically, ‘160 teaches the CR002 anti-PDGFDD antibody comprising VH and VL of SEQ ID NOs: 2 and 4 respectively (i.e., 100% query match to SEQ ID NOs: 3 and 4 of the instant application, respectively, see OA.APPENDIX) (claim 4).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the PDGF isoform x PDGF isoform bispecific antibody disclosed by ‘233 by specifically targeting PDGFB x PDGFD due to the importance in PDGFRß-mediated liver fibrosis, utilizing known anti-PDGFB and anti-PDGFD antibodies (i.e., MOR8457 and CR002) and having reduced Fc gamma receptor activity as disclosed by Papadopoulos, ‘577 and ‘160 because the specific sequences for binding to the respective targets provided target specificity and therefore reduced immunogenicity and modification of the Fc region afforded reduced immune system response. One would have been motivated to do so, given the teachings of ‘233 that the bispecific antibodies (i.e., multispecific antigen-binding molecule) comprising a first antigen binding site that specifically binds to PDGF-A, -B, -C, or -D and a second antigen binding site that specifically binds to PDGF-A, -B, -C, or -D, could be modified for the improved treatment of fibrosis and that the CDRs of the bispecific antibodies may be modified to provide increased specificity or affinity. There would have been a reasonable expectation of success, given the knowledge that the known anti-PDGFB and anti-PDGFD antibodies were highly specific and proven to neutralize the respective PDGF isoforms from binding the PDGFRß; that targeting multiple PDGF isoforms provides functional redundancy for treatment; and that humanization of the binding regions as well as reducing the Fc region interactions with the Fc gamma receptor would lead to immunospecific, therapeutically effective, non-immunogenic, and low immune system responsive bispecific antibodies, as taught by the combination of Papadopoulos, ‘577 and ‘160 for treatment of fibrosis.
RESPONSE
Applicant’s arguments, see p 7-10, Claim rejections—35 USC §103 section, filed 19MAR2026, that prior art ‘233 in view of ‘577 and ‘174 fails to establish a prima facie case of obviousness and is based on impermissible hindsight, that ‘233 “teaches away” from the claimed combination, there is no motivation to combine ‘233, ‘577, and ‘174 because the PDGFB x PDGFD bispecific antibody is considered a redundant method of blocking the same PDGFRß pathway and because of the safety concerns, and that if there were a motivation to combine that the combination would not result in a reasonable expectation of success because the ratio of PDGFB and PDGFD is highly variable and therefore requires balancing the “arms” to match the concentration of the targets presents a significant pharmacological hurdle have been fully considered but are found non-persuasive essentially for the reasons of record and as described further below.
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 this instance it was known at the time of filing that PDGFB and PDGFD were important in PDGFRß-mediated fibrosis, that targeting multiple PDGF isoforms in the same pathway, provided functional redundancy which could be therapeutically beneficial, and that both anti-PDGFB and anti-PDGFD antibodies were known in the art to inhibit binding of the respective ligand to PDGFRß and therefore in the use of treating fibrosis.
In response to applicant’s argument that the primary prior art reference, ‘233 teaches away from the claimed invention combination because ‘233 teaches a preferable combination (i.e., PDGF-C x PDGF-D) out of a list of claimed combinations of PDGF-A, -B, -C, -D x PDGF-A, -B, -C, -D bispecific antibodies. Although, ‘233 claims a preference for bispecific antibodies, at the same time it provides the motivation for one of ordinary skill in the art to focus on the modification of the bispecific antibodies for the improved treatment of fibrosis and that the antigen-binding domains may be modified to provide increased specificity or affinity to the targets.
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, per the discussion supra, targeting redundancy in the PDGF/PDGFR pathway may provide for more effective therapy as taught by Papadopoulos and therefore, targeting PDGFRß, by inhibiting activation by binding both PDGFB and PDGFD to PDGFRß could provide a more effective therapeutic.
In response to applicant’s argument that if there were a motivation to combine the references that there is no reasonable expectation of success, examiner has considered the predictability of the technology and it was well known at the time of filing that there were many bispecific antibodies, which can be directed to infinite antigens in infinite combinations and that while ‘233 does not specifically provide examples of PDGFB x PDGFD combinations, ‘233 does teach how to make and use a PDGF isoform x PDGF isoform bispecific antibody. Furthermore, the instantly claimed invention utilizes known in the art anti-PDGFB and anti-PDGFD antibodies, which show excellent binding specificity and inhibition of binding of the ligands to PDGFRß as taught by Papadopoulos, ‘577 and ‘160, and therefore would be an obvious choices for one of ordinary skill in the art to combine with ‘233 to make and use a PDGFB x PDGFD bispecific antibody. Additionally, examiner notes 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)).
Thus, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time of filing.
Conclusion
No claims are allowed.
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/SAMANTHA LAKE HOPKINS/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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