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 2-4, 6-9, 11, 21, and 29-37 have been cancelled; claims 1, 5, 16-18, and 25-27 have been amended; and, claims 38-41 have been newly added, as requested in the amendment filed on 11/21/2025. Following the amendment, claims 1, 5, 10, 12-14, 16-20, 22-28, and 38-41 are pending in the instant application.
Claims 13-14 and 23-24 stand as withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention in the Response filed 03/07/2024, there being no allowable generic or linking claim.
Claims 1, 5, 10, 12, 16-20, 22, 25-28, and 38-41 are under examination in the instant office action.
Priority - Updated
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. Additionally, a translation of the foreign priority document has been provided as of 11/21/2025.
Claims 1, 5, 10, 12, 16-20, 22, 25-28, and 38-41 have an effective filing date of July 23, 2018 corresponding to JP2018-137464.
Claim Rejections - 35 USC § 112 - Withdrawn
With regard to the rejection of claims 1 and 5 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite, Applicant has amended claims 1 and 5 to recite “wherein the antigen-binding molecule is specifically delivered into the cytosol of the target cell”. The recitation of “specifically delivered” in view of the instant specification is considered to be definite. Additionally, as argued by Applicant on Pages 8-9 of Remarks (11/21/2025), “substantially not delivered” is sufficiently defined in the instant specification. As such the rejection of claims 1 and 5 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn.
With regard to the additional rejection of claim 1 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite, Applicant has amended claim such that claim 1 now clearly indicates that the “wherein” clause following embodiment 1(G) applies to each of 1(A)-1(G). As such, the rejection of claim 1 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn.
With regard to the rejection of claims 29, 31, and 34-37 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite, it is noted that claims 29, 31, and 34-37 have been cancelled, rendering the rejection moot. As such, the rejection of claims 29, 31, and 34-37 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn.
With regard to the rejection of claims 16-19, 25-28, and 34-37 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, regarding scope of enablement, it is noted that: (i) claims 34-37 have been cancelled, rendering their rejection moot; and (ii) claims 16-18 and 25-27 have been amended to recite an “isolated nucleic acid” an/or a “host cell transfected with the isolated nucleic acid of claim [18 or 25] in vitro”. As such, claims 16-19 and 25-28 are considered to be enabled. Thus, the rejection of claims 16-19, 25-28, and 34-37 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, regarding scope of enablement, is withdrawn.
With regard to the rejection of claims 1, 5, 10, 12, 16-20, 22, and 25-28 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, regarding written description, it is noted that Applicant’s arguments on Pages 10-13 of Remarks (11/21/2025), regarding the existing extensive knowledge in the art and the exemplified embodiments of the instant disclosure, have been considered and are deemed persuasive. As such, the rejection of claims 1, 5, 10, 12, 16-20, 22, and 25-28 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, regarding written description is withdrawn.
Claim Rejections - 35 USC § 103 - Maintained/Updated
Claims 1, 10, 12, 16-19, 29, 31, and 34-35 stand as rejected, and new claims 38-39 are newly rejected, under 35 U.S.C. 103 as being unpatentable over non-patent literature by Choi et. al. (mAbs, 2014, 6(6), 1402-1414; cited on previous PTO-892 and herein after referred to as "Choi") in view of WO 2017/157305 A1 (herein after referred to as “Cui”) and non-patent literature by Leriche et. al. (Bioorganic & Medicinal Chemistry, 2012, 20, 571-582; previously cited on PTO-892 and herein after referred to as “Leriche”).
Claims 1, 5, 10, 12, 16-20, 22, and 25-28 stand as rejected, and new claims 38-41 are newly rejected, under 35 U.S.C. 103 as being unpatentable over Choi, Cui, and Leriche as applied to claims 1, 10, 12, and 16-19 above, and further in view of non-patent literature by DiGammarino et. al. (Humana Press, 2012, Second Edition, Chapter 9, 145-156; previously cited on PTO-892 and herein after referred to as "DiGammarino"), KR 20170133930 A (previously cited on PTO-892 and herein after referred to as “Kim”), and non-patent literature by Hussack et. al. (Protein Engineering, Design & Selection, 2012, 25(6), 33-318; previously cited on PTO-892 and herein after referred to as “Hussack”).
It is noted that new claims 38-41 are newly rejected in view of Choi, Cui, Leriche, DiGammarino, Kim, and/or Hussack as applied to claims 16-19 and 25-28 previously. It is specifically noted that the antigen binding molecules of claims 1 and 5 are rendered obvious by the cited references as previously made of record. Additionally, Cui further teaches isolated nucleic acid molecules that encode the MSFPs, anti-EpCAM antibodies or antigen-binding fragments thereof described above, expression vectors encoding the isolated nucleic acid molecules, isolated host cells comprising the expression vectors, and methods of producing the MSFPs, anti-EpCAM antibodies or antigen-binding fragments thereof, comprising culturing the isolated host cells and recovering the MSFPs, anti-EpCAM antibodies or antigen-binding fragments thereof from the cell culture (Paragraph 22). Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to the above-listed claim rejections under 35 U.S.C. 103, Applicant argues the following:
The simple fact that the cited art is analogous to the present invention does not provide motivation to combine or modify. The Office has failed to provide sufficient rationale to establish that a person having ordinary skill in the art would have been motivated to combine and modify the teachings/compositions of Choi in view of Cui and Leriche to arrive at the instantly claimed invention. The obviousness analysis relies on impermissible hindsight; antibody engineering is an unpredictable art and a person skilled in the art would appreciate that simultaneous incorporation of disparate modifications and components into a new antibody format – even if individual parts are useful in isolation – often results in unforeseen effects. By failing to cite prior art or scientific principle suggesting the combination of components would result in an antigen-binding molecule format maintaining the desired functions, the Office has not met the standard of establishing that one of ordinary skill in the art would have had a reasonable expectation of success.
Choi does not disclose or suggest an antigen-binding molecule that contains, inter alia, a Fab region or single chain unit that binds specifically to a cell surface antigen and/or a single variable region that has cytosol penetrating ability; Choi teaches a bivalent configuration of KT4 that is bivalent for the cytosol-penetrating VL, which is an advantageous feature over a composition that contains a single cytosol penetrating VL. Thus, Applicant argues that Choi discourages a person skilled in the art from modifying its teaching/compositions so as to arrive at an antigen-binding molecule such as an intact full-length antibody composition that contains only one copy of a cytosol penetrating VH/VL.
Cui provides no intimation that contrary to the teaching of Choi, it is desirable to produce an antigen-binding molecule such as an intact full-length antibody composition that contains only one copy of a cytosol penetrating VH/VL.
Leriche does not cure the deficiencies of Choi and Cui; Leriche alone, nor in combination with Choi and Cui, disclose or suggest an antigen-binding molecule that contains, inter alia, a Fab region or single chain unit that binds specifically to a cell surface antigen and/or a single variable region that has cytosol penetrating ability, let alone wherein the antigen-binding molecule is specifically delivered into the cytosol of the target cell.
The Office has failed to provide sufficient rationale to establish that a person having ordinary skill in the art would have been motivated to combine and modify the teachings/compositions of Choi in view of Cui and Leriche, and in further view of DiGammarino, Kim, and Hussack to arrive at the instantly claimed invention. By failing to cite prior art or scientific principle suggesting the combination of components would result in an antigen-binding molecule format maintaining the desired functions, the Office has not met the standard of establishing that one of ordinary skill in the art would have had a reasonable expectation of success, and DiGammarino, Kim, and Hussack fail to remedy the deficiencies of the combination of Choi, Cui, and Leriche. None of the cited prior art references disclose an antigen-binding molecule such as an intact full-length antibody composition that contains only one copy of a cytosol penetrating VH/VL. More specifically, DiGammarino discloses a DVD-Ig, wherein a single arm of said DVD-Ig is bispecific whereas instant claim 5 is trispecific and DiGammarino does not disclose cytosol penetrating domains. Kim discloses endosomal escape activity of an intact full-length antibody that is tetravalent for the endosomal escape motif is further improved compared to those bivalent for the endosomal escape motif. Hussack does not cure the deficiencies of the combined prior art references detailed above.
Applicant’s arguments have been fully considered but are deemed not persuasive.
With regard to predictability and expectation of success, it is 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). Choi is relied upon for its disclosure of a cytosol-penetrating cytotransmab, Cui is relied upon for its disclosure of a fusion-protein format, and Leriche is relied upon for its teachings regarding cleavable linkers. As noted in the previous Office Action (05/23/2025), the rationale for the modification of Choi based on the teachings of Cui and Leriche was provided and is reproduced below (emphasis added):
“[M]odification of Choi to a format of Cui with consideration of the teachings of Leriche, one of ordinary skill in the art would recognize that a variety of cleavable linkers exist and are of benefit for particular situations; for example, enzyme cleavable linkers are commonly used in drug delivery/diagnostic tools in the context of targeting cancer (Page 573, Colum 1, Paragraph 3) and biocompatible acid cleavable linkers must be responsive to minor changes in pH wherein acidic pH-gradients are widely used to trigger cleavage for drug delivery systems as it is well known that the local acidic conditions are correlated with various diseased states, such as tumors, ischemia and inflammation (Page 578, Column 2, Paragraphs 1-3). Choi notes that full-length immunoglobulin G (IgG) antibodies that specifically bind to a target molecule with high affinity have been extensively developed as research tools, as well as for diagnostic and therapeutic purposes, but their targets are primarily the proteins expressed on the cell-surface and some secreted proteins because antibodies normally cannot cross intact cellular or subcellular membranes in living cells due to their large size and hydrophilicity (Page 1402, Column 1, Paragraph 1) and also disclosed that the murine anti-DNA m3D8 scFv, which, unlike other anti-DNA antibodies, internalized into living cells and was localized in the cytosolic regions without further trafficking into other subcellular compartments, including the nucleus, wherein the ability of m3D8 scFv to penetrate cells and then localize into the cytosol (referred to herein as ‘cytosol-penetrating ability’) was derived from the m3D8 VL; thus, the authors concluded that the m3D8 VL is an ideal moiety for the generation of cytosol-penetrating antibodies that can be used for diverse purposes (Page 1403, Column 1, Paragraph 2). Thus, larger full-length antibodies still struggle to be internalized, however smaller scFvs monovalent for a cytosol penetrating domain (i.e., VL domain) are still capable of internalization. One of ordinary skill in the art would recognize that a cleavable Fab fragment would thus be more likely to be internalized than a full-length antibody, and Cui teaches a fusion protein that comprises a cell-surface targeting domain fused to a second Fab via cleavable linker. Thus, a cleavable linker selected to be cleaved in the appropriate environment by particular proteases/pH conditions would allow for the release of a cytosol-penetrating Fab also capable of binding a cytosolic antigen would likely allow for more efficient delivery of said Fab to the cytosol (either by direct cytosolic penetration or via endocytosis and subsequent escape). Thus, the modifications of Choi based on additional teachings of Cui and Leriche would have been obvious because combining prior art elements according to known methods would be expected to yield predictable results (i.e., an antigen binding molecule comprising two Fab domains wherein one Fab domain has cytosol penetrating ability) wherein the cell surface antigen binding Fab would target the antigen binding molecule to the target cell (tumor that expresses surface target like EpCAM), wherein the linker could be selectively cleaved to allow for specific cytosol penetration of the second Fab to the target cells while not targeting cells that do not express the cell surface antigen.
Thus, the antigen binding molecule comprises (i) a first Fab which targets a cell surface antigen to direct the antigen binding molecule to a target cell (binding cell surface targets is suggested by both Choi and Cui; e.g., Cui specifically discloses antibodies/Fab domains specific to EpCAM) and (ii) a second Fab domain wherein the first and second Fab domains may be linked via cleavable linker (as supported by the format of Cui). The second Fab could be monovalent for a cytosol-penetrating domain and be specific for cytosolic antigen (e.g., KRS), an approach discussed/suggested by Choi. As supported by Leriche, the cleavable linker may be selected such that after the intact antibody is directed to the target cell (via the first Fab) and internalized via endosomes (a mechanism that is known and disclosed by Choi), the linker is triggered to be cleaved based on the endosomal environment (e.g., by proteases, pH, etc.). Once cleaved, the second Fab that is monovalent for a cytosol penetrating domain (which is substantially smaller than the uncleaved antigen binding molecule) would reasonably be expected to escape the endosome, as Choi supports the notion that smaller antibody/antigen binding constructs have an increased propensity to escape the endosome, even when monovalent for a cytosol penetrating domain. Thus, it would reasonably be expected that the antibody format rendered obvious by the combination of Choi, Cui, and Leriche would specifically be delivered into the cytosol of a target cell; the cell surface antigen-specific Fab would target the antigen binding molecule selectively to target cells for internalization, and thus it would be expected that the antigen binding molecule would not substantially be delivered to/internalized by non-target cells. Additionally, with regard the hindsight reasoning argument, it is noted that “[a]ny judgement on obviousness is in a sense necessarily a reconstruction based on hindsight reasoning, but so long as it takes into account only knowledge which was within the level of ordinary skill in the art at the time the claimed invention was made and does not include knowledge gleaned only from applicant’s disclosure, such a reconstruction is proper.” In re McLaughlin 443 F.2d 1392, 1395, 170 USPQ 209, 212 (CCPA 1971).
It is further noted that in view of the above, the combination of Choi, Cui, and Leriche are deemed to not have any deficiencies and rely on knowledge within the level of ordinary skill in the art, as provided by the teachings of the cited references; the arguments presented regarding additional references DiGammarino, Kim, and Hussack are directed to not curing the asserted deficiencies of Choi, Cui, and Leriche and as such there are no arguments against the additional references themselves.
Thus, in view of the above, the claim rejections under 35 U.S.C. 103 as listed above are deemed proper and are maintained.
Double Patenting - Maintained/Updated
Claims 1, 5, 10, 12, 16-20, 22, 25-29, 31, and 34-37 stand as provisionally rejected, and new claims 38-40 are newly rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 14-15, 18-20 of copending Application No. 18/269,099 (herein after referred to as “reference application”) in view of non-patent literature by Choi et. al. (mAbs, 2014, 6(6), 1402-1414; cited on previous PTO-892 and herein after referred to as "Choi"), WO 2017/157305 A1 (previously cited on PTO-892 and herein after referred to as “Cui”), non-patent literature by Leriche et. al. (Bioorganic & Medicinal Chemistry, 2012, 20, 571-582; previously cited on PTO-892 and herein after referred to as “Leriche”), non-patent literature by DiGammarino et. al. (Humana Press, 2012, Second Edition, Chapter 9, 145-156; previously cited on PTO-892 and herein after referred to as "DiGammarino"), KR 20170133930 A (previously cited on PTO-892 and herein after referred to as “Kim”), and non-patent literature by Hussack et. al. (Protein Engineering, Design & Selection, 2012, 25(6), 33-318; previously cited on PTO-892 and herein after referred to as “Hussack”).
It is noted that new claims 38-41 are newly rejected in view of the reference application, Choi, Cui, Leriche, DiGammarino, Kim, and/or Hussack as applied to claims 16-19 and 25-28 previously. It is specifically noted that the antigen binding molecules of claims 1 and 5 are rendered obvious by the cited references and reference application as previously made of record. Additionally, Cui further teaches isolated nucleic acid molecules that encode the MSFPs, anti-EpCAM antibodies or antigen-binding fragments thereof described above, expression vectors encoding the isolated nucleic acid molecules, isolated host cells comprising the expression vectors, and methods of producing the MSFPs, anti-EpCAM antibodies or antigen-binding fragments thereof, comprising culturing the isolated host cells and recovering the MSFPs, anti-EpCAM antibodies or antigen-binding fragments thereof from the cell culture (Paragraph 22). Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
It is noted that no arguments against the above-listed provisional claim rejection under nonstatutory double patenting have been provided, and as such the claim rejection listed above is maintained.
Conclusion
Claims 1, 5, 10, 12-14, 16-20, 22-28, and 38-41 are pending. Claims 13-14 and 23-24 are withdrawn. Claims 1, 5, 10, 12, 16-20, 22, 25-28, and 38-41 are rejected. No claims are allowed.
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.
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/ALYSSA RAE STONEBRAKER/Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642