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 4, 8 and 16 were canceled.
Claims 1-3, 5-7, and 9-15 are pending and under consideration.
Election/Restrictions
Applicant’s election without traverse of Group I in the reply filed on 7/16/2026 is acknowledged.
Claim Objections
Claim 9 is objected to because of the following informalities: it is suggested that Applicant delete “wherein the antigen-binding domain comprises a single-domain antibody” in line 1-2 because same limitation was already recited by the second from last line of claim 1 and therefore the limitation is redundant. Appropriate correction is required.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 1-3, 5-7, 10 and 12-15 is/are rejected under 35 U.S.C. 103 as being unpatentable over West et al (WO2014/052462; 9/11/2024 21-page IDS) in view of Michaels et al (WO2015048272; PTO-892).
Regarding claims 1-2, 5-6, 10 and 12-13, West teaches “An activatable antibody that in an activated state binds Interleukin-6 Receptor (IL- 6R) comprising: an antibody or an antigen binding fragment thereof (AB) that specifically binds to IL-6R (corresponds to “antigen-binding domain” of instant claim 1); a masking moiety (MM) (corresponds to “inhibiting domain” of instant claim 1) that inhibits the binding of the AB to IL-6R in an uncleaved state (corresponds to instant claim 2 and 5-6); and a cleavable moiety (CM) (corresponds to “protease cleavage sequence” of instant claim 1) coupled to the AB, wherein the CM is a polypeptide that functions as a substrate for a protease” (claim 1). The broadest reasonable interpretation of limitation “association” of instant claims 5-6 encompasses association by peptide linker between inhibiting domain and antigen-binding domain, and therefore the limitation “association” of instant claims 5-6 is taught by West. West teaches that the antigen binding fragment thereof is a single domain antibody (claim 12). West teaches “In addition, the formulae above provide for additional amino acid sequences that may be positioned N-terminal or C- terminal to the activatable antibodies elements. Examples include, but are not limited to, targeting moieties (e.g., a ligand for a receptor of a cell present in a target tissue) and serum half-life extending moieties (e.g., polypeptides that bind serum proteins, such as immunoglobulin (e.g., IgG)” [0232]. Therefore, West teaches activatable antibody comprising IgG-like molecule as claimed by instant claim 13. Because West teaches that IgG-like molecule is serum half-life extending moiety, and because “carrying moiety” of instant claim 1 is interpreted as portion of the activatable antibody except antigen-binding domain, the serum half-life of antigen-binding domain of West is shorter than the carrying moiety comprising Fc domain of IgG-like molecule. Further, it is well known in the art that Fc domain of IgG-like molecule is half-life extending moiety.
Regarding claim 3, West teaches “The activatable antibody of claim 1, wherein the MM does not interfere or compete with the AB for binding to IL-6R in a cleaved state.” (claim 16). In other words, AB has higher antigen-binding activity in a cleaved state.
Regarding claim 7, West teaches “In some embodiments the CM is a substrate for MMP9” [0134]. As evidenced by instant specification, MMP-9 is cancer tissue specific protease (instant specification, page 73, [0108]).
Regarding claim 14, West teaches “Activatable anti-IL-6R antibodies can be administered in the form of pharmaceutical compositions.” [0339].
Regarding claim 15, West teaches “A method of producing an activatable antibody by culturing a cell under conditions that lead to expression of the activatable antibody” (claim 38).
The difference between prior art and the instant invention is that West does not teach specific sequence for the protease cleavage sequence.
Regarding claim 1, Michaels teaches “In some embodiments the linker between the CH3 region and the second segment containing a variable region plus a CL or CH1 region on one polypeptide chain of a V-C-Fc-V-C can contain an amino acid sequence that can be cleaved by a protease, for example, a furin protease, which can be present in a host cell, a metalloproteinase, for example, matrix metalloproteinase 2 (MMP2) or MMP9, a membrane anchored serine protease, which can be present of the surface of a target cell, or any other appropriate protease. Examples of such linkers include, without limitation, the following sequences: … GGGGSGPLGIAGQGGGGS (SEQ ID NO:54)”. SEQ ID NO: 54 of Michaels is 100% identical to instant SEQ ID NO: 194 (result 1 of 194.rag).
result 1 of 194.rag
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It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used specific cleavage sequence for MMP-9 protease because West teaches that the CM is a substrate for MMP9 and because Michaels teaches specific cleavage sequence for same protease MMP9. Therefore, the invention as a whole would have been obvious to one of ordinary skill in the art.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success because West teaches that the CM is a substrate for MMP9 and because Michaels teaches specific cleavage sequence for same protease MMP9. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
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.
NSDP 1
Claims 1-3, 5-7, 9-10 and 12-14 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 11,168,139 (hereinafter patent’139; 9/11/2024 21-page IDS) in view of Michaels et al (WO2015048272; PTO-892).
Regarding claim 1-2, 5-6, and 9, claim 1 of patent’139 claims “A polypeptide comprising an antigen binding domain, a cleavage site and a carrying moiety, the carrying moiety having an inhibiting domain that inhibits the antigen binding activity of the antigen binding domain, and the antigen binding domain having a shorter half-life in blood than that of the carrying moiety, wherein the carrying moiety is the moiety other than the antigen binding domain in the polypeptide, wherein the antigen binding domain comprises a single-domain antibody or is a single-domain antibody, and the inhibiting domain of the carrying moiety is an antibody VL, wherein the inhibiting domain of the carrying moiety associates with the antigen binding domain and thereby inhibits the antigen binding activity of the antigen binding domain, wherein the molecular weight of the antigen binding domain is 60 kDa or smaller, and the molecular weight of the antigen binding domain is smaller than that of the carrying moiety, or wherein the carrying moiety has FcRn binding activity, and the antigen binding domain has no FcRn binding activity or has weaker FcRn binding activity than that of the carrying moiety, wherein the cleavage site comprises a protease cleavage sequence, and wherein the cleavage site is in a position in the polypeptide such that if the cleavage site is cleaved, then the inhibiting domain of the carrying moiety and the antigen binding domain are no longer associated.”
Regarding claim 3, claim 2 of patent’139 claims “The polypeptide according to claim 1, wherein the antigen binding domain released from the polypeptide has higher antigen binding activity than that before the release.”
Regarding claim 7, claim 6 of patent’139 claims “the protease cleavage sequence is a target tissue specific protease cleavage sequence.”
Regarding claim 10, claim 3 of patent’139 claims “The polypeptide according to claim 1, wherein the carrying moiety comprises an antibody constant region.”
Regarding claim 12-13, claim 7 of patent’139 claims “The polypeptide of claim 3, wherein the antibody constant region is an IgG antibody constant region.”
Regarding claim 14, claim 5 of patent’139 claims “A pharmaceutical composition comprising the polypeptide of claim 1.”
The difference between patent’139 and the instant invention is that patent’139 does not claim specific sequence for the protease cleavage sequence.
Regarding claim 1, Michaels teaches “In some embodiments the linker between the CH3 region and the second segment containing a variable region plus a CL or CH1 region on one polypeptide chain of a V-C-Fc-V-C can contain an amino acid sequence that can be cleaved by a protease, for example, a furin protease, which can be present in a host cell, a metalloproteinase, for example, matrix metalloproteinase 2 (MMP2) or MMP9, a membrane anchored serine protease, which can be present of the surface of a target cell, or any other appropriate protease. Examples of such linkers include, without limitation, the following sequences: … GGGGSGPLGIAGQGGGGS (SEQ ID NO:54)”. SEQ ID NO: 54 of Michaels is 100% identical to instant SEQ ID NO: 194 (result 1 of 194.rag).
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It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used specific cleavage sequence for MMP-9 protease as protease cleavage sequence because Michaels teaches specific cleavage sequence for protease MMP9. It is well known in the art that MMP-9 is expressed in cancer microenvironment. One of ordinary skill in the art would be motivated to used MMP-9 cleavage sequence as protease cleavage sequence in order to activate the activatable antibody only in the cancer microenvironment. Therefore, the invention as a whole would have been obvious to one of ordinary skill in the art.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success because Michaels teaches specific cleavage sequence for protease MMP9. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
NSDP 2
Claims 1-3, 5-6, 9-11 and 14-15 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 11,932,697 (hereinafter patent’697; PTO-892) in view of Michaels et al (WO2015048272; PTO-892).
Regarding claims 1-2, 5-6, and 9, claim 1 of patent’697 claims “A polypeptide comprising an antigen binding domain and a carrying moiety, the carrying moiety having an inhibiting domain that inhibits the antigen binding activity of the antigen binding domain, and the antigen binding domain having a shorter half-life in blood than that of the carrying moiety, wherein the antigen binding domain comprises a single-domain antibody or is a single-domain antibody, the inhibiting domain comprises a VL, the antigen binding activity of the single-domain antibody is inhibited by the VL, and the antigen binding domain and/or inhibiting domain is capable of being released from the polypeptide.” Claims 3-4 of patent’697 claim that the cleavage site comprises a protease cleavage sequence.
Regarding claim 3, claim 2 of patent’697 claims “The polypeptide according to claim 1, wherein the antigen binding domain is capable of being released from the polypeptide, and the antigen binding domain released from the polypeptide has higher antigen binding activity than that before the release.”
Regarding claim 10, claim 5 of patent’697 claims “The polypeptide according to claim 1, wherein the carrying moiety comprises an antibody CH1 constant region linked to the antigen binding region and an antibody light chain constant region linked to the inhibiting domain.”
Regarding claim 11, claim 6 of patent’697 claims “The polypeptide according to claim 5, wherein the polypeptide comprises a protease cleavage sequence, wherein the protease cleavage sequence is located near the boundary between the antigen binding domain and the antibody CH1 constant region.”
Regarding claim 14, claim 7 of patent’697 claims “A pharmaceutical composition comprising the polypeptide of claim 1.”
Regarding claim 15, claim 8 of patent’697 claims “A method for producing the polypeptide of claim 1, comprising culturing a host cell comprising a polynucleotide encoding the polypeptide.”
The difference between patent’697 and the instant invention is that patent’697 does not claim specific sequence for the protease cleavage sequence.
Regarding claim 1, Michaels teaches “In some embodiments the linker between the CH3 region and the second segment containing a variable region plus a CL or CH1 region on one polypeptide chain of a V-C-Fc-V-C can contain an amino acid sequence that can be cleaved by a protease, for example, a furin protease, which can be present in a host cell, a metalloproteinase, for example, matrix metalloproteinase 2 (MMP2) or MMP9, a membrane anchored serine protease, which can be present of the surface of a target cell, or any other appropriate protease. Examples of such linkers include, without limitation, the following sequences: … GGGGSGPLGIAGQGGGGS (SEQ ID NO:54)”. SEQ ID NO: 54 of Michaels is 100% identical to instant SEQ ID NO: 194 (result 1 of 194.rag).
result 1 of 194.rag
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It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used specific cleavage sequence for MMP-9 protease as protease cleavage sequence because Michaels teaches specific cleavage sequence for protease MMP9. It is well known in the art that MMP-9 is expressed in cancer microenvironment. One of ordinary skill in the art would be motivated to used MMP-9 cleavage sequence as protease cleavage sequence in order to activate the activatable antibody only in the cancer microenvironment. Therefore, the invention as a whole would have been obvious to one of ordinary skill in the art.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success because Michaels teaches specific cleavage sequence for protease MMP9. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHEOM-GIL CHEONG whose telephone number is (571)272-6251. The examiner can normally be reached Monday - Friday 9:00 am - 5:00 pm.
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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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/CHEOM-GIL CHEONG/Examiner, Art Unit 1645
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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