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 .
Application Status
The amended claims filed with the Response to the non-final Office Action are acknowledged. Claims 1, 12, 18, 25, 28, 30, 32, 34, and 36 are amended. Claims 10-11, 24, 39, and 41 are newly canceled. Claims 1-2, 12, 17-19, 21, 25, 28, 30, and 32-26 are pending and under examination herein.
The Power of Attorney filed on March 26, 2026 has been accepted by the Office as of April 2, 2026.
WITHDRAWN OBJECTIONS AND REJECTIONS
All prior grounds of rejection over claims 10-11, 24, 39, and 41 are rendered moot by the cancelation of the claims.
The objection to claim 30 for reciting Table 2 is withdrawn in view of Applicant's claim amendments.
The prior grounds of rejection of claims 18, 28, 34, and 36 under 35 U.S.C. § 112(b) are withdrawn in view of Applicant's claim amendments.
The rejection of claims 1-2, 17-19, 21, 25, 28, 32-36 under 35 U.S.C. § 102 as being anticipated by Lazar (US 2011/0054151 A1; cited in IDS) is withdrawn in view of Applicant's amendments to claims 1 and 32 incorporating the subject matter of claims 11 and 41 (now canceled), respectively.
MAINTAINED REJECTIONS AND NEW REJECTIONS NECESSITATED BY AMENDMENT
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 28 and 36 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. This is a new rejection necessitated by claim amendment.
Claim 28 recites the limitation that the first and second polypeptide chains comprise one or more of the alterations of L234A, L235A, or any substitution at N297. However, while the claim recites that the substitutions correspond to the EU numbering system, it is noted that positions 234 and 235 do not consistently have “L” as the wild-type residue at these positions depending on the IgG isotype of the antibody. For example, as illustrated in Table 2 (pages 25-26) of the specification, wild-type position 234 comprises “L” in IgG1 and IgG3, “V” in IgG2, and “F” in IgG4 antibodies. Wild-type position 235 comprises “L” in IgG1, IgG3, and IgG4, and “A” in IgG2.
Claim 36, which recites similar limitations, is similarly rejected.
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.
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.
(1)
Claims 1-2, 12, 17-19, 21, 25, 28, and 32-36 are rejected under 35 U.S.C. 103 as being unpatentable over Lazar (US 2011/0054151 A1; cited in IDS) in view of Brinkmann (WO 2012/025525 A1; cited in IDS). This is a maintained rejection that has been updated to reflect Applicant's claim amendments.
Lazar discloses immunoglobulin compositions that simultaneously engage two antigens, preferably utilizing heterodimeric Fc regions (e.g., Abstract). Relevant to claims 1-2, 19, 21, and 32, Lazar discloses an embodiment termed “Fab-Fab”, illustrated in Figure 8, comprising two polypeptide chains that together form a combination of variable domains and constant domains arranged as recited in the instant claims to bind two antigens monovalently. See also ¶ 0016, 0048, 0111. Lazar further teaches that it is advantageous in anti-cancer therapies to target one antigen expressed specifically on cancerous cells while co-targeting a second antigen that mediates immunological killing activity, e.g., the combinations of Her2 (cancer cell target) and FcγRIIIa (effector cell target) or of CD19 (tumor cell target) and CD3 (T cell target), and Lazar discloses that immunoglobulins of the invention may target these antigens and others (e.g., ¶ 0134-0142). Lazar notes that for certain antigens, e.g., CD3 on T cells, engaging such antigens monovalently, rather than multivalently, avoids nonspecific cross-linking and subsequent undesirable side effects (e.g., cytokine storm and toxicity) in a clinical setting (¶ 0136). Lazar teaches that the VH and VL domains of the second antigen-binding region of the immunoglobulin constructs are linked C-terminally to the Fc region via flexible linkers (e.g., ¶ 0104, 0153-0155). See also Figure 8.
Regarding claims 17-18 and 33-34, Lazar further teaches that the Fc domains of the immunoglobulin constructs may comprise substitutions in the CH3 regions of each polypeptide chain which favor heterodimerization, such as the charge pair substitutions of 409D/E, 392D/E, 399K, and 356K numbered according to the EU index as in Kabat (e.g., ¶ 0119-0125).
Relevant to claim 25, Lazar teaches that the antibodies of the invention comprise constant region and hinge region sequences belonging to human IgG1, IgG2, IgG3, or IgG4, and light chain constant regions encoded by the kappa (Cκ) or lambda (Cλ) light chains (e.g., ¶ 0059-0061, 0090-0091, 0114-0118).
Relevant to claims 28 and 35-36, Lazar teaches that Fc modifications to reduce FcγR binding, including at least substitutions of 234A and 235A (numbering according to the EU index), may be introduced to the Fc domains of the antibodies of the invention (e.g., ¶ 0126-0130).
However, Lazar does not expressly teach that the linkers between the CH3-1 and V-2 regions or between the CH3-2 and V-4 regions of the antibodies of the invention comprise a protease cleavage site.
Brinkmann discloses bispecific antibodies that can be activated by tumor- or inflammation-specific proteases (e.g., Abstract). In one embodiment of the invention, Brinkmann teaches a bispecific antibody construct (analogous to the “mAb-Fab construct” taught by Lazar, which has a bivalent instead of monovalent first (N-terminal) antigen-binding site), wherein a VH1-CH1 moiety is fused to the CH3 of the first polypeptide chain of the mAb via a peptide linker without a protease cleavage site and a VL1-CL moiety is fused to the CH3 of the second polypeptide chain of the mAb via a peptide linker with a tumor- or inflammation-specific protease cleavage site (Figure 2B). Brinkmann teaches that protease expression is higher at the sites of a tumor or inflammatory region (e.g., of a tumor tissue) (e.g., page 21; Example 3, page 43). Brinkmann discloses exemplary tumor- or inflammation-specific proteases in Table 1 (pages 22-26), including matrix metalloproteinases (e.g., MMP2, MMP9). Brinkmann teaches an embodiment in which specific protease recognition sites for MMP2 and MMP9 were introduced into the linker (connection) between one CH3/variable domain chain but not the second (e.g., Figure 2B; Figure 3B; Example 2, pages 41-43). Brinkmann teaches that since the C-terminal antigen-binding moiety would remain covalently linked after proteolytic cleavage at one connection point, the C-terminal binding moiety could rotate more flexibly, allowing free rotation of the C-terminal antigen-binding moiety to facilitate access to the antigen for binding (e.g., Example 2, pages 41-43; Figure 3B). Brinkmann teaches that bispecific constructs containing C-terminal antigen-binding moieties may be expressed as inactive precursors but become activated upon exposure to MMP2 and/or MMP9 in diseased tissue (Example 2).
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to modify the Fab-Fab construct taught by Lazar by incorporating a protease cleavage site for a matrix metalloproteinase (e.g., MMP2 or MMP9) into one of the peptide linkers connecting a CH3 region and a variable region of the C-terminal antigen-binding moiety, based on the teachings of Brinkmann. The skilled artisan would have been motivated to do so because Brinkmann teaches that such an approach could be used to selectively activate the C-terminal antigen-binding moiety in a tumor tissue (which is characterized by higher expression of proteases). In further view of the teachings of Lazar, this could be advantageous when the C-terminal antigen-binding moiety is specific for an immune effector cell antigen such as CD3, as activating binding only after the construct is localized to the tumor microenvironment would reduce off-target immune cell activation. There would have been a reasonable expectation of success because one of ordinary skill in the art would have recognized that the incorporation of a protease-cleavage linker would have been an art-recognized alternative design for the Fab-Fab construct described by Lazar suitable for the intended purpose of minimizing non-specific crosslinking, e.g., when the C-terminal antigen-binding moiety is specific for an immune effector cell antigen.
Response to Arguments
Applicant's arguments filed March 26, 2026 have been fully considered but they are not persuasive.
Applicant submits that the amendments to claim 1 incorporating the subject matter of now-canceled claim 24 and the amendments to claim 32 incorporating the subject matter of now-canceled claim 39 render the claims non-obvious over the cited prior art references.
In response, it is noted that the subject matter of now-canceled claims 24 and 39 were both rejected as being anticipated by Lazar in the previous 35 U.S.C. § 102 rejection of record. Specifically, Lazar teaches the subject matter of now-canceled claim 24 at, e.g., ¶ 0059-0061, 0090-0091, and 0114-0118, and Lazar teaches the subject matter of now-canceled claim 39 at, e.g., ¶ 0134-0142.
For these reasons, the rejection is maintained.
(2)
Claims 1 and 30 are rejected under 35 U.S.C. 103 as being unpatentable over Lazar (US 2011/0054151 A1; supra) in view of Brinkmann (WO 2012/025525 A1; cited in IDS) as applied to claims 1-2, 12, 17-19, 21, 25, 28, and 32-36 above, and further in view of Sun (WO 2013/096221 A1; cited in IDS). This is a new rejection necessitated by claim amendment.
The teachings of Lazar and Brinkmann are recited in the 35 U.S.C. § 103 rejection above.
However, Lazar does not expressly teach inserting a peptide comprising the amino acid sequence of any one of SEQ ID NO: 13-24 between positions 384 and 385 (according to EU numbering) in the CH3 domains of the first and second polypeptide chains.
Sun discloses variant human IgG1, IgG2, IgG3, and IgG4 Fc fragments containing an insertion within or adjacent to a loop that binds to the neonatal Fc receptor (FcRn), which have higher affinity and/or binding activity at acidic pH and also have longer in vivo half-lives than control Fc polypeptides (e.g., Abstract, pages 1-4). Among the insertions which were observed to be particularly favorable included those comprising the amino acid sequences of SEQ ID NO: 41 (Isolate “5-51”), SEQ ID NO: 43 (Isolate “5-104”), SEQ ID NO: 42 (Isolate “5-69”), SEQ ID NO: 359 (Isolate “5-57”), SEQ ID NO: 360 (Isolate “5-64”), SEQ ID NO: 366 (Isolate “5-1 13”), SEQ ID NO: 362 (Isolate “5-73”), and SEQ ID NO: 361 (Isolate “5-66”), which share 100% sequence identity to those insertions comprising instant SEQ ID NO: 14, 15, 16, 20, 21, 22, 23, 24, respectively (e.g., Example 3, page 44-48; Table 2). Sun describes the generation of variant IgG2 antibodies in which an insertion sequence of the invention (e.g., isolate “5-51” or “5-104”) was inserted between amino acid residues 384 and 385 (EU numbering) and discloses that said variants displayed increased exposure values, decreased clearance, and increase half-lives (e.g., Example 9, pages 56-59; Table 6).
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to modify a Fab-Fab construct comprising a protease cleavage site, such as that collectively taught by Lazar and Brinkmann, by incorporating one of an insertion comprising, e.g., the amino acid sequence of instant SEQ ID NO: 14, 15, 16, 20, 21, 22, 23, or 24, between residues 384 and 385 (according to EU numbering) in the CH3 region of each of the first and second polypeptide chains, based on the teachings of Sun. The skilled artisan would have been motivated to do so because Sun teaches that said insertions confer favorable pharmacokinetic properties, including increased half-life, increased exposure, and decreased clearance. There would have been a reasonable expectation of success because the construct described by Lazar has a human IgG backbone, and the insertions taught by Sun may be incorporated into a human IgG1, IgG2, IgG3, or IgG4 Fc region.
Conclusion
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Elizabeth A Shupe whose telephone number is (703) 756-1420. The examiner can normally be reached Monday to Friday, 9:30am - 6:00pm EST.
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/ELIZABETH A SHUPE/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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