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 October 28, 2022 are acknowledged. Claims 3-9, 13-16, 20, 22-23, 26-27, 29, 31, 37-38, 40, and 42-56 are canceled. Claims 1-2, 10-12, 17, 19, 21, 24-25, 28, 30, 32, 35-36, 39, and 41 are amended. Claims 1-2, 10-12, 17-19, 21, 24-25, 28, 30, 32-36, 39, and 41 are pending and under examination herein.
It is noted that the papers filed on October 28, 2022 with the amended claims under consideration herein recite “Application No. 16/352,213” in the header region. Because the papers were filed with a response to a Notice to File Missing Parts for the instant application (Application No. 17/702,131), recite a date of the “Notice to File Missing Parts” consistent with that of the instant application, and have a separate Attorney Docket Number than the ‘213 application, the Examiner is operating under the assumption that the claims filed October 28, 2022 are intended to be considered with the instant ‘131 application.
It is further noted that a Power of Attorney is not on record for the instant application. The Applicant is encouraged to file a Power of Attorney in the event that the Examiner needs to communicate with an authorized representative for the Applicant during the prosecution of the case.
Claim Objections
Claim 30 is objected to because the claim recites Table 2. MPEP § 2173.05(s) states: “Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table ‘is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience.’ Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted).” In the present case, Table 2 recites the amino acid sequences of the human IgG Fc polypeptide chains corresponding to IgG1 (SEQ ID NO: 26), IgG2 (SEQ ID NO: 27), IgG3 (SEQ ID NO: 28), and IgG4 (SEQ ID NO: 29). The IgG Fc polypeptide chain amino acid sequences could be incorporated into the claims to define the invention.
Appropriate correction is required.
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 18, 28, 34, 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.
Claim 18 recites the limitation that (a) the CH3-1 comprises the charge pair substitutions of K409D or K409E and K392D or K392E and CH3-2 comprises the charge pair substitutions of D399K or D399R and D356K or D356R, or vice versa, at specific amino acid positions. However, the claim does not recite a corresponding numbering system against which to compare the intended locations of the amino acid substitutions, rendering the claim ambiguous. By way of example, IMGT.org illustrates that the wildtype positions 409 and 392 of the IgG1 heavy chain both correspond to “K” under EU numbering, but not under Kabat numbering. See Office Action Appendix.
Claim 34, which recites similar limitations, is similarly rejected. It is also noted that claim 34 recites both “E356K or E356R” (in lines 3-4) and “D356K or D356R” (in lines 6-7), appearing to reference the same positions. Based on Applicant’s specification (Table 2, pages 25-26), the amino acid residue at position 356 (according to EU numbering) corresponds to “E” in human IgG1, IgG2, IgG3, and IgG4.
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, the claim does not recite a corresponding numbering system against which to compare the intended locations of the amino acid substitutions, rendering the claim ambiguous. By way of example, IMGT.org illustrates that the wildtype positions 234, 235, and 297, respectively, of the IgG1 heavy chain correspond to “L”, “L”, and “N”, respectively, under EU numbering, but not under Kabat numbering. See Office Action Appendix.
Claim 36, which recites similar limitations, is similarly rejected.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
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.
Claims 1-2, 10, 17-19, 21, 24-25, 28, 32-36, and 39 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lazar (US 2011/0054151 A1; cited in IDS).
Lazar discloses immunoglobulin compositions that simultaneously engage two antigens, preferably utilizing heterodimeric Fc regions (e.g., Abstract). Regarding claims 1-2, 19, 21, 32, and 39, 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).
Regarding claim 10, 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).
Regarding claims 24-25, Lazar teaches that the antibodies of the invention comprise constant region and hinge region sequences belonging to human IgG1, IgG2, IgG3, or IgG4 (e.g., ¶ 0059-0061, 0090-0091, 0114-0118).
Regarding 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).
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.
Claims 1, 10-12, 32, and 41 are rejected under 35 U.S.C. 103 as being unpatentable over Lazar (US 2011/0054151 A1; supra) as applied to claims 1-2, 10, 17-19, 21, 24-25, 28, 32-36, and 39 above, and further in view of Brinkmann (WO 2012/025525 A1; cited in IDS).
The teachings of Lazar are recited in the 35 U.S.C. § 102 rejection above.
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.
Claims 1 and 30 are rejected under 35 U.S.C. 103 as being unpatentable over Lazar (US 2011/0054151 A1; supra) as applied to claims 1-2, 10, 17-19, 21, 24-25, 28, 32-36, and 39 above, and further in view of Sun (WO 2013/096221 A1; cited in IDS).
The teachings of Lazar are recited in the 35 U.S.C. § 102 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 the Fab-Fab construct taught by Lazar 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
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Gunasekaran (The Journal of Biological Chemistry (2010) 285(25): 19637-19646; cited in IDS) describes modifications to the IgG CH3 domain interface of the antibody Fc region that result in Fc proteins which preferentially form heterodimers (Abstract). Gunasekaran teaches that these mutations “create altered charge polarity across the Fc dimer interface such that coexpression of electrostatically matched Fc chains support favorable attractive interactions thereby promoting desired Fc heterodimer formation, whereas unfavorable repulsive charge interactions suppress unwanted Fc homodimer formation” (Abstract). Gunasekaran generated, inter alia, antibody proteins in which the charge mutations K409D:K392D were introduced in one Fc fragment and the charge mutations D399K:E356K were introduced in an scFv-Fc, which resulted in heterodimer formation almost exclusively (page 19640, right column; Figure 2c). Gunasekaran recites that the combination of two pairs of charge mutations (K409D:K392D/D399K:E356L) on two respective Fc chains performed the best for predominantly producing Fc heterodimers without a significant reduction in product yield (page 19642, left column). Gunasekaran further engineered a monovalent IgG antibody comprising the charge-pair mutations, and mass spectrometric analysis indicated that more than 90% of the final protein product was the desired Fc heterodimer (pages 19643-19644; Figure 4). The incorporation of the charge pair mutations did not compromise the ability of the Fc to mediate a long serum half-life (page 19644, right column) and offers utility for therapeutic applications in which a monovalent antibody form with extended serum half-life is desired (page 19645).
No claims are allowed.
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, 9:00am - 5:30pm EST.
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/ELIZABETH A SHUPE/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643