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
Claims 80-99 are pending and examined on the merits herein.
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 82 and 84 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 82 is written as dependent on claim 1 which is canceled. For the purpose of compact prosecution claim 82 will be examined as dependent on claim 80.
Claims 82 and 84 are ambiguous because it is not clear if the Bi-Fc must bind the molecule recited (e.g., HER2, FOLR1, CD33) or only “a cell expressing” that molecule, which would then mean the Bi-Fc could bind various other molecules without binding the recited molecule. It is suggested that applicant revise the language to make clear what is actually bound by the Bi-Fc. For example, the claims could be revised to recite, "wherein the Bi-Fc binds human CD33, HER2 or FOLR1 expressed on the target cell."
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 80-81 and 89-99 are rejected under 35 U.S.C. 103 as being unpatentable over Kufer (US 2010/0150918 A1; IDS entered November 13, 2018), Kannan (World Bispecific Antibody Summit, September 27–28, 2011, Boston, MA, mAbs, 4:1, 4-13; PTO-892), Zhou (WO 2011/063348 A1; IDS entered November 13, 2018), and Sun (WO 2013/096221 A1; IDS entered November 13, 2018).
Regarding claim 80 and 82, Kufer teaches anti-CD3 binding domains that are preferably part of bispecific constructs comprising an additional binding domain that binds a cell surface antigen that is preferably a tumor antigen. See entire document, e.g. Abstract, but particularly [0066]-[0067], [0108]- [0110]; [0117]-[0118], “claims” A wide variety of exemplified bispecific constructs are provided in the Examples beginning at [0473] and summarized in the various Tables, such as Table 13 at [0756] (anti-CD3xanti-HER2) and Table 14 at [0852] (anti-CD3xanti-CD33). The scFv’s prepared by Kufer have VH and VL domains linked using a linker that is 15 amino acids in length, namely, a (G4S)3 standard scFv linker. E.g., see SEQ ID No: 1152, 523. That is, L1 and L3 are each at least 14 amino acids long. As also shown in those sequences, a linker is also included between the two scFv (i.e., “L2”) that is five amino acids in length, which is “not more than 12”. The anti-CD3 components are advantageous because they are human sequences that bind not only human CD3 but also primate CD3, thereby allowing the same molecule to be used in pre-clinical testing and therapy. E.g. [0023]- [0029]. This results in a structure comprising V1(CD3)-L1 (15aa)-V2(CD3)-L2(5aa)- V3(Her2)-L3(15aa)-V4(HER2)-L4(absent).
Regarding claims 84-85, 87-88, and 93, Kufer teaches anti-CD3 scFv constructs include the same CDR, VH, and VL sequences as, SEQ ID NOS: 159 and 167 (identical to instant SEQ ID NO: 7); SEQ ID NOS: 161 and 169 (identical to instant SEQ ID NO: 8) which also comprise the CDRs as recited in instant claim 93; SEQ ID NOS: 33 and 177 (identical to instant SEQ ID NO: 29); and SEQ ID NOS: 161 and 179 (identical to instant SEQ ID NO: 31) of Kufer, as well as antibodies “I2C" and "F12Q." Those sequences necessarily comprise the recited CDRs since they are subcomponents of the VH/VL. The anti-CD3 components are advantageous because they are human sequences that bind not only human CD3 but also primate CD3, thereby allowing the same molecule to be used in pre-clinical testing and therapy. E.g. [0023]-[0029]. The tumor targets exemplified by Kufer include CD33 and Her2. SEQ ID NO: 1152 of Kufer comprises both an anti-CD3 scFv (i.e., comprising instant SEQ ID NOS: 7 and 8) and anti-tumor (Her2) scFv comprising instant SEQ ID NOS:60-65. Kufer also teaches bispecific scFv comprising an anti-CD33 scFv comprising the sequences set forth in instant claim 85 (e.g., SEQ ID NO: 523 of Kufer is identical to instant SEQ ID NOs: 29 and 31, comprising both the anti-CD33 and anti-CD3 scFv linked in the same way).
Regarding claim 89, Kufer teaches that compositions comprising the bispecific scFv can be used to treat cancer. E.g., [0176]-[0179]
Regarding claims 90 and 91, Kufer teaches a bispecific tandem single chain antibody fragment directed at CD3 and Hepatitis virus antigens, specifically hepatitis B virus (HBV) [0923-0924].
Regarding claim 92, Kufer teaches a very sensitive test for the importance of the structural integrity of the amino acid 1-27 of the N-terminal polypeptide fragment of CD3 epsilon was performed. Individual amino acids of amino acids 1-27 of the N-terminal polypeptide fragment of CD3 epsilon were changed to alanine (alanine scanning) to test the sensitivity of the amino acids 1-27 of the N-terminal polypeptide fragment of CD3 epsilon for minor disruptions [0014].
Regarding claim 93, Kufer teaches anti-CD3 scFv constructs include the same CDR, VH, and VL sequences as, SEQ ID NOS: 159 and 167 (identical to instant SEQ ID NO: 7); SEQ ID NOS: 161 and 169 (identical to instant SEQ ID NO: 8) which also comprise the CDRs as recited in instant claim 93; SEQ ID NOS: 33 and 177 (identical to instant SEQ ID NO: 29); and SEQ ID NOS: 161 and 179 (identical to instant SEQ ID NO: 31) of Kufer, as well as antibodies “I2C" and "F12Q." The anti-CD3 components are advantageous because they are human sequences that bind not only human CD3 but also primate CD3, thereby allowing the same molecule to be used in pre-clinical testing and therapy. E.g. [0023]-[0029].
Regarding claims 94 and 99, Kufer teaches a pharmaceutical composition comprising a polypeptide according to claim 1 for the prevention, treatment or amelioration of a disease selected from a proliferative disease, a tumorous disease, or an immunological disorder (claim 24).
Regarding claims 95-98, Kufer teaches nucleic acids encoding, vectors comprising, host cells and methods of expressing the bispecific scFv are taught at least at [0131]-[0156].
Kufer does not teach bispecific scFv [(scFv)2] constructs comprising a monomeric Fc polypeptide with a Y349T substitution or the Fc substitutions recited in claim 80 or the insertion of a sequence into that Fc.
Regarding claims 80-81 and 83, Kannan teaches novel applications of antibody Fc heterodimers and monomeric form of Fc, specifically using charged pair mutation strategy to promote heterodimerization of the Fc by mutation of K409D, D399K and that this approach was utilized to produce a bispecific scFv-Fc with 98% heterodimer that bound T cells and cancer cells. Kannan further demonstrated binding of the heterodimer to target antigens as well as killing of tumor cells with the bispecific scFv-Fc which retained FcRn binding (longer half-life) and thermal stability. Kannan further taught formation of a stable monomeric Fc using K392D, K409D and Y349T mutation to discourage dimer formation and stabilize the monomer while maintaining FcRn binding and production of monomeric scFv-Fc fusion proteins that can be applied to fusion proteins for bispecific-Fcs (page 11, col 2- page 12 col 1).
Zhou teaches monomeric Fc polypeptides prepared by introducing substitutions of one or more hydrophobic amino acid in the CH3 region with a polar amino acid. See entire document, e.g., Abstract. Zhou teaches that the wildtype Fc is homodimeric in nature via high-affinity interactions in the wildtype CH3 domain. E.g., [0018]. But Zhou teaches that even in the monomeric form, the Fc still retains the ability to bind FcRn, so that even constructs that comprise only one Fc domain have extended half-life relative to constructs that do not comprise an Fc domain. E.g., [0028], [0033]. In addition to the increased half-life relative to a construct lacking an Fc domain, Zhou also teaches that monomeric constructs are advantageous in that their smaller size facilitates tissue penetration, a feature that can be particularly important for targeting cancers. E.g. [0033].
Regarding claims 80-81 and 83, Zhou teaches that formation of heterodimers of two Fc can be discouraged by substitutions at one or more of positions in the CH3 domain. E.g., [0024], [0025], claims on pages 24 and 25. Substitutions in human IgG CH3 at positions D356, E357, K392, D399, and K409 with another residue that results in an unfavorable charge help to avoid formation of the homodimer, while substitutions at Y349, L351, L368, L398, F405, and Y407 with a small polar residue such as threonine (T/Thr) improve the stability of the polypeptide in monomeric form. Id. Zhou teaches exemplary substitution combinations in human IgG1-CH3 that favor monomer formation are K392D, K409D, Y349T or K392D, K409D, F405T. E.g. [0026], see also [0062].
Regarding claim 81, Zhou teaches a half IgG molecule comprising the K392D, K409D, Y349T substitution combination was shown to have significantly increased AUC and T1/2 relative to the size matched control lacking any Fc. E.g. pages 21-22.
Sun teaches methods of improving the binding characteristics of an Fc-containing polypeptides, including bispecific molecules, for the neonatal Fc receptor (FcRn). See entire document, e.g., Abstract. The peptides inserted in claim 80, are taught as useful for increasing the half-life of the antibody to which and Fc domain comprising an insertion of those sequences between positions 384 and 385. E.g., Example 9.
Accordingly, in view of the teachings of Kannan and Zhou, the ordinary artisan before the effective filing date would have understood that adding a monomeric Fc domain to the bispecific, single-chain antibody of Kufer could increase the half-life relative to the bispecific construct lacking an Fc, particular when the Fc was monomeric and included a K392D, K409D, Y349T substitution combination. Further, as also taught by Zhou, bispecific constructs comprising a monomeric Fc would have been expected to have enhanced tumor penetration relative to forms containing a dimeric Fc. As Kannan teaches successful production of scFv-scFv-Fc with the same Fc substitutions as taught by Zhou this provides a reasonable expectation of success. Accordingly, the ordinary artisan at least for these reasons would have prepared a monomeric construct in addition to, and as an alternative of, the constructs of Kufer that while bispecific, lacked an Fc domain. Depending upon the specificities of the bispecific monomer or dimer, the ordinary artisan would have recognized that not only cancer, but also diseases mediated by pathogens could be treated. Given the teachings of Kannan and Zhou regarding the desirability of increasing half-life for the bispecific, tumor targeting antibodies, the ordinary artisan prior to the effective filing date of the claimed invention would have predictably inserted any of the peptides taught by Sun into the Fc region of the constructs of Kufer in view of Kannan and Zhou to predictably further improve its half-life in vivo and enhance its therapeutic activity.
The rationale to apply a technique taught by the prior art as improving the therapeutic and production characteristics of a similar construct is to predictably obtain an improvement to the second construct and is consistent with the exemplary rationales provided by the Supreme Court in KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385, 1395-97 (2007) and discussed in M.P.E.P. § 2143. For these reasons, the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention.
Claim 86 is rejected under 35 U.S.C. 103 as being unpatentable over Kufer (US 2010/0150918 A1; IDS entered November 13, 2018), Kannan (World Bispecific Antibody Summit, September 27–28, 2011, Boston, MA, mAbs, 4:1, 4-13; PTO-892), Zhou (WO 2011/063348 A1; IDS entered November 13, 2018), and Sun (WO 2013/096221 A1; IDS entered November 13, 2018) as applied to claims 81-85 and 88-99 above and further in view of Ast (WO 2013/026837 A1; IDS entered November 13, 2018).
The teachings of Kufer, Kannan, Zhou and Sun are detailed above.
Kufer, Kannan, Zhou and Sun do not teach that the bispecific scFv [(scFv)2] constructs comprise Fc polypeptide with the substitutions recited in claim 86.
According to Ast, adding an Fc domain to the bispecific construct improved the half-life of the molecule relative to prior art constructs, thereby improving efficacy, and improved production. E.g., Background at 2. However, Ast also cautions that toxicity issues known to be associated with the Fc need to be avoided to provide an improved therapeutic. The constructs of Ast comprise a first scFv specific for an activating T cell antigen, in particular CD3, and a second scFv specific for an antigen on a tumor cells, such as EGFR or CD33. E.g., “claims” 15 and 16. The bispecific constructs with an added Fc region, like prior art constructs lacking the Fc, could re-direct T cell cytotoxicity to tumor cells. E.g., Example 4, pages 69-71. To link the various components, Ast teaches that the scFv and Fc domains may be fused either directly or via a linker peptide, typically of between about 2-20 amino acids. E.g. page 22, line 17 to page 23, line 3; page 31, line 10-17. When the scFv molecule is fused to the Fc domain, Ast teaches it can also be fused directly (i.e., “L4” is absent) or the linker can be 2-20 amino acids and, particularly when the scFv is fused to the N-terminus of the Fc, it may be fused using the hinge, with or without an additional linker. E.g., page 22, lines 17-24.
Regarding claim 86, Ast addresses the Fc toxicity issue by introducing mutations in the Fc that reduce effector function. E.g., page 4, lines 7-25; page 23, line 23 to page 29, line 2. In particular, Ast notes mutations can be made in the Fc at one or more of positions E233, L234, L235, N297, P331, and p329. E.g., page 26, lines 6-26.
To improve association between the Fc polypeptide to which the (scFv)2 is linked and the second Fc polypeptide, Ast also teaches introducing mutations that promote association between first and second Fc polypeptides. E.g., page 3, lin30 to page 4, line 6; page 29, line 4 to page 31, line 2; “claims” 12-13.
Like Kufer, Ast teaches that the bispecific scFv-Fc constructs can be used to treat cancers, as well as other diseases where it is desirable to activate T cells to induce lysis of target cells. E.g. pages 52-54.
In view of the combined teachings of Kufer, Kannan, Zho and Sun in view of Ast, the ordinary artisan before the effective filing date of the claimed invention would have been motivated to attach an Fc polypeptide as taught by Zhou to any of the constructs of Kufer with the insertion as taught by Sun and further to incorporate the specific Fc mutations as taught by Ast. Ast teaches that adding the Fc provides therapeutic and production benefits. A bispecific construct comprising an anti-CD3 scFv as taught by Kufer would be linked to any of a variety of tumor targeting scFv, such as the anti-Her2 scFv or the anti-CD33 scFv exemplified by Kufer. An Fc domain would be incorporated as taught by Zhou and Sun to increase the half-life of the construct. Further, following the teachings of Ast, the ordinary artisan would have avoided potential negative effects of adding an Fc domain by incorporating mutations into the Fc polypeptide that included the L234A, L235A, N297 substitutions. Because Ast teaches expressing the construct along with a second Fc polypeptide, the resulting molecule would be a heterodimer comprising two Fc domains, with one domain linked to the scFv’s.
Accordingly, the combined teachings of Kufer, Kannan, Zhou, Sun and Ast would have lead the ordinary artisan to prepare a construct as recited in independent claim 86 before the effective filing date of the claimed invention. The ordinary artisan would have predictably added the Fc polypeptide of Ast to the constructs of Kufer, Kannan, Zhou and Sun using the techniques taught by Ast with a reasonable expectation of attaining a construct that retained the functions taught by both Kufer and Ast (i.e., tumor cell killing by targeting CD3+ effector cells to the tumor), but also having an improved half-life following administration as well as decreased toxicity, which would in turn provide more effective tumor cell killing. For these reasons, the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention.
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.
Claims 80-81 and 90-99 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No.11,753,475 in view of Zhou (WO 2011/063348 A1; IDS entered November 13, 2018) and Sun (WO 2013/096221 A1; IDS entered November 13, 2018).
Regarding claims 80, 82, 89, 93 the patented claims teach a bispecific-Fc molecule (Bi-Fc) monomer which mediates cytolysis of a cancer cell by a T cell, wherein the Bi-Fc comprises a polypeptide chain comprising an amino acid sequence having the following formula: V1-L1-V2-L2- V3-L3-V4-L4-Fc or Fc-L4-V1-L1-V2-L2-V3-L3-V4; wherein two of V1, V2, V3, and V4 are heavy chain variable (VH) regions and the other two are light chain variable (VL) regions; wherein one VH region and one VL region binds CD3 epsilon on a T cell and one VH region and one VL region binds HER2 on the cancer cell; wherein Fc is human IgG Fc polypeptide chain; wherein L1, L2, L3, and L4 are linkers; wherein L4 can be present or absent; and wherein the Bi-Fc monomer comprises a single chain antiHER2/CD3 epsilon antibody comprising the amino acid sequence of SEQ ID NO: 9 or a single chain antiFOLR1/CD3 epsilon antibody comprising the amino acid sequence of SEQ ID NO: 14 (claims 1 and 4). The patented claims further teach the Bi-Fc monomer of claim 1 comprising the amino acid sequence of SEQ ID NO: 10 (claim 3) and The Bi-Fc monomer of claim 4 comprising the amino acid sequence of SEQ ID NO: 15 (claim 5).
The patented SEQ ID NO: 10 and 15 incorporate mutations K392D/K409D, L234A and L235A in the anti-HER2/CD3 Bi-Fc and anti-FOLR1/CD3 Bi-Fc sequence respectively, with the requisite linkers, thereby meeting the limitations of claim 80 except the insertion between position 384 and 385. SEQ ID NOs: 10 and 15 100% sequence identity to the instant claimed SEQ ID NOs: 48-53 recited in claim 93.
Regarding claims 94 and 99, the patented claims teach a pharmaceutical composition comprising the Bi-Fc monomer of claim 1/3/4/5 and a physiologically acceptable carrier, excipient, and/or diluent (claims 2 and 6-8).
The patented claims do not teach an insertion of one of SEQ ID NOs: 36-47 between position 384 and 385 in the Fc or a Y349T mutation in the Fc.
Zhou teaches monomeric Fc polypeptides prepared by introducing substitutions of one or more hydrophobic amino acid in the CH3 region with a polar amino acid. See entire document, e.g., Abstract. Zhou teaches that the wildtype Fc is homodimeric in nature via high-affinity interactions in the wildtype CH3 domain. E.g., [0018]. But Zhou teaches that even in the monomeric form, the Fc still retains the ability to bind FcRn, so that even constructs that comprise only one Fc domain have extended half-life relative to constructs that do not comprise an Fc domain. E.g., [0028], [0033]. In addition to the increased half-life relative to a construct lacking an Fc domain, Zhou also teaches that monomeric constructs are advantageous in that their smaller size facilitates tissue penetration, a feature that can be particularly important for targeting cancers. E.g. [0033].
Regarding claims 80-81 and 83, Zhou teaches that formation of heterodimers of two Fc can be discouraged by substitutions at one or more of positions in the CH3 domain. E.g., [0024], [0025], claims on pages 24 and 25. Substitutions in human IgG CH3 at positions D356, E357, K392, D399, and K409 with another residue that results in an unfavorable charge help to avoid formation of the homodimer, while substitutions at Y349, L351, L368, L398, F405, and Y407 with a small polar residue such as threonine (T/Thr) improve the stability of the polypeptide in monomeric form. Id. Zhou teaches exemplary substitution combinations in human IgG1-CH3 that favor monomer formation are K392D, K409D, Y349T or K392D, K409D, F405T. E.g. [0026], see also [0062].
Regarding claim 81, Zhou teaches a half IgG molecule comprising the K392D, K409D, Y349T substitution combination was shown to have significantly increased AUC and T1/2 relative to the size matched control lacking any Fc. E.g. pages 21-22.
Regarding claim 95, Zhou teaches an isolated nucleic acid encoding the monomeric Fc polypeptide (claim 22).
Regarding claim 96, Zhou teaches an expression vector comprising a nucleic acid encoding the monomeric Fc polypeptide (claim 23).
Regarding claim 97, Zhou teaches a host cell comprising a nucleic acid encoding the monomeric Fc polypeptide (claim 24).
Regarding claim 98, Zho teaches a method of preparing a monomeric Fc polypeptide, said method comprising the steps of: (a) culturing a host cell comprising a nucleic acid encoding the monomeric Fc polypeptide of claim 1 under conditions wherein said monomeric Fc polypeptide is expressed; and (b) recovering the monomeric Fc polypeptide from the host cell culture (claim 25).
Regarding claim 80, Sun teaches methods of improving the binding characteristics of an Fc-containing polypeptides, including bispecific molecules, for the neonatal Fc receptor (FcRn). See entire document, e.g., Abstract. The peptides recite in instant claim 31 are taught as useful for increasing the half-life of the antibody to which and Fc domain comprising an insertion of those sequences between positions 384 and 385. E.g., Example 9.
Accordingly, in view of the teachings of Zhou, the ordinary artisan before the effective filing date would have understood that adding a Y349T mutation to the bispecific, single-chain antibody with monomeric Fc of the patented claims could increase the half-life. Further, as also taught by Zhou, bispecific constructs comprising a monomeric Fc would have been expected to have enhanced tumor penetration relative to forms containing a dimeric Fc. Given the teachings of Zhou regarding the desirability of increasing half-life for the bispecific, tumor targeting antibodies, the ordinary artisan prior to the effective filing date of the claimed invention would have predictably inserted any of the peptides taught by Sun into the Fc region of the constructs of the patented claims in view of Zhou to predictably further improve its half-life in vivo and enhance its therapeutic activity.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMBER K FAUST whose telephone number is (703)756-1661. The examiner can normally be reached Monday - Thursday 9:00am-6:00pm EST.
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/AMBER K FAUST/ Examiner, Art Unit 1643
/JULIE WU/ Supervisory Patent Examiner, Art Unit 1643