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 .
Detailed Action
The Amendments and Remarks filed 6/24/26 in response to the Office Action of 3/25/26 are acknowledged and have been entered.
Claims 1-24, 26, 27, 30-32, and 35 are pending.
Claims 26, 27, 30-32, and 35 remain withdrawn.
Claims 1-8, 16-24, 31 and 32 have been amended by Applicant.
Claims 1-24 are currently under consideration.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The following Office Action contains NEW GROUNDS of rejections Necessitated by Amendments.
Rejections Withdrawn
All previous rejections are withdrawn.
New Rejections Necessitated by Amendments
Claim Rejections - 35 USC § 103
Claims 1-8, 11-21, 23, and 24 are rejected under 35 U.S.C. 103(a) as being unpatentable over Ast et al (US 2012/0276125 A1; 11/1/2012; 3/14/24 IDS) in view of Lunia-Perez et al (Cancer Res, 2010, 70 (8_Supplement): LV-304; “Perez1”), Luria-Perez et al (Cytokine 2019, 120: 220-226; “Perez2”; 2/10/23 IDS), and Hasan et al (The Journal of Immunology, 1999, 162: 1064-1070).
Figure 1, Figure 2A, and Figure 2B of Ast et al teaches antigen-specific immunoconjugates for delivering an effector moiety with the following fusion protein comprising an IgG structure comprising N-terminal Fab binding domains and an effector moiety that is a cytokine attached via a linker to the C-terminus of one more heavy chain of the Fc domain:
PNG
media_image1.png
530
638
media_image1.png
Greyscale
PNG
media_image2.png
563
810
media_image2.png
Greyscale
Ast et al further teaches said immunoconjugates wherein the cytokine is selected from a group comprising IL-12 ([0019], in particular). Ast et al further teaches said immunoconjugates wherein the IL-12 is SEQ ID NO:4 ([0191], in particular), which is identical to instant SEQ ID NO:73. Instant SEQ ID NO:73 comprises IL-12B(p40)---(G4S)3 linker---IL-12A where IL-12A(p35) is instant SEQ ID NO:75. Further, IL-12B(p40) of instant SEQ ID NO:73 comprises instant SEQ ID NO:74 comprising K258, K260, K263, and K264. Ast et al further teaches said IL-12 can elicit proliferation of NK cells, differentiation in an NK cell, proliferation in a T cell and differentiation in a T cell ([0191], in particular). Ast et al further teaches said immunoconjugates wherein the antigen binding domains bind Fibroblast Activation Protein (FAP; same as “fibroblast activation protein alpha”) on tumor cells ([0018] and [0204], in particular). Ast et al further teaches said immunoconjugates wherein the Fc domain is derived from human IgG1 ([0154], in particular). Ast et al further teaches said immunoconjugates wherein one of the two subunits of the Fc domain comprises a knob and the other comprises a hole ([0011], in particular). Ast et al further teaches said immunoconjugates wherein he effector moiety is fused to the amino- or carboxy-terminal amino acid of the subunit of the Fc domain comprising the knob modification ([0011], in particular). Ast et al further teaches said immunoconjugates and a pharmaceutically acceptable carrier ([0022], in particular).
Ast et al did not specifically demonstrate generating an immunoconjugate comprising an IL-12 effector moiety wherein the immunoconjugate targets FAP or wherein the IL-12 effector moiety comprises a variant of IL-12B(p40) comprising instant SEQ ID NO:74 with a substitution selected from K258A, K260A, K263A, and K264A. However, these deficiencies are made-up in the teachings of Perez1, Perez2, and Hasan et al.
The Abstract of Perez1 teaches IL-12 comprises p40 and p35 subunits and that systemic injection of anti-tumor antibody-IL-12 fusion protein constructs can result in non-specific targeting due to IL-12 of the constructs to exhibit heparin-binding activity, which allows the constructs to bind glycosaminoglycans present on the surface of a broad variety of cells and the extracellular matrix in normal tissues.
Perez2 teaches heparin-binding activity of human and mouse IL-12 involves a cluster of basic amino acids within the C-terminal domain of the p40 subunit of human and mouse IL-12 (second paragraph on page 3, in particular). Perez2 further teaches substituting the basic arginine and lysine residues of amino acids 254-260 of murine IL-12 (p40) with neutral alanine inhibits IL-12 from binding heparin (Abstract, in particular).
Hasan et al teaches amino acids 256-268 within the C-terminal domain of human IL-12(p40) as a region of IL-12 with basic lysine residues that interacts with heparin that corresponds to a region comprising amino acids 254-260 of murine IL-12 (p40) of Perez2 that interacts with heparin (Figure 7 and page 1069, in particular).
One ordinary skill in the art would have been motivated, with a reasonable expectation of success, to generate any immunoconjugate of Ast et al comprising any IL-12 effector moiety of Ast et al (including SEQ ID NO:4) wherein the immunoconjugate targets FAP on tumor cells, comprises any immunoconjugate structure of Figures 1-2 of Ast et al, and comprises Fc domains with knobs-and-holes as taught by Ast et al to promote proper heterodimerization because Ast et al teaches immunoconjugates are to target FAP on tumor cells and ([0018] and [0204], in particular) and the IL-12 effector moiety of Ast et al is taught to provide therapeutic benefits of eliciting proliferation of NK cells, differentiation in an NK cell, proliferation in a T cell and differentiation in a T cell ([0191], in particular).
Further, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of generating the immunoconjugate wherein the basic lysine residues of amino acids 256-258 of IL-12 (p40) of Ast et al (same as instant SEQ ID NO:74) are substituted with neutral alanine residues in order to prevent the non-specific targeting of the tumor-targeted immunoconjugate because Perez1 teaches anti-tumor antibody-IL-12 fusion protein constructs can result in non-specific targeting due to IL-12 of the constructs to exhibit heparin-binding activity, Perez2 teaches heparin-binding activity of human and mouse IL-12 involves a cluster of basic amino acids within the C-terminal domain of the p40 subunit of human and mouse IL-12 (second paragraph on page 3, in particular), Perez2 further teaches substituting the basic arginine and lysine residues of amino acids 254-260 of murine IL-12 (p40) with neutral alanine inhibits IL-12 from binding heparin (Abstract, in particular), Hasan et al teaches amino acids 256-268 within the C-terminal domain of human IL-12(p40) as a region of IL-12 with basic lysine residues that interacts with heparin that corresponds to a region comprising amino acids 254-260 of murine IL-12 (p40) of Perez2 that interacts with heparin (Figure 7 and page 1069, in particular), and substituting the basic residues of amino acids 256-268 of human IL-12(p40) with neutral alanine residues would be expected to inhibit heparin binding of human IL-12 just like substituting the basic residues amino acids 254-260 of murine IL-12(p40) inhibits heparin binding of murine IL-12 due to Hasan et al teaches amino acids 256-268 within the C-terminal domain of human IL-12(p40) as a region of IL-12 with basic lysine residues that interacts with heparin that corresponds to a region comprising amino acids 254-260 of murine IL-12 (p40) of Perez2 that interacts with heparin (Figure 7 and page 1069, in particular).
This is an example of some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference to arrive at the claimed invention. See MPEP 2143.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Claim Rejections - 35 USC § 103
Claim(s) 1-24 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ast et al (US 2012/0276125 A1; 11/1/2012; 3/14/24 IDS) in view of Lunia-Perez et al (Cancer Res, 2010, 70 (8_Supplement): LV-304; “Perez1”), Luria-Perez et al (Cytokine 2019, 120: 220-226; “Perez2”), and Hasan et al (The Journal of Immunology, 1999, 162: 1064-1070) as applied to claim 1-8, 11-21, 23, and 24 above, and further in view of Park et al (US 2002/0052480 A1; 5/2/02; 11/20/25 IDS).
Teachings of Ast et al, Perez1, Perez2, and Hasan et al are described above.
Ast et al, Perez1, Perez2, and Hasan et al do not specifically teach antibody binding domains that bind FAP comprising heavy chains comprising instant SEQ ID NOs: 96-98 and 102 and light chains comprising instant SEQ ID NOs: 99-101 and 103. However, these deficiencies are made up in the teachings of Park et al.
At [0050], Park et al teaches an antibody that specifically targets FAP with a heavy chain consisting of SEQ ID NO:12 (which is identical to instant SEQ ID NO:102 and comprises instant SEQ ID NOs:96-98 and a heavy chain consisting of SEQ ID NO:2 (which is identical to instant SEQ ID NO:103 and comprises instant SEQ ID NOs: 99-101).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to generate the immunoconjugates of the combination of Ast et al, Perez1, Perez2, and Hasan et al wherein the light chain and heavy chain sequences of the FAP binding domains comprise just any combination of anti-FAP light chains and heavy chains of Park et al (including the combination of SEQ ID NOs: 12 and 102) because the immunoconjugates are to target FAP via Fab binding domains of the immunoconjugates that comprise heavy and light chain sequences and the heavy and light chain sequences of Park specifically target FAP. This is an example of a simple substitution of one known element for another to obtain predictable results See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Conclusion
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 SEAN E AEDER whose telephone number is (571)272-8787. The examiner can normally be reached M-F 9am-6pm ET.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis can be reached at (571)270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/SEAN E AEDER/Primary Examiner, Art Unit 1642
Prosecution Insights