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 24, 2025 in response to the non-final Office action mailed July 24, 2025 are acknowledged. Claim 2 is canceled. Claim 1 is amended.
Claims 1 and 3-16 are pending and under examination herein.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. However, support for the claimed invention cannot be determined because the foreign priority documents provided for CN202010305482.7 are not in English. Therefore, the instant application is not entitled to the benefit of the foreign priority date of April 17, 2020.
Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e). Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Accordingly, the filing date of the PCT/CN2021/087582 application, filed on April 15, 2021, will be used for the purpose of applying prior art.
Objection to the Specification and Drawings Withdrawn
The objections to the disclosure are withdrawn in view of Applicant's amendments thereto.
The objections to the Drawings are withdrawn in view of Applicant's amendments to Figure 3 and Applicant's clarifying remarks regarding Figure 2.
Claim Objections and Rejections Withdrawn
All prior objections and rejections of claim 2 are rendered moot by the cancelation of the claim.
The rejection of claims 1 and 3-16 under 35 U.S.C. 112(a) as failing to comply with the written description requirement are withdrawn in view of Applicant's amendments to claim 1.
NEW AND MAINTAINED CLAIM OBJECTIONS AND REJECTIONS
Claim Objections
Claim 1 is objected to because of the following informalities: It is suggested that “or” be placed at the end of list item 7, before the last list item (i.e., “the VL comprises an amino acid sequence as set forth in SEQ ID NO: 10, and the VH comprises an amino acid sequence as set forth in SEQ ID NO: 21; or”). This is a new objection necessitated by claim amendment.
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.
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, 3-7, 10, 12, and 14-16 are rejected under 35 U.S.C. 103 as being obvious over Xu (WO 2020/077635 A1; published April 23, 2020; earliest priority date: October 19, 2018) in view of Kang (BioProcess International (2016) 14(4): 40-45; cited in PTO-892 mailed July 24, 2025). This is a new rejection.
The applied reference of Xu has common inventors (Jianjian Peng; Kai Fu) with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
Relevant to claim 1, Xu teaches an antibody or antigen-binding fragment thereof that specifically binds to CD137 (e.g., Abstract; Summary of the invention), wherein the antibody or antigen-binding fragment thereof comprises a VL and a VH, wherein:
Said VL comprises the amino acid sequence set forth in SEQ ID NO: 104 (which shares 100% sequence identity to instant SEQ ID NO: 1) and said VH comprises the amino acid sequence set forth in SEQ ID NO: 128 (which shares 100% sequence identity to instant SEQ ID NO: 12);
Said VL comprises the amino acid sequence set forth in SEQ ID NO: 106 (which shares 100% sequence identity to instant SEQ ID NO: 3) and said VH comprises the amino acid sequence set forth in SEQ ID NO: 130 (which shares 100% sequence identity to instant SEQ ID NO: 14);
Said VL comprises the amino acid sequence set forth in SEQ ID NO: 108 (which shares 100% sequence identity to instant SEQ ID NO: 5) and said VH comprises the amino acid sequence set forth in SEQ ID NO: 132 (which shares 100% sequence identity to instant SEQ ID NO: 16);
Said VL comprises the amino acid sequence set forth in SEQ ID NO: 110 (which shares 100% sequence identity to instant SEQ ID NO: 7) and said VH comprises the amino acid sequence set forth in SEQ ID NO: 134 (which comprises 100% sequence identity to instant SEQ ID NO: 18);
Said VL comprises the amino acid sequence set forth in SEQ ID NO: 111 (which shares 100% sequence identity to instant SEQ ID NO: 8) and said VH comprises the amino acid sequence set forth in SEQ ID NO: 135 (which comprises 100% sequence identity to instant SEQ ID NO: 19);
Said VL comprises the amino acid sequence set forth in SEQ ID NO: 112 (which shares 100% sequence identity to instant SEQ ID NO: 9) and said VH comprises the amino acid sequence set forth in SEQ ID NO: 136 (which shares 100% sequence identity to instant SEQ ID NO: 20);
Said VL comprises the amino acid sequence set forth in SEQ ID NO: 113 (which shares 100% sequence identity to instant SEQ ID NO: 10) and said VH comprises the amino acid sequence set forth in SEQ ID NO: 137 (which shares 100% sequence identity to instant SEQ ID NO: 21); or
Said VL comprises the amino acid sequence set forth in SEQ ID NO: 114 (which shares 100% sequence identity to instant SEQ ID NO: 11) and said VH comprises the amino acid sequence set forth in SEQ ID NO: 138 (which shares 100% sequence identity to instant SEQ ID NO: 22).
Relevant to claims 15-16, Xu further recites pharmaceutical compositions comprising the antibody of the invention and pharmaceutical uses thereof in a method of treating cancer (e.g., melanoma, prostate cancer, and others) (Summary of the invention; Detailed Description/Pharmaceutical composition and pharmaceutical use). Xu discloses that the pharmaceutical compositions may comprise pharmaceutically acceptable adjuvants including buffers, antioxidants, preservatives, sugars, and chelating agents (Detailed Description/Pharmaceutical composition and pharmaceutical use).
However, Xu does not expressly teach that the pharmaceutical preparations of the invention comprise a specific buffer salt, stabilizer, and/or surfactant, and/or a specific pH level, nor a kit comprising the preparation and a container, as set forth in the instant claims.
Kang reviews formulation development for monoclonal antibodies (mAbs) and summarizes observations based on 37 commercial mAb formulations. Kang observed that phosphate, citrate, and acetate are among the most commonly used buffers and keep pH levels between 4.7 and 7.4 (page 40; Table 1), relevant to claims 3 and 12. In a case study, Kang found that a range of 10-50 mM phosphate-citrate buffer did not significantly influence the mAb’s stability (pages 42-43; Figures 2-5), relevant to claims 4-5. Polysorbate 80 and polysorbate 20 were among the most commonly used surfactants, with polysorbate 80 found in 72% of formulations (page 40; Table 1), relevant to claim 10. Relevant to claims 6-7, Kang describes several stabilizers (e.g., sucrose, trehalose, mannitol, and NaOAc or sodium acetate) (e.g., page 40; Table 1). Kang teaches that sugars provide bulk and serve as a stabilizing agent in antibody formulations. Sucrose was found in 80% of lyophilized formulations and 30% of liquid formulations (page 40; Table 1). Kang further teaches that in their platform approach, after selecting buffers to optimize for their desired pH, they will perform a screening study and choose one or two excipients from each of the categories of stabilizers (e.g., a sugar), surfactants (e.g., polysorbate 80), sodium chloride, amino acids, and antioxidants (page 42). Following screening, during the in-depth evaluation of the most stabilizing buffer(s) and excipient(s), the mAb preparation is formulated at a target concentration and filled into the intended vial/stopper system (i.e., a container) to mimic a final-product configuration, relevant to claim 14.
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to formulate an anti-CD137 antibody preparation taught by Xu with (1) a buffer salt selected from one or more of phosphate, citrate, and acetate, (2) a stabilizer selected from one or more of sucrose, trehalose, mannitol, or sodium acetate, and (3) a surfactant selected from one or more of polysorbate 80 and polysorbate 20, and with a pH of 6.5-7.4, into a pharmaceutical composition and/or kit. The skilled artisan would have been motivated to do so because Kang teaches that (1) commonly used buffers such as phosphate and citrate (e.g., 10-50 mM phosphate-citrate buffer) keep pH levels of antibody formulations between 4.7 and 7.4 (which overlaps with the range of 6.5 and 7.5), without significantly influencing the mAb’s stability; (2) more than 80% of formulations use one of three surfactants, e.g., polysorbate 80; and (3) sugars (e.g., sucrose) provide bulk for lyophilized formulations and serve as stabilizing agents for therapeutic proteins. Furthermore, it would have been obvious for one of ordinary skill in the art to try various combinations of the buffers, surfactants, and sugars taught by Kang in a mAb formulation to arrive at an optimal, stable formulation, though the process of routine optimization. As illustrated by Kang, there are a finite number of previously identified, predictably behaving options for buffers, surfactants, and sugars available that one of ordinary skill in the art would reasonably expect to be successful based on their use in commercially available formulations. There would have been a reasonable expectation of success because one of ordinary skill in the art would have recognized that each of the possible excipients within each category (surfactants, sugars, buffers) have utility for the same respective purposes and are functionally equivalent variants.
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
(2)
Claims 1 and 3-16 are rejected under 35 U.S.C. 103 as being obvious over Xu (WO 2020/077635 A1; supra) in view of Wang (US 2019/0284292 A1; cited in PTO-892 mailed July 24, 2025) and Akamatsu (US 2019/0194329 A1; cited in PTO-892 mailed July 24, 2025). This is a new rejection.
The applied reference of Xu has common inventors (Jianjian Peng; Kai Fu) with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
The teachings of Xu are summarized in the 35 U.S.C. § 103 rejection above.
However, Xu does not expressly teach that the pharmaceutical preparations of the invention comprise a specific buffer salt, stabilizer, and/or surfactant, and/or a specific pH level, nor a kit comprising the preparation and a container, as set forth in the instant claims.
Wang discloses antibodies that specifically bind to 4-1BB (CD137) and pharmaceutical compositions comprising the same (e.g., Abstract; Summary). Wang teaches that antibodies of the invention formulated for parenteral administration may be prepared in a suitable buffer including sodium citrate, and contained in a flint or amber vial, ampule or pre-filled syringe (e.g., pages 21-22), relevant to claims 3-4 and 14. Wang further teaches that sucrose (0-10%, optimally 0.5-1.0%) or trehalose may be added to lyophilized formulations as a cryoprotectant and that mannitol can be incorporated as a bulking agent (e.g., pages 21-22), relevant to claims 6-9. Relevant to claims 10-11, Wang teaches that polysorbate 80 (0-0.05%, optimally 0.005-0.01%) and polysorbate 20 may be included as surfactants (e.g., page 22).
Wang further teaches that antibody formulations suitable for parenteral administration may be formulated in powder form for reconstitution with a suitable vehicle (e.g., sterile pyrogen-free water) before being administered to a subject (e.g., pages 21-22), relevant to claim 13.
Akamatsu also discloses anti-4-1BB antibodies and pharmaceutical compositions comprising the same (e.g., Abstract). Akamatsu teaches that pharmaceutical compositions of the invention may be prepared for storage as lyophilized formulations or as aqueous solutions by mixing an antibody of the invention with a pharmaceutically acceptable carrier, e.g., buffering agents (e.g., page 13). Akamatsu teaches that buffering agents help to maintain the pH of the formulation in the range simulating physiological conditions, and that buffering agents may be present in a wide range of concentrations from about 2 mM to about 50 mM (e.g., page 13). Suitable buffering agents for use in the formulations of the invention include phosphate buffers (e.g., monosodium phosphate (also known as sodium dihydrogen phosphate) and disodium phosphate (also known as disodium hydrogen phosphate) and citrate buffers (e.g., monosodium citrate-disodium citrate mixture) (e.g., page 13), relevant to claims 3-5 and 13. As understood by those of ordinary skill in the art, physiological pH typically ranges between 7.35 to 7.45, relevant to claim 12.
Further relevant to claims 6-9 and 13, Akamatsu teaches that stabilizers may be added which range in function from acting as a bulking agent, solubilizing the therapeutic agent, or helping to prevent denaturation or adherence to the container wall (e.g., page 13). Typical stabilizers include sucrose, trehalose, and mannitol, and may be present in amounts ranging from 0.5-10% (wt). Relevant to claims 10 and 13, Akamatsu teaches that non-ionic surfactants (e.g., polysorbate 80 or polysorbate 20) may be added to help solubilize the glycoprotein or protect the glycoprotein from agitation-induced aggregation (e.g., pages 13-14).
Further relevant to claim 14, Akamatsu teaches that dry powder unit dosage forms may be packaged in a kit with a syringe and that liquid formulations may be pre-filled in a syringe in an amount suitable for a single administration (e.g., page 13).
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to formulate the anti-CD137 antibody preparation taught by Xu with (1) a buffer salt comprising sodium citrate and/or a phosphate buffer (e.g., monosodium phosphate or disodium phosphate), (2) a stabilizer selected from one or more of sucrose, trehalose, and mannitol, (3) a surfactant selected from one or more of polysorbate 80 and polysorbate 20, and (4) water, based on the further teachings of Wang and Akamatsu. The skilled artisan would have been motivated to do so because:
buffering agents (e.g., sodium citrate, monosodium phosphate, disodium phosphate) help to maintain the formulation at physiologically relevant pH conditions (as taught by Akamatsu);
stabilizers (e.g., sucralose, trehalose, mannitol) can be used to function as bulking agents, solubilize the therapeutic agent, or prevent denaturation or adherence to the container wall (as taught by Akamatsu and Wang);
surfactants (e.g., polysorbate 80, polysorbate 20) help to solubilize the glycoprotein and protect the glycoprotein against agitation-induced aggregation (as taught by Akamatsu), and
water acts as a suitable vehicle for (re)constituting antibody formulations into a liquid form suitable for parenteral administration (as taught by Wang).
Furthermore, it would have been obvious for one of ordinary skill in the art to try various combinations of the buffers, surfactants, and sugars taught by Wang and Akamatsu in a mAb formulation to arrive at an optimal, stable formulation, though the process of routine optimization. There are a finite number of previously identified, predictably behaving options for buffers, surfactants, and sugars, and these excipients have been successfully incorporated into previously described anti-CD137 antibody formulations. There would have been a reasonable expectation of success because one of ordinary skill in the art would have recognized that each of the possible excipients within each category (surfactants, sugars, buffers) have utility for the same respective purposes and are functionally equivalent.
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
(3)
Claims 1, 3-7, 10-12, and 14-16 are rejected under 35 U.S.C. 103 as being obvious over Zhang (WO 2020/078149 A1; published April 23, 2020; earliest priority date: October 19, 2018) in view of Kang (BioProcess International (2016) 14(4): 40-45; supra). This is a new rejection.
The applied reference of Zhang has common inventors (Xin Zhang; Jianjian Peng; Kai Fu) with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
Relevant to claim 1, Zhang teaches an antibody or antigen-binding fragment thereof that specifically binds to CD137 (e.g., Abstract; Summary of the invention), wherein the antibody or antigen-binding fragment thereof comprises a VL and a VH, wherein:
Said VL comprises the amino acid sequence set forth in SEQ ID NO: 104 (which shares 100% sequence identity to instant SEQ ID NO: 1) and said VH comprises the amino acid sequence set forth in SEQ ID NO: 128 (which shares 100% sequence identity to instant SEQ ID NO: 12);
Said VL comprises the amino acid sequence set forth in SEQ ID NO: 106 (which shares 100% sequence identity to instant SEQ ID NO: 3) and said VH comprises the amino acid sequence set forth in SEQ ID NO: 130 (which shares 100% sequence identity to instant SEQ ID NO: 14);
Said VL comprises the amino acid sequence set forth in SEQ ID NO: 108 (which shares 100% sequence identity to instant SEQ ID NO: 5) and said VH comprises the amino acid sequence set forth in SEQ ID NO: 132 (which shares 100% sequence identity to instant SEQ ID NO: 16);
Said VL comprises the amino acid sequence set forth in SEQ ID NO: 110 (which shares 100% sequence identity to instant SEQ ID NO: 7) and said VH comprises the amino acid sequence set forth in SEQ ID NO: 134 (which comprises 100% sequence identity to instant SEQ ID NO: 18);
Said VL comprises the amino acid sequence set forth in SEQ ID NO: 111 (which shares 100% sequence identity to instant SEQ ID NO: 8) and said VH comprises the amino acid sequence set forth in SEQ ID NO: 135 (which comprises 100% sequence identity to instant SEQ ID NO: 19);
Said VL comprises the amino acid sequence set forth in SEQ ID NO: 112 (which shares 100% sequence identity to instant SEQ ID NO: 9) and said VH comprises the amino acid sequence set forth in SEQ ID NO: 136 (which shares 100% sequence identity to instant SEQ ID NO: 20);
Said VL comprises the amino acid sequence set forth in SEQ ID NO: 113 (which shares 100% sequence identity to instant SEQ ID NO: 10) and said VH comprises the amino acid sequence set forth in SEQ ID NO: 137 (which shares 100% sequence identity to instant SEQ ID NO: 21); or
Said VL comprises the amino acid sequence set forth in SEQ ID NO: 114 (which shares 100% sequence identity to instant SEQ ID NO: 11) and said VH comprises the amino acid sequence set forth in SEQ ID NO: 138 (which shares 100% sequence identity to instant SEQ ID NO: 22).
Relevant to claims 15-16, Zhang further recites pharmaceutical compositions comprising the antibody of the invention and pharmaceutical uses thereof in a method of treating cancer (e.g., melanoma, prostate cancer, and others) (Summary of the invention; Detailed Description/Pharmaceutical composition and pharmaceutical use). Zhang discloses that the pharmaceutical compositions may comprise pharmaceutically acceptable adjuvants including buffers, antioxidants, preservatives, sugars, and chelating agents (Detailed Description/Pharmaceutical composition and pharmaceutical use).
However, Zhang does not expressly teach that the pharmaceutical preparations of the invention comprise a specific buffer salt, stabilizer, and/or surfactant, and/or a specific pH level, nor a kit comprising the preparation and a container, as set forth in the instant claims.
The teachings of Kang are discussed in the 35 U.S.C. § 103 rejection above.
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to formulate an anti-CD137 antibody preparation taught by Zhang with (1) a buffer salt selected from one or more of phosphate, citrate, and acetate, (2) a stabilizer selected from one or more of sucrose, trehalose, mannitol, or sodium acetate, and (3) a surfactant selected from one or more of polysorbate 80 and polysorbate 20, and with a pH of 6.5-7.4, into a pharmaceutical composition and/or kit. The skilled artisan would have been motivated to do so because Kang teaches that (1) commonly used buffers such as phosphate and citrate (e.g., 10-50 mM phosphate-citrate buffer) keep pH levels of antibody formulations between 4.7 and 7.4 (which overlaps with the range of 6.5 and 7.5), without significantly influencing the mAb’s stability; (2) more than 80% of formulations use one of three surfactants, e.g., polysorbate 80; and (3) sugars (e.g., sucrose) provide bulk for lyophilized formulations and serve as stabilizing agents for therapeutic proteins. Furthermore, it would have been obvious for one of ordinary skill in the art to try various combinations of the buffers, surfactants, and sugars taught by Kang in a mAb formulation to arrive at an optimal, stable formulation, though the process of routine optimization. As illustrated by Kang, there are a finite number of previously identified, predictably behaving options for buffers, surfactants, and sugars available that one of ordinary skill in the art would reasonably expect to be successful based on their use in commercially available formulations. There would have been a reasonable expectation of success because one of ordinary skill in the art would have recognized that each of the possible excipients within each category (surfactants, sugars, buffers) have utility for the same respective purposes and are functionally equivalent variants.
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
(4)
Claims 1 and 3-16 are rejected under 35 U.S.C. 103 as being obvious over Zhang (WO 2020/078149 A1; supra) in view of Wang (US 2019/0284292 A1; supra) and Akamatsu (US 2019/0194329 A1; supra). This is a new rejection.
The applied reference of Zhang has common inventors (Xin Zhang; Jianjian Peng; Kai Fu) with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
The teachings of Zhang are summarized in the 35 U.S.C. § 103 rejection above.
However, Zhang does not expressly teach that the pharmaceutical preparations of the invention comprise a specific buffer salt, stabilizer, and/or surfactant, and/or a specific pH level, nor a kit comprising the preparation and a container, as set forth in the instant claims.
The teachings of Wang and Akamatsu are discussed in the 35 U.S.C. § 103 rejection above.
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to formulate an anti-CD137 antibody preparation taught by Zhang with (1) a buffer salt comprising sodium citrate and/or a phosphate buffer (e.g., monosodium phosphate or disodium phosphate), (2) a stabilizer selected from one or more of sucrose, trehalose, and mannitol, (3) a surfactant selected from one or more of polysorbate 80 and polysorbate 20, and (4) water, based on the further teachings of Wang and Akamatsu. The skilled artisan would have been motivated to do so because:
buffering agents (e.g., sodium citrate, monosodium phosphate, disodium phosphate) help to maintain the formulation at physiologically relevant pH conditions (as taught by Akamatsu);
stabilizers (e.g., sucralose, trehalose, mannitol) can be used to function as bulking agents, solubilize the therapeutic agent, or prevent denaturation or adherence to the container wall (as taught by Akamatsu and Wang);
surfactants (e.g., polysorbate 80, polysorbate 20) help to solubilize the glycoprotein and protect the glycoprotein against agitation-induced aggregation (as taught by Akamatsu), and
water acts as a suitable vehicle for (re)constituting antibody formulations into a liquid form suitable for parenteral administration (as taught by Wang).
Furthermore, it would have been obvious for one of ordinary skill in the art to try various combinations of the buffers, surfactants, and sugars taught by Wang and Akamatsu in a mAb formulation to arrive at an optimal, stable formulation, though the process of routine optimization. There are a finite number of previously identified, predictably behaving options for buffers, surfactants, and sugars, and these excipients have been successfully incorporated into previously described anti-CD137 antibody formulations. There would have been a reasonable expectation of success because one of ordinary skill in the art would have recognized that each of the possible excipients within each category (surfactants, sugars, buffers) have utility for the same respective purposes and are functionally equivalent.
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
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.
(1)
Claims 1, 3-7, 10, 12, and 14-16 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 and 19-20 of U.S. Patent No. 12,252,542 (‘542 patent; cited in PTO-892 mailed July 24, 2025) in view of Kang (BioProcess International (2016) 14(4): 40-45; supra). This is a maintained rejection that has been updated to reflect Applicant's amendments to the claims.
Relevant to claim 1, the ‘542 patent claims a pharmaceutical composition comprising an antibody or antigen-binding fragment thereof that specifically binds to CD137 (see patented claims 1-9 and 19; Table 1, col 23-24), wherein the antibody or antigen-binding fragment thereof comprises a VL and a VH, wherein:
Said VL comprises the mutations V3A, D71N, V77I and the amino acid sequence set forth in SEQ ID NO: 104 (which shares 100% sequence identity to instant SEQ ID NO: 1), and said VH comprises the mutation N78K and the amino acid sequence set forth in SEQ ID NO: 128 (which shares 100% sequence identity to instant SEQ ID NO: 12);
Said VL comprises the mutation D71N and the amino acid sequence set forth in SEQ ID NO: 106 (which shares 100% sequence identity to instant SEQ ID NO: 3), and said VH comprises the mutations N78K, H84Q, and D86N and the amino acid sequence set forth in SEQ ID NO: 130 (which shares 100% sequence identity to instant SEQ ID NO: 14);
Said VL comprises the mutations D71N and V771I and the amino acid sequence set forth in SEQ ID NO: 108 (which shares 100% sequence identity to instant SEQ ID NO: 5), and said VH comprises the mutations N78K, H84Q, and D86N and the amino acid sequence set forth in SEQ ID NO: 132 (which shares 100% sequence identity to instant SEQ ID NO: 16);
Said VL comprises the mutations A10V, D71N, and V77I and the amino acid sequence set forth in SEQ ID NO: 110 (which shares 100% sequence identity to instant SEQ ID NO: 7), and said VH comprises the mutations N78K, H84Q, and D86N and the amino acid sequence set forth in SEQ ID NO: 134 (which comprises 100% sequence identity to instant SEQ ID NO: 18);
Said VL comprises the mutations A10V and D71N and the amino acid sequence set forth in SEQ ID NO: 111 (which shares 100% sequence identity to instant SEQ ID NO: 8), and said VH comprises the mutations Q13K, N78K, H84Q, and D86N and the amino acid sequence set forth in SEQ ID NO: 135 (which comprises 100% sequence identity to instant SEQ ID NO: 19);
Said VL comprises the mutations V3A, A10V, K44T, D71N, and V77I and the amino acid sequence set forth in SEQ ID NO: 112 (which shares 100% sequence identity to instant SEQ ID NO: 9), and said VH comprises the mutations Q13K and N78K and the amino acid sequence set forth in SEQ ID NO: 136 (which shares 100% sequence identity to instant SEQ ID NO: 20);
Said VL comprises the mutations A10V and V77I and the amino acid sequence set forth in SEQ ID NO: 113 (which shares 100% sequence identity to instant SEQ ID NO: 10), and said VH comprises the mutations Q13K, H84Q, D86N, A90T, and F97Y and the amino acid sequence set forth in SEQ ID NO: 137 (which shares 100% sequence identity to instant SEQ ID NO: 21); or
Said VL comprises the mutations A10V and V77I and the amino acid sequence set forth in SEQ ID NO: 114 (which shares 100% sequence identity to instant SEQ ID NO: 11), and said VH comprises the mutations Q13K, N78K, H84Q, D86N, A90T, and F97Y and the amino acid sequence set forth in SEQ ID NO: 138 (which shares 100% sequence identity to instant SEQ ID NO: 22).
Relevant to claims 15-16, the ‘542 patent further recites a method of treating colorectal cancer that comprises administering an effective amount of a composition comprising said antibody.
However, the ‘542 patent does not expressly claim that the preparation (pharmaceutical composition) comprises a specific buffer salt, stabilizer, and/or surfactant, and/or a specific pH, nor a kit comprising the preparation and a container.
The teachings of Kang are summarized in the rejection under 35 U.S.C. § 103 above.
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to formulate an anti-CD137 antibody preparation taught in the ‘542 patent with (1) a buffer salt selected from one or more of phosphate, citrate, and acetate, (2) a stabilizer selected from one or more of sucrose, trehalose, mannitol, or sodium acetate, and (3) a surfactant selected from one or more of polysorbate 80 and polysorbate 20, and with a pH of 6.5-7.4, into a kit. The skilled artisan would have been motivated to do so because Kang teaches that (1) commonly used buffers such as phosphate and citrate (e.g., 10-50 mM phosphate-citrate buffer) keep pH levels of antibody formulations between 4.7 and 7.4 (which overlaps with the range of 6.5 and 7.5), without significantly influencing the mAb’s stability; (2) more than 80% of formulations use one of three surfactants, e.g., polysorbate 80; and (3) sugars (e.g., sucrose) provide bulk for lyophilized formulations and serve as stabilizing agents for therapeutic proteins. Furthermore, it would have been obvious for one of ordinary skill in the art to try various combinations of the buffers, surfactants, and sugars taught by Kang in a mAb formulation to arrive at an optimal, stable formulation, though the process of routine optimization. As illustrated by Kang, there are a finite number of previously identified, predictably behaving options for buffers, surfactants, and sugars available that one of ordinary skill in the art would reasonably expect to be successful based on their use in commercially available formulations. There would have been a reasonable expectation of success because one of ordinary skill in the art would have recognized that each of the possible excipients within each category (surfactants, sugars, buffers) have utility for the same respective purposes and are functionally equivalent variants.
(2)
Claims 1 and 3-16 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 and 19-20 of U.S. Patent No. 12,252,542 (‘542 patent; supra) in view of Wang (US 2019/0284292 A1; supra) and Akamatsu (US 2019/0194329 A1; supra). This is a maintained rejection that has been updated to reflect Applicant's amendments to the claims.
The teachings of the ‘542 patent are recited in the non-statutory double patenting rejection above.
However, the ‘542 patent does not expressly claim that the preparation (pharmaceutical composition) comprises a specific buffer salt, stabilizer, and/or surfactant, nor a kit comprising the preparation and a container.
The teachings of Wang and Akamatsu are summarized in the rejection under 35 U.S.C. § 103 above.It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to formulate an anti-CD137 antibody preparation taught in the ‘542 patent with (1) a buffer salt comprising sodium citrate and/or a phosphate buffer (e.g., monosodium phosphate or disodium phosphate), (2) a stabilizer selected from one or more of sucrose, trehalose, and mannitol, (3) a surfactant selected from one or more of polysorbate 80 and polysorbate 20, and (4) water, based on the further teachings of Wang and Akamatsu. The skilled artisan would have been motivated to do so because:
buffering agents (e.g., sodium citrate, monosodium phosphate, disodium phosphate) help to maintain the formulation at physiologically relevant pH conditions (as taught by Akamatsu);
stabilizers (e.g., sucralose, trehalose, mannitol) can be used to function as bulking agents, solubilize the therapeutic agent, or prevent denaturation or adherence to the container wall (as taught by Akamatsu and Wang);
surfactants (e.g., polysorbate 80, polysorbate 20) help to solubilize the glycoprotein and protect the glycoprotein against agitation-induced aggregation (as taught by Akamatsu), and
water acts as a suitable vehicle for (re)constituting antibody formulations into a liquid form suitable for parenteral administration (as taught by Wang).
Furthermore, it would have been obvious for one of ordinary skill in the art to try various combinations of the buffers, surfactants, and sugars taught by Wang and Akamatsu in a mAb formulation to arrive at an optimal, stable formulation, though the process of routine optimization. There are a finite number of previously identified, predictably behaving options for buffers, surfactants, and sugars, and these excipients have been successfully incorporated into previously described anti-CD137 antibody formulations. There would have been a reasonable expectation of success because one of ordinary skill in the art would have recognized that each of the possible excipients within each category (surfactants, sugars, buffers) have utility for the same respective purposes and are functionally equivalent.
Response to Arguments (Combined)
Applicant's arguments filed October 24, 2025, with respect to the non-statutory double patenting rejections of record, have been fully considered but they are not persuasive.
Applicant asserts that Kang, Wang, and Akamatsu do not disclose the specific formulation of the instantly claimed preparation, which according to Example 2 of the disclosure shows good stability. Applicant emphasizes that the prior art does not disclose the specific formulation of claim 13, which Applicant states showed good stability (e.g., Tables 4-1 to 4-7) and had relatively better binding activity (e.g., Table 4-10). Accordingly, Applicant argues that a skilled person “cannot get the specific formulation based on “Kang”, “Wang” or “Akamatsu” and cannot expect the stability and killing effect of preparations 13 and 14”. Remarks at pages 10-11.
In response, it is first noted that claim 13 was not rejected under non-statutory double patenting as being obvious over the ‘542 patent in view of Kang. Nonetheless, it is held that one of ordinary skill in the art would have recognized that the buffers, surfactants, and sugars disclosed by Kang, Wang, and Akamatsu are suitable for use in antibody formulations and have specific functions that are desirable for those formulating pharmaceutical compositions requiring a specific pH and stability. Wang and Akamatsu further provide that these specific pharmaceutically acceptable excipients are suitable for use in anti-CD137 antibody compositions. MPEP 2144.05 teaches, “"[w]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)”. With respect to the “killing effect” of preparations 13 and 14, it is generally expected that the active ingredient in such a pharmaceutical composition – namely, the anti-CD137 antibody – would have a greater influence on the killing effect of the pharmaceutical formulation than the pharmaceutically acceptable excipients included in the composition.
Applicant is reminded that rejections under the judicially created doctrine of non-statutory double patenting may be overcome by a complete reply including the filing of a terminal disclaimer.
For the reasons above, the rejections are maintained.
Conclusion
No claims are allowed.
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/ELIZABETH A SHUPE/Examiner, Art Unit 1643
/Brad Duffy/Primary Examiner, Art Unit 1643