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 .
Election/Restriction
Restriction to one of the following inventions is required under 35 U.S.C. 121:
I. Claims I-17, drawn to a bispecific antibody comprising a PD-L1 binding domain and a CD28-binding domain, classified in C07K 16/2827, 16/2818 and 16/468.
II. Claims 18-19, drawn to a method of reducing the proliferation of and/or enhancing the killing of tumor cells by contacting the cells with composition comprising the bispecific antibody, classified in A61K 39/001102.
The inventions are independent or distinct, each from the other because:
Inventions I and II are related as product and process of use. The inventions can be shown to be distinct if either or both of the following can be shown: (1) the process for using the product as claimed can be practiced with another materially different product or (2) the product as claimed can be used in a materially different process of using that product. See MPEP § 806.05(h). In the instant case the bispecific antibody of Invention I can be used for a materially different process, such as in the immunoprecipitation or column chromatography isolation of antigens PD-L1 and CD28.
Restriction for examination purposes as indicated is proper because all the inventions listed in this action are independent or distinct for the reasons given above and there would be a serious search and/or examination burden if restriction were not required because one or more of the following reasons apply: Because these inventions are distinct for the reasons given above, have acquired a separate status in the art as shown by their different classification, have recognized divergent subject matter, and because each invention requires a separate search, restriction for examination purposes as indicated is proper.
Applicant is advised that the reply to this requirement to be complete must include (i) an election of an invention to be examined even though the requirement may be traversed (37 CFR 1.143) and (ii) identification of the claims encompassing the elected invention.
The election of an invention may be made with or without traverse. To reserve a right to petition, the election must be made with traverse. If the reply does not distinctly and specifically point out supposed errors in the restriction requirement, the election shall be treated as an election without traverse. Traversal must be presented at the time of election in order to be considered timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are added after the election, applicant must indicate which of these claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other invention.
During a telephone conversation with Katheleen DiNapoli on March 18, 2026, a provisional election was made without traverse to prosecute the invention of Group I, claims 1-17. Affirmation of this election must be made by applicant in replying to this Office action. Claims 18-19 are withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention.
Applicant is reminded that upon the cancelation of claims to a non-elected invention, the inventorship must be corrected in compliance with 37 CFR 1.48(a) if one or more of the currently named inventors is no longer an inventor of at least one claim remaining in the application. A request to correct inventorship under 37 CFR 1.48(a) must be accompanied by an application data sheet in accordance with 37 CFR 1.76 that identifies each inventor by his or her legal name and by the processing fee required under 37 CFR 1.17(i).
The examiner has required restriction between product or apparatus claims and process claims. Where applicant elects claims directed to the product/apparatus, and all product/apparatus claims are subsequently found allowable, withdrawn process claims that include all the limitations of the allowable product/apparatus claims should be considered for rejoinder. All claims directed to a nonelected process invention must include all the limitations of an allowable product/apparatus claim for that process invention to be rejoined.
In the event of rejoinder, the requirement for restriction between the product/apparatus claims and the rejoined process claims will be withdrawn, and the rejoined process claims will be fully examined for patentability in accordance with 37 CFR 1.104. Thus, to be allowable, the rejoined claims must meet all criteria for patentability including the requirements of 35 U.S.C. 101, 102, 103 and 112. Until all claims to the elected product/apparatus are found allowable, an otherwise proper restriction requirement between product/apparatus claims and process claims may be maintained. Withdrawn process claims that are not commensurate in scope with an allowable product/apparatus claim will not be rejoined. See MPEP § 821.04. Additionally, in order for rejoinder to occur, applicant is advised that the process claims should be amended during prosecution to require the limitations of the product/apparatus claims. Failure to do so may result in no rejoinder. Further, note that the prohibition against double patenting rejections of 35 U.S.C. 121 does not apply where the restriction requirement is withdrawn by the examiner before the patent issues. See MPEP § 804.01.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
It is noted that US 2010/0028637 A1 (Tavsanli), cited in the IDS filed 4/16/2024, is drawn to “Multi-Layer Film Comprising A Barrier Layer And An Antistatic Layer”.
Specification
All references to location in the specification are to the clean substitute specification filed 04/16/2024.
The use of the term Yervoy, Keytruda, Litayo and Tecentriq ([004]) and CaptureSelect ([00162]), each of which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
The disclosure is objected to because of the following informalities: Throughout the specification SEQ ID NO:14, 19 or 24, which are all 3 amino acid-long sequences, are referenced; however, the actual sequences of which do not appear in the Sequence Listing (“000”). As a result, those SEQ ID NOs must be replaced with the actual amino acid sequence, respectively: FAS, WAS and WAS (see instant Table 1). See, e.g., [0013], [0031] and [0091]. In line 2 of [00236] it appears “PD-L-1” should be “PD-L1”.
Appropriate correction is required.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01. See [0072] and [0108].
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 1, 2, 15, 17 and dependent claims 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.
Claims 1 and 2 are indefinite because they reference SEQ ID NO:14, 19 or 24, which are all 3 amino acid-long sequences, the actual sequences of which do not appear in the Sequence Listing (“000”). As a result, those SEQ ID NOs must be replaced with the actual amino acid sequence, respectively: FAS, WAS and WAS (see instant Table 1).
Claim 15 recites the limitation "the antibodies" (plural) in line 2. There is insufficient antecedent basis for this limitation in the claim. The rejection could be obviated by instead indicating the variable regions thereof are human.
Claim 17 is indefinite because a composition must comprise more than one component. It is unclear what the composition includes besides the bispecific antibody. There is nothing in the claim to distinguish the composition from the bispecific antibody. According to 35 USC 101: “A composition of matter is a "combination of two or more substances and includes all composite articles." Digitech Image Techs. v. Electronics for Imaging, 758 F.3d at 1348-49, 111 USPQ2d 1717, 1719 (Fed. Cir 2014).
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 3-6 and 9-17 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims are drawn to a bispecific antibody binding both PD-L1 and CD28 and having a common variable heavy chain region (VH). Claim 1 recites the CDR1-3 of the common VH and also the light chain variable region (VL) of the PD-L1 binding domain but fails to recite a VL for the CD28-binding domain. This omitted VL sequence information is rectified in claims 2 and 7-8. Absent a description of structural features correlating with a functional ability to bind CD28 which are shared by members of a genus of CD28 binding variable regions, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish which light chain CDR sequences may be paired with the HCDR1-3 of SEQ ID NO: 6-8, respectively, such that a resultant antigen binding domain is capable of binding CD28. The only disclosed bispecific antibodies binding both PD-L1 and CD28 have a VL for the CD28 binding site with the CDR1-3 of SEQ ID NO:18-20 or 23-25 (see claim 2 and Table 1 on p. 22).
It is stated in AbbVie Deustschland GmbH v. Janssen Biotechnology, Ltd., 111 USPQ 1780, 1789 (759 F.3d 1285, 1298), (Fed. Cir. 2014) discussing Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005) that “When a patent claims a genus using functional language to define a desired result, the specification must demonstrate that the applicant has made a generic invention that achieves the claimed results and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus." Again in AbbVie at 1788, reiterating Enzo Biochem., Inc., 323 F.3d at 964, “It is true that functionally defined claims can meet the written description requirement if a reasonable structure-function correlation is established, whether by the inventor as described in the specification or known in the art at the time of the filing date…”In this instance, however, there has been no structure-function correlation established for the genus of CD28 binding sites having the common VH CDR1-3 of the claims. This is reinforced by the showing in US Patents 12,448,444 and 12,112,850, which disclose that the same common VH CDRs can cooperate with a variety of VL CDRs to bind distinctly GPC3, CD28, PD-L1 or CD47 (see claims of the patents). This points to the specificity provided by the VL for the required function of binding a particular antigen. None of the second antigen binding domains with a recited set of VH CDR1-3 in the absence of VL CDR1-3 sequences meets the written description provision of 35 USC 112(a).
For an antibody, it is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework (FR) sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites. MacCallum et al. (J. Mol. Biol 262:732, 1996, p. 733, paragraph bridging cols. 1-2) analyzed crystal structures for a variety of antibodies for their interaction with their antigen and found that “at least one residue from each CDR forms contacts in 18 or more structures except CDR-L2…. Residues from CDR-L3 dominate…. CDR-H3 is also dominant…” Although screening techniques can be used to isolate light chain CDR sequences that may be paired with the HCDRs 1-3 of SEQ ID NO(s):6-8, respectively, such that a resultant antigen binding domain is capable of binding CD28, ‘make and test’ is not the basis for the written description requirement of 35 U.S.C. 112(a). As stated in Vas-Cath Inc. V. Mahurkar (CA FC) 19 USPQ2d 1111, 935 F2d 1555, "The purpose of the "written description' requirement is broader than to merely explain how to 'make and use’; the applicant must also convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the "written description' inquiry, whatever is now claimed." Vas-Cath Inc. clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116).
With the exception of a CD28 binding domain comprising a VH comprising CDR1-3 of SEQ ID NO:6-8 and a VL comprising CDR1-3 of either SEQ ID NO:18-20 or 23-25, the skilled artisan cannot envision the detailed chemical structure of the encompassed CD28 binding domains, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The product itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991).
Therefore, only the bispecific antibody of claim 1 and claims depending therefore wherein the CD28 binding domain comprises not only the recited VH comprising CDR1-3 of SEQ ID NO:6-8, but also a VL comprising CDR1-3 of either SEQ ID NO:18-20 or 23-25, but not the full breadth of the claim meets the written description provision of 35 U.S.C. § 112(a). Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. § 112 is severable from its enablement provision (see page 1115).
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.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-17 is/are rejected under 35 U.S.C. 103 as being obvious over US Patent 12,122,850 B2 (Hatteterer) and US Patent 12,448,444 (Chauchet) in view of Zeng et al. (J. Immunother. Cancer, Abst. 698, 9(Suppl. 2):A726, 2021, cited in the IDS filed 4/16/2024) and Xu-Monette et al. (Front. Immuno. 8:1597, 29 pages, Dec. 2017).
The applied reference US Patent 12,448,444 B2 has a common applicant and inventor 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).
US 12,122,850 (Hatterer) teaches a bispecific antibody binding CD28 and GPC3. The structure of the antibody requires a common variable heavy chain region (VH) and two different variable light chain regions (VLs), one which is a kappa type and one a lambda type (claims 15-16), one which binds CD28 and one which binds GPC3 in conjunction with the VH. The common VH CDR1-3 are provided in Table 1 as SEQ ID NO:1-3 (identical to instant SEQ ID NO:6-8). They are contained in the VH of SEQ ID NO:4 (identical to instant SEQ ID NO:9) and heavy chain (HC) of SEQ ID NO:5 (identical to instant SEQ ID NO:12), which comprises an IgG1 Fc region with substitutions L234A, L235A and P329A (LALAPA), see also claims 28-30 describing the bispecific antibody Fc region as comprising one or more amino acid substitutions reducing binding to an activating Fc receptor and/or reducing effector function (claim 28), more specifically comprising L234A and L235A with or without a P329A/G/R substitution (claims 29 and 30). The VL of the CD28 binding site is comprised by the light chain (LC) of SEQ ID NO:45 (identical to instant SEQ ID NO:22) or SEQ ID NO:55 (identical to instant SEQ ID NO:27), which comprise the respective VL of SEQ ID NO:44 and 54 (identical to instant SEQ ID NO:21 and 26, respectively), comprising the respective CDR1-3 of SEQ ID NO:41-43 and 51-53 (identical to instant SEQ ID NO:18-20 and 23-25, respectively). Claim 32 specifies the antibodies are human and claim 33 is drawn to a composition comprising the bispecific antibody. Additionally, the patent discloses a bispecific GPC3xCD3 antibody comprising the same VH (CDR1-3 of SEQ ID NO:1-3) and different VLs (claim 1). It is noted that PD-L1 is an immune checkpoint protein and that antibody inhibitors thereof can induce durable anti-tumor responses in some cancer types (col. 1, lines 41-50). Hatterer does not teach a PD-L1 VL or LC that can act with the common HC of the bispecific antibody disclosed by Hatterer to form a PD-L1 binding site.
12,448,444 (Chauchet) teaches a bispecific antibody binding PD-L1 and CD47. The structure of the antibody requires a common variable heavy chain region (VH) and two different variable light chain regions (VLs), one which is a kappa type and one a lambda type (claims 4-11 and 18-25), one which binds PD-L1 and one which binds CD47 in conjunction with the VH. The common VH CDR1-3 are provided in Table 1 as SEQ ID NO:1-3 (identical to instant SEQ ID NO:6-8). They are contained in the VH of SEQ ID NO:6 (identical to instant SEQ ID NO:9). The claimed bispecific antibody is an IgG4 isotype (HC of SEQ ID NO:4 and 232, claims 13-14, 26, 29). The bispecific antibody is a human antibody (claim 12). The bispecific antibody can kill PD-L1- and/or CD47-expressing tumors cells or reduce proliferation thereof (claim 16 and Examples 5 and 6). It is discussed that PD-L1 is an immune checkpoint protein and counteracts T cell activation signals, thereby inhibiting T cell proliferation, cytokine production and release and cytotoxicity of T cells. “In fact, PD-1 has been shown to suppress T-cell activation at least in part through the inhibition of CD28 signaling, a major co-stimulatory pathway required for optimal activation of T cells. Therefore, the PD-1/PD-L1 pathway, by regulating the magnitude and the functional activity of the T-cell response, play a critical role in physiological conditions in limiting tissue damage during inflammatory reactions, and in maintaining self-tolerance. In pathological circumstances, it is involved in the development of tumor immunity and autoimmune diseases.” (col. 9, lines 40-60)
Zeng et al. teach a bispecific anti-PD-L1 x anti-CD28 antibody that blocked PD-1/PD-L1 interaction and enhanced T cell degranulation, cytokine secretion and cancer cell cytotoxicity only in the presence of PD-L1 (Results). The bispecific antibody was well tolerated in cynomolgus monkeys and inhibited tumor growth significantly more than an anti-PD-L1 antibody alone (end of Results).
Mayoux et al. teaches that inhibiting PD-1/PD-L1 interaction leads to durable clinical responses in several cancer types and that blocking the interaction can reinvigorate dysfunctional tumor-infiltrating effector T cells, thereby overcoming adaptive immune resistance (p. 1, start of first paragraph). PD-L1 also binds CD80 (B7.1), which may trap PD-L1 so its inhibitory activity is stopped (p. 1, col. 1, middle). An anti-PD-L1 blocking antibody enhanced binding between CD80 and CD28 (p. 3). It is discussed that (p. 6, col. 1, second paragraph):
We report the importance of tumor-associated DCs in explaining clinical response to immunotherapy blocking the PD-L1/PD-1 path-way. In this study, we introduce a mechanism for how PD-L1 check-point expression on DCs impairs their costimulatory function with respect to T cell priming and/or restimulation, or both. The described mechanism suggests that DCs are primary cellular targets of anti–PD-L1 Abs through disruption of the PD-L1/B7.1 cis inter-action. This allows CD28 costimulation by increased B7.1/CD28interaction and subsequent de novo antitumor T cell immunity. Our study provides mechanistic understanding of the role of DCs in response to a checkpoint inhibitor such as anti–PD-L1 Ab.
It would have been obvious to the artisan of ordinary skill before the effective filing date of the instant invention to have a bispecific antibody binding both CD28 and PD-L1, wherein the PD-L1 VL of Chaucet is substituted for the GPC3 VL of Hatterer with a reasonable expectation of success since both documents showed that a single common VH when paired with particular VLs can bind any of 4 different antigens and agonize or block the binding therewith. It would have been obvious to bind CD28 and block the PD-L1/PD-1 interaction with the bispecific antibody in order to treat cancers by enabling PD-L1-dependent T cell activation, reinvigorating T cells and overcoming adaptive immune resistance as discussed by the patents as well as Zeng et al. and Mayoux et al. The bispecific antibody is considered human and inherently has one kappa and one lambda light chain, an IgG Fc with a reduced effector function due to the LALAPA substitutions.
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.
Claims 1-17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 12-17 and 22-26 of copending Application No. 18/180,116 in view of US Patent 12,448,444 (Chauchet) and Xu-Monette et al. (Front. Immuno. 8:1597, 29 pages, Dec. 2017).
The instant claims are drawn to a bispecific antibody binding PD-L1 and CD28 and comprises a shared variable heavy chain region (VH) having the CDR1-3 of SEQ ID NO:6-7 (claim 1), VH of SEQ ID NO:9 (claim 3) and heavy chain (HC) of SEQ ID NO:11 or 12 (claim 4), and the PD-L1 variable light chain region (VL) having CDR1-3 of SEQ ID NO:13-15 (claim 1), VL of SEQ ID NO:16 (claim 5) and LC of SEQ ID NO:17 (claim 6), including wherein the Fc region is an IgG Fc and comprises the substitutions L234A and L235A and/or P329A (claims 11-14). The CD28 VL having the CDR1-3 of SEQ ID NO:18-20 or 23-25 (claim 2), VL of SEQ ID NO:21 or 26 (claim 7) and LC of SEQ ID NO:22 or 27 (claim 8), respectively, are set forth. The light chains being a kappa or lambda are claimed (claims 9-10). Claim 17 is drawn to a composition comprising the bispecific antibody.
Copending application 18/180,116 does not specifically recite a PD-L1 antigen binding site, but claim 1 is drawn to a bispecific antibody binding a generic tumor associated antigen (TAA) with a common VH and also binding CD28 wherein the binding domain comprises the common VH CDR1-3 of SEQ ID NO:1-3 (claim 1), VH of SEQ ID NO:4 (claim 12) and heavy chain (HC) of SEQ ID NO:6 or 7 (claim 13), and the CD28 variable light chain region (VL) having respectively CDR1-3 of SEQ ID NO:23-25 or 47-49 (claim 1), VL of SEQ ID NO:80 or 88 (claim 2) and LC of SEQ ID NO:99 or 107 (claim 3), including wherein the Fc region comprises the substitutions L234A and L235A and/or P329A (claims 16-17). The light chains being a kappa or lambda are claimed (claims 14-15). Claim 22 is drawn to a composition comprising the bispecific antibody. The same CD28 binding structure defined by CDRs is recited in claim 25. Claim 26 further defines the CD28 antibody as being an F(ab) fragment.
12,448,444 (Chauchet) teaches a bispecific antibody binding PD-L1 and CD47. The structure of the antibody requires a common variable heavy chain region (VH) and two different variable light chain regions (VLs), one which is a kappa type and one a lambda type (claims 4-11 and 18-25), one which binds PD-L1 and one which binds CD47 in conjunction with the VH. The common VH CDR1-3 are provided in Table 1 as SEQ ID NO:1-3 (identical to instant SEQ ID NO:6-8). They are contained in the VH of SEQ ID NO:6 (identical to instant SEQ ID NO:9). The claimed bispecific antibody is an IgG4 isotype (HC of SEQ ID NO:4 and 232, claims 13-14, 26, 29). The bispecific antibody is a human antibody (claim 12). The bispecific antibody can kill PD-L1- and/or CD47-expressing tumors cells or reduce proliferation thereof (claim 16 and Examples 5 and 6). It is discussed that PD-L1 is an immune checkpoint protein and counteracts T cell activation signals, thereby inhibiting T cell proliferation, cytokine production and release and cytotoxicity of T cells. “In fact, PD-1 has been shown to suppress T-cell activation at least in part through the inhibition of CD28 signaling, a major co-stimulatory pathway required for optimal activation of T cells. Therefore, the PD-1/PD-L1 pathway, by regulating the magnitude and the functional activity of the T-cell response, play a critical role in physiological conditions in limiting tissue damage during inflammatory reactions, and in maintaining self-tolerance. In pathological circumstances, it is involved in the development of tumor immunity and autoimmune diseases.” (col. 9, lines 40-60)
Mayoux et al. teaches that PD-L1 is expressed on tumor cells and immune cells (p. 1, col. 1). Inhibiting PD-1/PD-L1 interaction leads to durable clinical responses in several cancer types and that blocking the interaction can reinvigorate dysfunctional tumor-infiltrating effector T cells, thereby overcoming adaptive immune resistance (p. 1, start of first paragraph). PD-L1 also binds CD80 (B7.1), which may trap PD-L1 so its inhibitory activity is stopped (p. 1, col. 1, middle). An anti-PD-L1 blocking antibody enhanced binding between CD80 and CD28 (p. 3). It is discussed that (p. 6, col. 1, second paragraph):
We report the importance of tumor-associated DCs in explaining clinical response to immunotherapy blocking the PD-L1/PD-1 path-way. In this study, we introduce a mechanism for how PD-L1 check-point expression on DCs impairs their costimulatory function with respect to T cell priming and/or restimulation, or both. The described mechanism suggests that DCs are primary cellular targets of anti–PD-L1 Abs through disruption of the PD-L1/B7.1 cis inter-action. This allows CD28 costimulation by increased B7.1/CD28interaction and subsequent de novo antitumor T cell immunity. Our study provides mechanistic understanding of the role of DCs in response to a checkpoint inhibitor such as anti–PD-L1 Ab.
All CD28 HC and LC sequences set forth above in the instant and copending application are the same despite different SEQ ID NOs. It would have been obvious to have a bispecific antibody binding both CD28 and PD-L1, wherein the PD-L1 is the TAA of the bispecific antibody of the copending application and has the VL of Chaucet. Mayoux et al. teach that PD-L1 is a TAA. Chaucet teaches the PD-L1 VL can use a common VH, which is the same VH claimed in the instant copending application.
This is a provisional nonstatutory double patenting rejection.
Prior Art
The prior art made of record and not relied upon is considered pertinent to Applicant's disclosure.
US 2022/0135684 A1, cited in the IDS filed 4/16/2024, teaches bispecific antibodies binding PD-L1 and CD28 comprising a scFv binding domain. As discussed in [0005], the bispecific antibodies enhance antitumor activity by providing a costimulatory signal for T cell activation against tumor cells and blocking the immune checkpoint inhibitory PD-L1/PD-1 pathway (see also Fig. 34). They induced proliferation of effector T cells in cynomolgus monkeys ([0531]). The antigen binding sequences of the antibodies are different than those of the instant claims. This reference is cumulative with Zeng et al. relied upon above for teaching motivation and in vivo activity of a PD-L1xCD28 bispecific antibody.
US 2012/0189716, cited in the IDS filed 4/16/2024, teaches antibodies with common heavy chain variable domains fused to an Ig heavy chain constant region, wherein the first light chain variable domain is a kappa type and the second is a lambda type, or vice versa. It shows the state of the art a decade before the instant invention.
US 2024/0002544 A1 (priority March 7, 2022) is cumulative with Hatterer above for teaching CD28-binding bispecific antibodies comprising a common HC (also binding CEA or MSLN). The VH CDR1-3 are SEQ ID NO:1-3, identical to instant SEQ ID NO:6-7 and comprised by the HC of SEQ ID NO:6, identical to instant SEQ ID NO:11 (comprising LALA), and SEQ ID NO:7, identical to instant SEQ ID NO:12 (comprising LALAPA). The CD28 VL is SEQ ID NO:80 or 88, identical respectively to instant SEQ ID NO:21 and 26. It is also taught that PD-L1 is an immune checkpoint protein and antibodies thereto have provided durable anti-tumor responses ([0004]).
US Patent 10,780,120 B2 teaches single chain PD-L1/CD28 bispecific antibodies 13G4-1211, 1B12-1412 and 10A5-1412 PD-L1/CD28. They have different structures and sequence than the instantly claimed antibodies.
Conclusion
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Claire Kaufman
/Claire Kaufman/
Primary Examiner, Art Unit 1674
June 5, 2026
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