DETAILED ACTION
Disposition of Claims
Claims 1, 3-4, 7, 9-12, 15, 17-18, 21-22, 25, and 27-32 were pending. Claims 2-6, 8-21, 23-24, 26, and 32 have been cancelled. Amendments to claims 1, 7, 22, 25, and 27-31 are acknowledged and entered. Claims 1, 7, 22, 25, and 27-31 will be examined on their merits.
Examiner’s Note
All paragraph numbers (¶) throughout this office action, unless otherwise noted, are from the US PGPub of this application US20240343810A1, Published 10/17/2024. Amendments to the specification presented on 12/30/2025 are acknowledged and entered.
Applicant is encouraged to utilize the new web-based Automated Interview Request (AIR) tool for submitting interview requests; more information can be found at https://www.uspto.gov/patent/laws-and-regulations/interview-practice.
Optional Authorization to Initiate Electronic Communications
The Applicant’s representative may wish to consider supplying a written authorization in response to this Office action to correspond with the Examiner via electronic mail (e-mail). This authorization is optional on the part of the Applicant’s representative, but it should be noted that the Examiner may not initiate nor respond to communications via electronic mail unless and until Applicant’s representative authorizes such communications in writing within the official record of the patent application. A sample authorization is available at MPEP § 502.03, part II. If Applicant’s representative chooses to provide this authorization, please ensure to include a valid e-mail address along with said authorization.
Response to Arguments
Applicant's arguments filed 12/30/2025 regarding the previous Office action dated 07/01/2025 have been fully considered. If they have been found to be persuasive, the objection/rejection has been withdrawn below. Likewise, if a rejection/objection has not been recited, said rejection/objection has been withdrawn. If the arguments have not been found to be persuasive, or if there are arguments presented over art that has been utilized in withdrawn rejections but utilized in new rejections, the arguments will be addressed fully with the objection/rejection below.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/08/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Specification
(Objection withdrawn.) The objection to the abstract of the disclosure is withdrawn in light of the amendments to the abstract.
(Objection withdrawn.) The objection to the disclosure is withdrawn in light of the amendments to the disclosure.
Claim Rejections - 35 USC § 112(b); Second Paragraph
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
(Rejection withdrawn). The rejection of Claim 25 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of the amendments to the claim.
(Rejection withdrawn). The rejection of Claim 27 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of the amendments to said claim.
(Rejection withdrawn). The rejection of Claim 28 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of the amendments to said claim.
(Rejection withdrawn). The rejection of Claim 32 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of the cancellation of said claim.
(Rejection withdrawn). The rejection of Claim 32 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of the cancellation of said claim.
(New rejection – necessitated by amendment.) Claim 1 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites the limitation "multispecific" in line 2. There is insufficient antecedent basis for this limitation in the claim. It is suggested claim 1 be amended to read upon “bispecific” to provide proper antecedence.
(New rejection – necessitated by amendment.) Claim 1 and dependent claims 7, 22, 25, and 27-31 thereof 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.
With the amendments to claim 1, the bispecific antibody as now claimed has specific CDRs for the Heavy chain variable region (VH) and light chain variable region (VL) for the binding arm that binds to PD-L1, wherein the CDRs may be one of two options. The antibody also has CDRs claimed for the VH and VL binding arms for ICOS, but only one CDR has been claimed for each of the 6 positions. However, as the antibody is claimed as “a bispecific antibody”, it is unclear what framework said CDRs are inserted into and what numbering system should be utilized to identify said CDRs which perform said function.
Looking to the specification for guidance regarding the variable CDRs for the PD-L1 binding arm, it appears as though these are the same CDRs taken from the same full length VH and VL sequences for an antibody which binds to PD-L1, but the CDRs are different as they were identified utilizing different numbering schemes. Again, as instant claim 1 is drawn to “an antibody”, and then states that said antibody may have any combination of one of two options for each of the 6 identified CDRs in the VH/VL region of this binding arm without identifying the numbering scheme, this makes it unclear as to the metes and bounds of the antibody being claimed, as there is an unknown framework utilized and there are at least 30 different permutations of CDRs possible in the PD-L1 binding arm alone.
While the CDRs of the ICOS-binding arm appear to have been identified using the IMGT numbering scheme (Table S1), the breadth of the CDRs in instant claim 1 is not limited to CDRs that are only using this numbering scheme.
Since only the sequences of the CDRs and position of the CDRs are claimed, and not the antibody numbering system utilized to identify said CDR, it would be unclear to a skilled artisan if they are infringing on the metes and bounds of the claim. It is suggested that the numbering system used for the CDRs be identified within the claim to ensure the correct antibody with the correct function is being claimed and is clear to one of skill in the art. Additionally, the entire VH and/or VL sequence may be claimed so that it is clear as to the metes and bounds of the CDRs (e.g. CDRs identified using Chothia or Kabat numbering systems of the VH sequence as provided by SEQ ID NO: X).
For instance, Figure 6 of Dondelinger et. al. (Dondelinger M, et. al. Front Immunol. 2018 Oct 16;9:2278.) illustrates the issue. If a sequence of SEQ ID NO: 1 is provided for the VH chain, the CDRs would be different depending on what numbering system is used. Say the claims are drawn to an antibody that consists of a CDR1 of SEQ ID NO: 3(SGSAMH) (CDR identified with Martin numbering and Contact definition schema), wherein the longer antibody sequence is that of SEQ ID NO:1. Using a program or online tool such as AbRSA (http://cao.labshare.cn/AbRSA/abrsa.php) or NovoPro (https://www.novoprolabs.com/tools/cdr), a skilled artisan can identify the CDR regions in a longer antibody sequence that at least consists of a variable heavy (VH) or variable light (VL) chain complete sequence. Under Chothia numbering, an antibody with a VH of SEQ ID NO:1 would have its CDRs identified as the following:
EVQLVETGGGVVRPGRSLRLSCTTSGFSFSGSAMHWVRQAPGKGLEWVAVISHDGNIIQYHDSVKGRFTISRDNSKNVLLLQMNSLRVDDTAMYYCARDVWLLPATISYAFDFWGQGTMVTVSS
Under Kabat numbering, an antibody with a VH of SEQ ID NO:1 would have its CDRs identified as the following:
EVQLVETGGGVVRPGRSLRLSCTTSGFSFSGSAMHWVRQAPGKGLEWVAVISHDGNIIQYHDSVKGRFTISRDNSKNVLLLQMNSLRVDDTAMYYCARDVWLLPATISYAFDFWGQGTMVTVSS
As one can see, the antibody with a VH of SEQ ID NO:1 under Kabat numbering has a CDR1 which consists of GSAMH, while the CDR1 using Chothia numbering consists of GFSFSGS. Neither therefore would be infringing upon the antibody with a CDR1 that consists of SGSAMH, even though all three of these sequences were found within the same VH region of the same original antibody. Therefore, providing the CDR sequences without providing the numbering system used to identify said sequences within the claim is insufficient, as one of skill in the art is not clear as to the metes and bounds of the claimed invention.
Since a skilled artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant Claim 1 is rejected on the grounds of being indefinite. Claims 7, 22, 25, and 27-31 are also rejected since they depend from claim 1, but do not remedy these deficiencies of claim 1.
Claim Interpretation
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.
Claim 1 is drawn to a bispecific antibody which binds ICOS and PD-L1, wherein the bispecific antibody comprises a binding arm that binds PD- L1 and a binding arm that binds ICOS, wherein the binding arm that binds PD-L1 comprises a (i) heavy chain variable region (VH) comprising a CDRH1 identical to SEQ ID NO: 7 or SEQ ID NO: 10, a CDRH2 identical to SEQ ID NO: 8 or SEQ ID NO: 11, and a CDRH3 identical to SEQ ID NO: 9 or 12, and (ii) a light chain variable region (VL) comprising a CDRL1 identical to SEQ ID NO: 17 or SEQ ID NO: 20, a CDRL2 identical to SEQ ID NO: 18 or SEQ ID NO: 21, and a CDRL3 identical to SEQ ID NO: 19 or SEQ ID NO: 22; and wherein binding arm that binds ICOS comprises a (i) heavy chain variable region (VH) comprising a CDRH1 identical to SEQ ID NO: 405, a CDRH2 identical to SEQ ID NO: 406, and a CDRH3 identical to SEQ ID NO: 407, and (ii) a light chain variable region (VL) comprising a CDRL1 identical to SEQ ID NO: 412, a CDRL2 identical to SEQ ID NO: 413, and a CDRL3 identical to SEQ ID NO 414.
Further limitations on the bispecific antibody of claim 1 are wherein the bispecific antibody has agonistic activity against ICOS (claim 7); a nucleic acid that encodes a heavy chain and/or a light chain of the bispecific antibody according to claim 1 (claim 29); a vector comprising the nucleic acid according to claim 29 (claim 30); and an isolated host cell comprising the vector of claim 30 (claim 31).
Claim 22 is drawn to a composition comprising the bispecific antibody of claim 1 and a pharmaceutically acceptable excipient, diluent, or carrier and, optionally, further comprising a further therapeutic agent independently selected from the group consisting of:
a) other immune checkpoint inhibitors;
b) immune stimulators;
c) chemokine receptor antagonists;
d) targeted kinase inhibitors;
e) angiogenesis inhibitors;
f) immune stimulating peptides or chemokines;
g) cytokines;
h) bispecific T-cell engagers (BiTEs) having at least one specificity against CD3;
i) other bi-specific molecules;
j) oncolytic viruses;
k) vaccination with tumour associated antigens;
l) cell-based therapies; and
m) adoptive transfer of tumour specific T-cells or LAK cells.
Claim 25 is drawn to a method of treating or preventing a disease or condition in a subject in need thereof, the disease or condition selected from neurological disease, neoplastic or non-neoplastic disease, chronic viral infections, and malignant tumors, comprising administering to said human a therapeutically effective amount of the bispecific antibody of claim 1, wherein the disease or condition is thereby treated or prevented.
Further limitations on the method according to claim 25 are wherein the cancer is selected from melanoma, Merkel cell carcinoma, non-small cell lung cancer, renal cell cancer, bladder cancer, head and neck squamous cell carcinoma, and mesothelioma (claim 27); wherein the method is further comprising administering to the human a further therapy (claim 28).
Claim Rejections - 35 USC § 101
The text of those sections of Title 35, U.S. Code, and AIA not included in this action can be found in a prior Office action.
(Rejection withdrawn.) The rejection of Claim 31 under 35 U.S.C. 101 and section 33(a) of the America Invents Act is withdrawn in light of the amendments to the claim.
Claim Rejections - 35 USC § 112(a); First Paragraph
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
(Rejection maintained in part and extended – necessitated by amendment.) Claims 1, 7, 22, 25, and 27-31 remain 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 rejection of claims 3-4, 9-12, 15, 17-18, 21, and 32 is withdrawn in light of the cancellation of said claims. 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. 1, 7, 22, 25, and 27-31
The following quotation from section 2163 of the Manual of Patent Examination Procedure is a brief discussion of what is required in a specification to satisfy the 35 U.S.C. 112 written description requirements for a generic claim covering several distinct inventions:
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice .... reduction to drawings .... or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus... See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
Thus, when a claim covers a genus of inventions, the specification must provide written description support for the entire scope of the genus. Support for a genus is generally found where the applicant has provided a number of examples sufficient so that one in the art would recognize from the specification the scope of what is being claimed.
Claims 1, 7, 22, 25, and 27-31 are rejected as lacking adequate descriptive support for any bispecific antibody which results in the function of binding ICOS and PD-L1. The claims are also drawn towards the use of said antibody in treating or preventing a disease or condition in a human (see Markush group of claimed diseases/conditions in instant claim 25).
In support of the claimed genus (any bispecific antibody that binds any ICOS and any PD-L1), the application discloses one example in which a bispecific antibody is generated that binds to both PD-L1 and ICOS, wherein said antibody is two Fabs in tandem fused with an Fc (Example 1 at ¶[1120]). The anti-ICOS antibody domains were those of STIM003 (see ¶[0769] for sequences for VH and VL of said antibody) and the anti-PD-L1 antibody domains were those of Antibody W. It is not clear what the sequences are for antibody “W” (it appears as though antibody W is “AbW” from ¶[1206], but again, the sequence for said antibody is not clear.) Variants of this bispecific antibody were generated using human IgG1 or mouse IgG2a (see ¶[1127-1129]). It appears as though said bispecific antibodies can bind to both human and mouse ICOS. No further derivatives or variants or mutants thereof of any further bispecific antibodies are disclosed that can achieve this function of binding to any ICOS and any PD-L1. The breadth of binding to “PD-L1” and “ICOS” is large, as this reasonably includes human and non-human versions of these proteins (e.g. mouse ICOS, mouse PD-L1), and includes any linear or conformational epitope generated by any full-length version of these proteins, including variants and mutants thereof. Thus, the application fails to provide a sufficient number of examples of species within the claimed genera to demonstrate possession of the entire genera.
Further, while the claims provide both a structure and a function, the application fails to draw any correlation between the two. In other words, there is insufficient evidence that any bispecific antibody can be generated comprising the CDRs claimed specific to ICOS and specific to PD-L1, especially in light of the uncertainty regarding the CDR regions claimed for the binding arm which binds to ICOS and PD-L1 (see 35 USC 112b rejection supra.) Limited correlation has been made to which sequences for said ICOS binding arm and said PD-L1 binding arm are required in order to achieve the claimed function. As the CDRs for each position in the PD-L1 binding arm can have up to 30 combinations, and because the framework region is unclaimed (e.g. the binding arms are claimed by their CDR sequences and not the entire VH/VL sequences), and as the CDR numbering system which can be used for said positions in both the ICOS and PD-L1 binding arm is not claimed, the breadth of potential antibodies encompassed by the drafted claims goes well beyond the simple 30 possible permutations of CDRs for the VH/VL regions of the PD-L1 binding arm. Lastly, the specification does not establish any additional mutations, variants, or alterations to said bispecific antibody that may be generated that still allow the antibodies to recognize and bind to their targets.
The teachings of the art also fail to indicate that, without such evidence, those in the art would have expected the full scope of the claimed bispecific antibody would confer the claimed binding function. For example, a search of the art indicates that modifications to biological molecules such as proteins are unpredictable, and require experimentation regarding the relationships between alterations in sequence bases/side chains and the function and structure of the protein in order to determine the actual effects of the modifications as discussed by Bowie et al. (Bowie JU, et. al. Science. 1990 Mar16;247(4948):1306-10; CITED ART OF RECORD; See page 1306). The art also shows that single amino acid mutations in the antibodies can greatly affect the ability of said antibody to bind to its target antigen (Winkler K, et. al. J Immunol. 2000 Oct 15;165(8):4505-14.; See also Kussie PH, et. al. J Immunol. 1994 Jan 1;152(1):146-52; BOTH CITED ART OF RECORD.) When single amino acid mutations are generated, or when the combination or order of CDRs within an antibody is altered, it affects the neutralizing capability of the resulting antibody or fragment thereof (Chen Z, et. al. Nat Commun. 2015 Mar 30;6:6714; CITED ART OF RECORD.) The art has further highlighted the importance of the order of CDRs, the interaction of non-CDR domains with respect to antigen/epitope binding, and that antigen-antibody algorithms or epitope prediction software/rational antibody design is highly inaccurate (Sela-Culang I, et. al. Front Immunol. 2013 Oct 8;4:302; CITED ART OF RECORD.) Computational in silico methods have traditionally struggled to predict the effect of mutations in antibody–antigen complexes on binding affinity, and generation of actual mutants in vitro of antibodies is the preferred and reliable method to determine the effect of mutations on antigen-antibody binding (Sirin S, et. al. Protein Sci. 2016 Feb;25(2):393-409. Epub 2015 Nov 6; CITED ART OF RECORD.) These results contradict the claimed functional characteristics of the bispecific antibody.
Lastly, the Federal Circuit opinion in Amgen v. Sanofi No. 2017-1480 slip op. Fed. Cir. Oct. 5, 2017 (“Amgen”) has shown that mere possession of an antigen does not satisfy the written description requirement for possession of any antibodies that may bind to said antigen. This recent finding is the current guidance utilized by the Office, and the opinion overrides the MPEP guidance regarding “newly characterized antigens” (MPEP § 2163 II.A.3). In other words, it is improper to describe a protein, such as an antibody, by its function, such as the antigen to which it binds.
Thus, in view of the above, there would have been significant uncertainty as to which bispecific antibodies with the CDR combinations claimed would be able to confer the claimed function of binding to any ICOS and any PD-L1. In view of this uncertainty and the lack of sufficient examples of the claimed genera, the claims are rejected for lack of adequate written description support.
Response to Arguments
Applicant's arguments filed 12/30/2025 have been fully considered but they are not entirely persuasive.
Applicant argues that since claim 1 has been amended to recite the CDRs of each binding arm of the bispecific antibody, that there is sufficient written description for the invention as presently claimed. The Office disagrees. As the amendments to claim 1 have created uncertainty as to the metes and bounds of what is being claimed, the potential breadth of bispecific antibodies is large and it is unclear that the Applicant has demonstrated possession of said bispecific antibodies capable of performing the claimed function.
For at least these reasons, the rejection has been maintained with respect to the pending claims.
(Rejection maintained in part and extended – necessitated by amendment.) Claims 1, 7, 22, 25, and 27-31 remain rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for bispecific ICOS/PD-L1 antibody comprised of antibodies STIM003 and AbW in a mAb2 backbone format and methods of using said antibody to treat cancers associated with a higher incidence of ICOS+ Treg cells, does not reasonably provide enablement for any bispecific antibody format/framework which binds to any portion of any ICOS and also binds to any portion of any PD-L1 that comprises any combination of the CDRs as claimed, or for any method of treatment or prevention of any disease with said bispecific antibody. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims. The rejection of claims 3-4, 9-12, 15, 17-18, 21, and 32 is withdrawn in light of the cancellation of said claims.
The legal considerations that govern enablement determinations pertaining to undue experimentation have been clearly set forth. Enzo Biochem, Inc., 52 U.S.P.Q.2d 1129 (C.A.F.C. 1999). In re Wands, 8 U.S.P.Q.2d 1400 (C.A.F.C. 1988). See also MPEP § 2164.01(a) and § 2164.04. Ex parte Forman 230 U.S.P.Q. 546 (PTO Bd. Pat. App. Int., 1986). The courts concluded that several factual inquiries should be considered when making such assessments including: the quantity of experimentation necessary, the amount of direction or guidance presented, the presence or absence of working examples, the nature of the invention, the state of the prior art, the relative skill of those in that art, the predictability or unpredictability of the art and the breadth of the claims. In re Rainer, 52 C.C.P.A. 1593, 347 F.2d 574, 146 U.S.P.Q. 218 (1965). The disclosure fails to provide adequate guidance pertaining to a number of these considerations as follows:
Nature of the invention/Breadth of the claims. The claims are drawn to a bispecific antibody which binds to any portion of any ICOS and also binds to any portion of any PD-L1, and a method of treating or preventing a disease or condition in a human, comprising administering to said human a therapeutically effective amount of said bispecific antibody according to claim 1, wherein the disease or condition is selected from the group consisting of neurological disease, neoplastic disease, non-neoplastic disease, chronic viral infection, and malignant tumors, and wherein the disease or condition is thereby treated or prevented. The bispecific antibody of claim 1 has the functional limitations of binding to any portion of any ICOS and also binding to any portion of any PD-L1. The binding to PD-L1 and ICOS broadly claims only binding, and covers antibodies that may have inhibitory or stimulatory effects on PD-L1 and/or ICOS activity. While the specific CDRs for each specific position have been claimed, the numbering system one should use to identify said CDR has not, making the breadth of potential antibodies large and unclear (see 35 USC 112b rejection supra.) The “bispecific” antibody refers to any type of format of antibody that recognizes more than one target and more than one way of engineering such an antibody, including DVD-Ig, mAb2, FIT-Ig, mAb-dAb, dock and lock, SEEDbody, scDiabody-Fc, diabody-Fc, tandem scFv-Fc, Fab-scFv- Fc, Fab-scFv, intrabody, BiTE, diabody, DART, TandAb, scDiabody, scDiabody-CH3, Diabody-CH3, minibody, knobs-in-holes, knobs-in-holes with common light chain, knobs-in-holes with common light chain and charge pairs, charge pairs, and charge pairs with common light chain.
State of the prior art/Predictability of the art. The state of the prior art/predictability of the art was set forth in the previous Office action and will not be repeated herein.
Guidance in the specification. The specification provides guidance towards the generation and use of related bispecific antibodies generated from STIM003 (anti-ICOS) and AbW (anti-PD-L1) in treating ICOS+ Treg cell-associated cancers.
84G09 has a heavy chain variable (VH) region amino acid sequence of SEQ ID NO:13, comprising the CDRH1 amino acid sequence of SEQ ID NO:7 (IMGT) or SEQ ID NO:10 (Kabat), the CDRH2 amino acid sequence of SEQ ID NO:8 (IMGT) or SEQ ID NO:11 (Kabat), and the CDRH3 amino acid sequence of SEQ ID NO:9 (IMGT) or SEQ ID NO:12 (Kabat). The heavy chain nucleic acid sequence of the VH domain is SEQ ID NO:14. 84G09 has a light chain variable region (VL) amino acid sequence of SEQ ID NO:23, comprising the CDRL1 amino acid sequence of SEQ ID NO:17 (IMGT) or SEQ ID NO:20 (Kabat), the CDRL2 amino acid sequence of SEQ ID NO:18 (IMGT) or SEQ ID NO:21 (Kabat), and the CDRL3 amino acid sequence of SEQ ID NO:19 (IMGT) or SEQ ID NO:22 (Kabat). The light chain nucleic acid sequence of the VL domain is SEQ ID NO:24 (¶[0122]).
STIM003 has a heavy chain variable region (VH) amino acid sequence of SEQ ID NO:408, comprising the CDRH1 amino acid sequence of SEQ ID NO:405, the CDRH2 amino acid sequence of SEQ ID NO:406, and the CDRH3 amino acid sequence of SEQ ID NO:407. The heavy chain nucleic acid sequence of the VH domain is SEQ ID NO:409 or SEQ ID NO:521. STIM003 has a light chain variable region (VL) amino acid sequence of SEQ ID NO:415, comprising the CDRL1 amino acid sequence of SEQ ID NO:412, the CDRL2 amino acid sequence of SEQ ID NO:413, and the CDRL3 amino acid sequence of SEQ ID NO:414. The light chain nucleic acid sequence of the VL domain is SEQ ID NO:4416 (¶[0769]).
The specification briefly discusses the FIT-Ig format of bispecific antibodies, wherein FIT-Ig (Fabs-In-Tandem Immunoglobulin) technology combines the functions of two parental antibodies into one single molecule. FIT-Ig (Fig. 1) are homodimeric, bispecific, tetravalent antibodies, wherein the FIT-Ig of the instant claims combines the PD-L1 binding arm of 84G09 with the ICOS-binding arm of STIM003 (¶[1121]). As detailed supra in the written description rejection, the Examples focused on a FIT-Ig wherein STIM0003 was joined with “Antibody W” (wherein the identity of “Antibody W” is an anti-PD-L1 antibody of unknown sequence ¶[1122]). Different structural formations were tested, either having the anti-ICOS as the “outer” or “inner” antibody, and wherein the Fc domains were either human IgG1 or mouse IgG2a, thus generating 4 total antibodies (¶[1122]; Fig. 2.)
Bispecific antibodies in mAb2 format were also generated and extensively studied (Fig. 3; ¶[1128]), wherein the ICOS antibody was either STIM001 or STIM003, and the PD-L1 antibody bound human or mouse PD-L1 but the origin of the PD-L1 antibody was not identified (¶[1128-1129]). In the mAb2 constructs, the antibodies were generated as IgG1, containing IgG1 CH1, CH2 and CH3 constant regions, with the Fcab binding loops (Fc with antigen-binding activity) in the IgG1 CH3 constant region. Unless otherwise stated, IgG1 was wild type human IgG1. The “LAGA” (SEQ ID NO: 568) variant IgG1 sequence was used where specified. The “LAGA” (SEQ ID NO: 568) variant includes mutations L235A and G237A which disable Fc-mediated effects ADCC and CDC as noted previously in the art (¶[1129]). These mAb2 antibodies were then assessed for their ability to bind to their native ICOS and/or PD-L1 targets as either isolated proteins or expressed on cells (Examples 2-4, ¶[1130-1171]). These mAb2 antibodies were also assessed for their ability to bind to different variants of Fcy receptors and for their potential to elicit ADCC (antibody-dependent cell-mediated cytotoxicity), complement-dependant cytotoxic activity (CDC) mediated responses, Fc-mediated phagocytosis or antibody dependant cellular phagocytosis (ADCP) and antibody recycling via the FcRn receptor. (Example 5 at ¶[1172]).
Therefore, while the specification generates four FIT-Ig antibodies, the extensive testing of the bispecific ICOS/PD-L1 antibody focused on the mAb2 format.
Amount of experimentation necessary. Additional research is required in order to generate any bispecific antibody that binds to any portion of any ICOS with the CDRs noted and any PD-L1 with any combination of the CDRs noted, as well as to determine how effective the use of any of said antibodies would be in preventing or inhibiting any type of cancer, malignancy, or disease listed within or encompassed by instant claim 25.
In light of the Supreme Court decision in Amgen Inc. et al. v. Sanofi et al., 143 S. Ct. 1243 (2023) (hereafter Amgen), updated guidelines were provided regarding the assessment of enablement (Federal Register, pp. 1563-1566; Pub. Jan. 10, 2024.) In Amgen, the Supreme Court unanimously affirmed that a genus of monoclonal antibodies were not enabled because when a range within a genus is claimed, there must be reasonable enablement of the scope of the range. The Court found in Amgen that due to the large number of possible candidates within the scope of the claims and the specification's corresponding lack of structural guidance, it would have required undue experimentation to synthesize and screen each candidate to determine which compounds in the claimed class exhibited the claimed functionality. In the instantly claimed invention, the breadth of “ICOS binding” is drawn to any protein, namely any type of antibody or binding fragment thereof, which may bind to any portion of any ICOS (e.g. human ICOS, murine ICOS, etc.) that also comprises the CDRs identified using any numbering system; as well as the breadth of “PD-L1 binding” is drawn to any protein, namely any type of antibody or binding fragment thereof, which may bind to any portion of any PD-L1 (e.g. human PD-L1, murine PD-L1, etc.) that also comprises the CDRs identified using any numbering system and in any allowable permutation/combination. Additionally, while there was support for the mAb2 format for specific antibodies with specific ICOS antibodies and unknown PD-L1 antibody binding regions, the platform for “bispecific antibodies” reasonably includes (but is not limited to): FIT-Ig, Quadromas (hybrid hybridomas), Knobs-into-holes (KIH), dual-variable domain Ig (DVD-Ig), BiTEs (Bispecific T-cell Engagers); DARTs (Dual-Affinity Re-targeting Proteins); Tandem Diabodies (TandAbs); and IgG-scFv. The breadth of the potential permutations of antibodies which may be generated is sufficiently large that it would require undue experimentation to show enablement of said claimed bispecific antibody, especially for the use of said claimed antibody in any method of treatment or prevention of any disease or condition claimed in instant claim 25 and dependent claims thereof.
For the reasons discussed above, it would require undue experimentation for one skilled in the art to make and/or use the claimed antibodies.
Response to Arguments
Applicant's arguments filed 12/30/2025 have been fully considered but they are not entirely persuasive.
Applicant argues that since claim 1 has been amended to recite the CDRs of each binding arm of the bispecific antibody, that there is sufficient written description for the invention as presently claimed. The Office disagrees. As the amendments to claim 1 have created uncertainty as to the metes and bounds of what is being claimed, the potential breadth of bispecific antibodies is large due to both the binding regions and potential “bispecific antibody” backbone structure, and the experimentation to generate any type of bispecific antibody with the CDRs as claimed that would still bind to ICOS and PD-L1 is large and undue.
For at least these reasons, the rejection has been maintained with respect to the pending claims.
Claim Rejections - 35 USC § 102
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
(Rejection withdrawn.) The rejection of Claims 1, 3-4, 7, 9-12, 15, 17-18, 21-22, 25, and 27-31 under 35 U.S.C. 102(a)(1) as being anticipated by Wu (WO2015103072A1, Pub. 07/09/2015; Priority 12/30/2013; CITED ART OF RECORD; hereafter “Wu”) is withdrawn in light of the amendments to the claims.
Double Patenting
The text regarding nonstatutory double patenting was presented in a previous Office action.
(Rejection withdrawn.) The rejection of Claims 1, 3-4, 7, 9-12, 15, 17-18, 21-22, 25, and 27-32 on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 9,567,399 is withdrawn in light of the amendments to the claims (e.g. the instant claims appear to be drawn to anti-PD-L1 antibody 84G09, while the ‘399 claims are drawn to antibody 1D05. While ‘399 discloses antibody 84G09, it does not appear to claim it.)
(Rejection maintained in part and extended – necessitated by amendment.) Claims 1, 7, 22, 25, and 27-31 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 9,617,338. The rejection of claims 3-4, 9-12, 15, 17-18, 21, and 32 is withdrawn in light of the cancellation of said claims.
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant application is claiming a bispecific antibody that binds to ICOS and PD-L1, wherein the possible CDRs for the PD-L1 binding arm appear to be from the antibody 84G09. The ‘338 patent claims an anti-PD-L1 antibody (84G09) with specific sequences that appear to be those disclosed by instant claim 1, as well as the addition of additional binding sequences to the claimed ‘338 antibody that allow it to bind to other target antigens, such as ICOS, PD-1, CTLA-4, and the like. Therefore, in light of the 35 USC 112b rejection showing the uncertainty as to the metes and bounds of the instantly claimed bispecific antibody, the breadth of the claimed antibody and methods of use thereof overlap under one reasonable interpretation and are within the same metes and bounds as those of the antibody of the instant claims, and are obvious variants of one another.
(Rejection withdrawn.) The rejection of Claims 1, 3-4, 7, 9-12, 15, 17-18, 21-22, 25, and 27-32 on the ground of nonstatutory double patenting as being unpatentable over claims 1-26 of U.S. Patent No. 9,957,323 in view of Wu (supra) is withdrawn in light of the amendments to the claims.
(Rejection withdrawn.) The rejection of Claims 1, 3-4, 7, 9-12, 15, 17-18, 21-22, 25, and 27-32 on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 10,604,576 is withdrawn in light of the amendments to the claims (e.g. the instant claims appear to be drawn to anti-PD-L1 antibody 84G09, while the ‘576 claims are drawn to antibody 1D05. While ‘576 discloses antibody 84G09, it does not appear to claim it.)
(Rejection withdrawn.) The rejection of Claims 1, 3-4, 7, 9-12, 15, 17-18, 21-22, 25, and 27-32 on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. US11,965,026B2 in view of Wu (supra) is withdrawn in light of the amendments to the claims (e.g. the instant claims appear to be drawn to anti-PD-L1 antibody 84G09, while the ‘026 claims are drawn to antibody 1D05. While ‘026 discloses antibody 84G09, it does not appear to claim it.)
(Rejection withdrawn.) The provisional rejection of Claims 1, 3-4, 7, 9-12, 15, 17-18, 21-22, 25, and 27-32 on the ground of nonstatutory double patenting as being unpatentable over claims 114-118 of copending Application No. 18/499,431 in view of Wu (supra) is withdrawn in light of the amendments to the claims.
(Rejection withdrawn.) The provisional rejection of Claims 1, 3-4, 7, 9-12, 15, 17-18, 21-22, 25, and 27-32 on the ground of nonstatutory double patenting as being unpatentable over claims 154-177 of copending Application No. 17/727,309 in view of Wu (supra) is withdrawn in light of the amendments to the claims.
(Rejection withdrawn.) The provisional rejection of Claims 1, 3-4, 7, 9-12, 15, 17-18, 21-22, 25, and 27-32 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-5, 9, 71-72, 78, 80, 87, 95, 99-100, 105, 110, 119, and 124 of copending Application No. 16/955,197 (NB: was incorrectly noted as being 16/995,197 in the previous Office action) in view of Wu (supra; NB: the ‘197 was recently allowed and was assigned US Pat. No. 12,404,330) is withdrawn in light of the amendments to the claims.
(Rejection withdrawn.) The provisional rejection of Claims 1, 3-4, 7, 9-12, 15, 17-18, 21-22, 25, and 27-32 on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5, 12, 69-70, 72, 76-77, 79-81, 87, 94, 97-98, 104, and 109-110 of copending Application No. 19/029,453 in view of Wu (supra) is withdrawn in light of the amendments to the claims (e.g. the ICOS antibody of the instant claims appears to be STIM003, which does not appear to be encompassed by the copending ‘453 claims.
(Rejection withdrawn.) The provisional rejection of Claims 1, 3-4, 7, 9-12, 15, 17-18, 21-22, 25, and 27-32 on the ground of nonstatutory double patenting as being unpatentable over claims 1-61 of copending Application No. 18/976,983 is withdrawn in light of the abandonment of the ‘983 application.
(Rejection withdrawn.) The rejection of Claims 1, 3-4, 7, 9-12, 15, 17-18, 21-22, 25, and 27-32 on the grounds of nonstatutory double patenting as being unpatentable over claims 1-6 of U.S. Patent No. 12,209,128 in view of Wu (supra) is withdrawn in light of the amendments to the claims.
(Rejection withdrawn.) The provisional rejection of Claims 1, 3-4, 7, 9-12, 15, 17-18, 21-22, 25, and 27-32 on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 65-83 of copending Application No. 18/592,425 in view of Wu (supra) is withdrawn in light of the amendments to the claims.
(Rejection withdrawn.) The provisional rejection of Claims 1, 3-4, 7, 9-12, 15, 17-18, 21-22, 25, and 27-32 on the ground of nonstatutory double patenting as being unpatentable over claims 41-42 and 45-62 of copending Application No. 18/174,925 in view of Wu (supra) is withdrawn in light of the amendments to the claims (e.g. the instant claims do not appear to teach the modifications to CH3, and said modifications do not appear to be obvious in the art at the time of filing.)
(Rejection withdrawn.) The provisional rejection of Claims 1, 3-4, 7, 9-12, 15, 17-18, 21-22, 25, and 27-32 on the ground of nonstatutory double patenting as being unpatentable over claims 154-177 of copending Application No. 17/727,309 in view of Wu (supra) is withdrawn in light of the amendments to the claims.
(Rejection withdrawn.) The rejection of Claims 1, 3-4, 7, 9-12, 15, 17-18, 21-22, 25, and 27-32 on the ground of nonstatutory double patenting as being unpatentable over claims 1-27 of U.S. Patent No. 11,629,189 in view of Wu (supra) is withdrawn in light of the amendments to the claims (e.g. the instant claims do not appear to teach the modifications to CH3, and said modifications do not appear to be obvious in the art at the time of filing.)
(Rejection withdrawn.) The provisional rejection of Claims 1, 3-4, 7, 9-12, 15, 17-18, 21-22, 25, and 27-32 on the ground of nonstatutory double patenting as being unpatentable over claims 21, 23, 28-29, 34, 36-41, 43, 45-49, and 51-53 of copending Application No. 16/471,161 in view of Wu (supra) is withdrawn in light of the abandonment of the ‘161 application.
(New rejection – necessitated by new copending application filing.) Claims 1, 7, 22, 25, and 27-31 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-5, 7-18, and 20 of copending Application No. 19/282,256 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both are claiming bispecific antibodies which bind to PD-L1 and ICOS, wherein the ICOS sequences between the claim sets are identical. The generic disclosure of a PD-L1 antibody of the ‘256 claims is a genus of PD-L1 antibodies, of which the species of the PD-L1 antibody of the instant claims anticipates. Therefore, the instant claims and the ‘256 claims are patentably indistinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
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.
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/RACHEL B GILL/
Primary Examiner, Art Unit 1671