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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 22Jun2026 has been entered.
Claims Status
The Amendment, filed on 22Jun2026, is acknowledged in which claim(s) 1-50, 61-73 are canceled by Applicant, and claim(s) 81-82 are new.
Claim(s) 51-60, 74-82 are presented for examination on the merits.
Priority
Acknowledgement is made of applicant’s claim of benefit to Application No. PCT/US2020/058328, filed on 30Oct2020, which claims domestic benefit to Provisional Patent Application Number 62/929,674, filed on 01Nov2019.
Domestic benefit to the Provisional Application (01Nov2019) is applied for claims 51, 54-60, 74-82.
Domestic benefit to the PCT Application (30Oct2020) is applied for claims 52-53 as the PCT discloses E3 ligase arm Kd testing/results (but the Provisional does not).
Response to Amendment
The previous rejection(s) of claim(s) 51-60, 74-80 under 35 U.S.C. § 103 have been withdrawn in view of the recent claim amendment filed on 22Jun2026, which added new limitations to the claims that were not considered in the previous rejections, necessitating new rejections. Applicant' s arguments are not addressed herein as they do not pertain to the new rejections (See below).
New Rejections/Objections as Necessitated by Claim Amendments
Claim Interpretation
Claim(s) 51-60, 74-82 recites “…wherein the second binding domain comprises…SEQ ID NO: 106, and…SEQ ID NO: 107.” in line(s) 12-14 of claim 51 and line(s) 9-11 or claim 74. The instant specification teaches SEQ ID NOs: 106 and 107 (e.g., LC and HC, respectively) correspond to anti-PDL1 antibody known commercially as atezolizumab (e.g., generic name) or Tecentriq® (e.g., brand-name) [e.g., ¶ 0169-0170].Tecentriq® is also known as MPDL3280A or RG7446 in research and development disclosures. Therefore prior art teachings of atezolizumab, Tecentriq®, MPDL3280A, or RG7446, are considered to teach the instant claimed anti-PDL1 antigen binding domain comprising SEQ ID NOs: 106 and 107.
Claim(s) 58, 74 recites “…antibody derivative…” in line 2. The instant specification provides “an antibody derivative” retains epitope binding, and may further include constructs based on the general binding properties [e.g., ¶ 0059]. The broadest reasonable interpretation of an “antibody derivative”, in view of the instant disclosure definition, is considered to be an antibody or antigen binding fragment thereof.
Claim(s) 74 recites “A bispecific binding agent…the bispecific binding agent comprising: a) a first binding domain that binds…E3 ligase of a target cell; and b) a second binding domain that binds…a PDL1 protein…wherein contacting of the target surface protein and the membrane-associated ubiquitin E3 ligase with the bispecific agent leads to internalization and lysosomal aggregation of the target protein…”. Briefly, claim 74 is directed to a composition (e.g., a bispecific binding agent), and the underlined portion of the above phrase is considered to be a description of properties that naturally flow from the instant claimed bispecific agent (e.g., composition) contacting the target cell. MPEP 212.01(II) recites “COMPOSITION CLAIMS — IF THE COMPOSITION IS PHYSICALLY THE SAME, IT MUST HAVE THE SAME PROPERTIES… "Products of identical chemical composition can not have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990)….”. Therefore, any prior art teaching of the instant claimed composition are considered to necessarily teach the limitations underlined in the phrase above.
Claim Rejections - 35 USC § 112(b)
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 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.
Claim(s) 51-60, 80-81 is/are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim(s) 51-60, 80-81, recite(s) “…the membrane non-receptor tyrosine kinase receptor PD-L1 protein…” in line(s) 3 of claim 51, rendering the claim(s) indefinite. Specifically, PD-L1 (programmed death ligand 1) is a ligand, and is not a tyrosine kinase receptor. Further, it is unclear if the underlined portion of the phrase requires (1) a non-receptor membrane bound protein (e.g., not necessarily PDL1); (2) a tyrosine kinase receptor; (3) a PDL1 protein; or (4) something else. For the purposes of compact prosecution, the phrase will be considered to mean “a membrane-bound PDL1 protein”. This rejection may be overcome by amending claim(s) 51 as recited above or to otherwise clearly recite the limitation(s) of the instant invention. Claim(s) 52-60, 80-81 can overcome this rejection by amending claim(s) 51 as recited above.
Claim Rejections - 35 USC § 112(a) -written description
Claim(s) 51-60 and 74-82 is/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.
Claimed Invention
Claim(s) 51-60 and 74-82, is/are drawn to a bispecific agent (e.g., antibody), wherein the first arm binds E3 ligase antigen and the second arm binds PDL1 antigen.
Breadth of Claims
The invention as disclosed in claim(s) 51, 74 (and 52-60, 75-80) recite(s) “…wherein the second binding domain comprises a variable light chain sequence having at least 80% sequence identity to SEQ ID NO: 106, and a variable heavy chain sequence having at least 80% sequence identity to SEQ ID NO: 107…” in line(s) 12-14 of claim 51 and line(s) 9-11 of claim 74; and claim(s) 81-82 recite(s) “…(a) a light chain sequence having at least 80% sequence identity to SEQ ID NO: 322, and a heavy chain sequence having at least 80% sequence identity to SEQ ID NO: 323, or (b) a light chain sequence having at least 80% sequence identity to SEQ ID NO: 324, and a heavy chain sequence having at least 80% sequence identity to SEQ ID NO: 325, or (c) a light chain sequence having at least 80% sequence identity to SEQ ID NO: 332, and a heavy chain sequence having at least 80% sequence identity to SEQ ID NO: 333…”. The claim(s) encompass a genus of heavy and/or light chain variable regions comprising variability (e.g., 80% identical) in both the heavy and/or light chain variable regions which are claimed as having the function of specifically binding to the target antigen (e.g., E3 ligase or PDL1). This means that the variability in sequence identity can also occur in the CDRs, the domains that are critical for the antibody binding to its target, which one of ordinary skill in the art would understand to result in unpredictable binding characteristics with no reasonable expectation of maintaining target antigen (e.g., E3 ligase or PDL1) binding. Additionally, the instant disclosure does not provide an adequate number of species of the claimed genus nor does the disclosure provide a structure-function correlation that would allow for a person of ordinary skill in the art to envision what variation can occur to the light and heavy chains, particularly in the CDR regions, such that the obtained structure would result in the claimed functions.
Further the invention as disclosed in claim(s) 52 recite(s) “…wherein the first domain binds to the membrane-associated ubiquitin E3 ligase with a Kd of less than 100 nM.”; and claim(s) 53 recite(s) “….wherein the first domain binds to the membrane-associated ubiquitin E3 ligase with a Kd of 12.5 nM or less…”. One of ordinary skill in the art would understand that the 6 CDRs of an antibody are responsible for antigen binding characteristics, including antigen specificity and binding affinity (e.g., Kd). The claim does not disclose the structure associated with the claimed function. The instant disclosure does not provide a structure-function correlation that would allow for a person of ordinary skill in the art to envision light and heavy chain sequences, particularly in the CDR regions, such that the obtained structure would result in the claimed functions.
Scope of Disclosed Species
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The anti-PDL1/anti-E3 ligase bispecific antibodies comprising the PLD1 binding domain and any one of the above E3 ligase binding domains in the Applicant disclosure (see summary table above for details) with 100% sequence identity in the CDR regions of the heavy and light chain variable regions represents the anti-PDL1/anti-E3 bispecific antibodies that the applicant was in possession of at the time of filing.
State of the Prior Art
At the time of filing, antibody functionality were known to depend on the entire structure, particularly a full complement of six CDRs. It is understood by one of ordinary skill in the art that that mutation to CDRs is unpredictable and that each construct requires function testing.
Sela-Culang, Kunik, and Ofran (Fron. Immuno., Vol. 4, Article 302, Oct. 2013), hereinafter “Sela-Culang”, reviews the structural basis of antibody-antigen recognition in the state of the art. Naturally occurring antibodies have six hypervariable loops are commonly termed complementary determining regions (CDRs) and are widely assumed to be responsible for antigen recognition [e.g., pg. 1, abstract; pg. 3, “The Role of CDRs and their Definition”]. A person of ordinary skill in the art would understand that although the above basics of antibody-antigen binding are known, that the specifics of antibody structure (e.g., within the CDRs) that underlie the antigen recognition are not well characterized [e.g., pg. 1, “The Motivations for…”].
Further, Herold et al. (Nature Scientific Reports, 7:12276, 25 Sep 2017), hereinafter “Herold”, teaches that it should be emphasized that there is no correlation between experimentally determined change in antibody binding affinity and a given mutation and additionally that no such correlation is expected because antigen binding is “affected by each CDR loop differently” and changes thereto “can in principle affect antigen binding affinity in an unpredictable way” [e.g., pg. 14, ¶ 2]. Further, Herold asserts that multiple determinants regulate antigen affinity and the interactions with CDRs are complex [e.g., pg. 14, ¶ 3].
At the time of filing, WO 2020/139950 A1 (published 02Jul2020; Effective Filing Date 27Dec2018; hereinafter “WO950”) taught anti-E3 ligase/anti-PDL1 bispecific antibodies , comprising various anti-E3 ligase binding domains [e.g., ¶ 0005, 0032-0033, 0080-0082 0117; fig. 4A]. Further, Wu et al. Wu et al. (Front. Immuno., Aug 2019, Vol. 10, Article 2022; hereinafter “Wu”) taught various species of PDL1 antigen binding domains were known in the art at the time of filing [e.g., tbl. 3]. Therefore, the prior art demonstrates that the binding of E3 ligase as well as binding of PDL1 is possible by various different antibody species. The prior art does not teach a known structure activity relationship for HCDR1-3 and LCDR1-3 in an antibody that would allow prediction of CDR residues that specifically bind to E3 ligase or PDL1 antigen.
Thus, making changes to the CDR sequence(s) of an antibody (e.g., a bispecific) sequence is a highly unpredictable process and one skilled in the art could not a priori make any predications regarding such alterations with any reasonable expectation of success nor envisage the breadth of structurally unrelated CDR combinations that would still possess the required function(s).
Conclusion
As indicated by the art, a full complement of 6 CDRs are required for antigen binding and one cannot predict which CDR residues may be changed and still result in an antibody that binds the target antigen(s). Written description can be met if the claims recite the minimal structure that is needed to perform the function recited in the claims. Above, the art indicates that the 6 CDRs in an antibody antigen-binding domain are the minimal structure that binds to a target antigen. Specifically, Applicant claim(s) 51 and 74 would need to recite (I) the 6 CDRs (e.g., LCDR1-3 and HCDR1-3) in the antibody that bind PDL1 antigen, without variability in the sequences thereof; or (II) remove all references to “at least 80% sequence identity”; claim(s) 52 and 53 would need to recite the 6 CDRs (e.g., LCDR1-3 and HCDR1-3) in the antibody that bind E3 ligase antigen with the instant claimed function (e.g., Kd), without variability in the sequences thereof; and claim(s) 81 and 82 would need to recite (I) the 6 CDRs (e.g., LCDR1-3 and HCDR1-3) in the antibody that bind E3 ligase antigen, without variability in the sequences thereof; or (II) remove all references to “at least 80% sequence identity”. Claim(s) 54-60 and 75-80 can overcome this rejection by amending claim(s) 51 and 74 as described above.
Claim Rejections - 35 USC § 103
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.
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.
Claim(s) 51-52, 54-60 and 74-80 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO 2020/139950 A1 (published 02Jul2020; Effective Filing Date 27Dec2018; hereinafter “WO950”), in view of Wu et al. (Front. Immuno., Aug 2019, Vol. 10, Article 2022; hereinafter “Wu”).
Regarding claim(s) 51, 54, 58, 60, 74, 77, 80, WO950 teaches bispecific antibodies for membrane clearance (e.g., internalization) and ubiquitination-mediated degradation of target receptors, wherein the bispecific antibody (e.g., not an immunoconjugate) comprises (I) an transmembrane E3 ubiquitin ligase (TMUL) specific scFv (e.g., first arm) and (II) a membrane bound target receptor-specific scFv (e.g., second arm) [e.g., title, abstract, ¶ 0004, 0105; figs. 1-2A]. WO950 teaches the target receptor is PDL1 [e.g., ¶ 0015; 0124; fig. 4A], and that target cell (e.g., cells expressing target receptor) is a cancer cell [e.g., ¶ 0095].
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Regarding claim(s) 52, 55-56, 78-79, WO950 further teaches the TMUL binding arm comprises an anti-ZNRF3 binding domain [e.g., ¶ 0005, 0032-0033, 0080, 0082 0117; fig. 4A], and that the Kd is 80nM [e.g., ¶ 0117; fig. 3B].
Regarding claim(s) 57, WO950 further teaches the TMUL binding arm comprises an anti-RNF43 binding domain [e.g., ¶ 0005, 0081-0082; fig. 4A].
Regarding claim(s) 59, 75-76, WO950 further teaches the antibody comprises a knob and hole (e.g., IgG knob and hole) format [e.g., ¶ 0014; 0046; 0051].
WO950 does not expressly teach the PDL1 arm comprises SEQ ID NOs: 106-107 (atezolizumab) and that the cancer targeted is NSCLC lung cancer.
Regarding claim(s) 51-52, 54-60, 74-80, Wu teaches the FDA approved PDL1 antibody atezolizumab (see claim interpretation above) was the first approved anti-PDL1 antibody for the treatment of NSCLC (e.g., a type of lung cancer) [e.g., ¶ tbl. 3].
It would have been prima facie obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date of the claimed invention to substitute the PDL1 binding domain of the anti-E3 ligase/anti-PDL1 bispecific as taught by WO950, with the atezolizumab anti-PDL1 antigen binding domain as taught by Wu, to arrive at the instant invention of an anti-E3 ligase/anti-PDL1 bispecific antibody wherein the PDL1 binding arm comprises the atezolizumab antigen binding domain (e.g., of instant SEQ ID NOs: 106-107; see claim interpretation above). A PHOSITA would have been motivated to substitute the PDL1 binding domain of the anti-E3 ligase/anti-PDL1 bispecific as taught by WO950, with the atezolizumab anti-PDL1 antigen binding domain as taught by Wu, because WO950 teaches the anti-E3 ligase/anti-PDL1 bispecific antibody but does not teach a specific PDL1 antigen binding domain sequence, and Wu teaches FDA-approved PDL1 binding atezolizumab. A skilled artisan would understand the benefit of using a known, clinically tested, approved antigen binding domain includes but is not limited to reduced research and development time and costs. There would have been a reasonable expectation of success for a PHOSITA to substitute PDL1 binding domain of the anti-E3 ligase/anti-PDL1 bispecific as taught by WO950, with the atezolizumab anti-PDL1 antigen binding domain as taught by Wu, because WO950 teaches the anti-E3 ligase/anti-PDL1 bispecific antibody, and Wu teaches an FDA-approved PDL1 antigen binding domain. This rationale aligns with the principle of simple substitution of one known element for another to obtain predictable results, supporting a conclusion of obviousness (see MPEP § 2141).
Further, it would have been obvious to a PHOSITA to modify the modified anti-E3 ligase/anti-PDL1 bispecific antibody wherein the PDL1 binding arm comprises the atezolizumab antigen binding domain as taught by WO950 and Wu (see above) to include the that the cancer targeted includes NSCLC lunger cancer as further taught by Wu, because WO950 and Wu teach the bispecific agent (e.g., bispecific antibody) and that therapeutic uses include targeting cancer, and Wu further teaches that the atezolizumab antigen binding domain alone is FDA-approved to treat (e.g., target PDL1 on) NSCLC lung cancer. There is an expectation of success for a PHOPSITA to include NSCLC lung cancer as a target cancer cell type for the modified anti-E3 ligase/anti-PDL1 bispecific antibody wherein the PDL1 binding arm comprises the atezolizumab antigen binding domain as taught by WO950 and Wu, because WO950 and Wu teach the bispecific agent (e.g., bispecific antibody) and PDL1 arm targeting of cancer cells, and Wu further teaches that the atezolizumab (e.g., an anti-PDL1 antibody) alone is FDA-approved to treat NSCLC lung cancer, so a PHOSITA would expect to be able to use the modified anti-E3 ligase/anti-PDL1 (atezolizumab antigen binding domain) bispecific to target NSCLC lung cancer cells. This rationale aligns with the principle of simple substitution of one known element for another to obtain predictable results, supporting a conclusion of obviousness (see MPEP § 2141).
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Free From the Prior Art
During the course of examination, the anti-E3 ligase/anti-PDL1 bispecific agent (e.g., bispecific antibody) comprising an E3 ligase antigen binding domain comprising 100% sequence identity to (1) a HC/LC of SEQ ID NOs: 323/322; (2) a HC/LC of SEQ ID NOs: 325/324; or (2) a HC/LC of SEQ ID NOs: 333/332, were found to nonobvious over the closest prior art. Briefly, a sequence search of the prior art returned no 100% matches to any of the instant claimed HC sequences. Additionally, none of the prior art matches in the search results retained E3 ligase antigen (e.g., E3 ligase, RNF43, RNF128, GRAIL, ZNRF3, MARCH11) recognition. Therefore the closest prior art cannot return any 100% sequence identity matches to the instant claimed E3 ligase binding domains comprising one of the above listed HC/LC pairs (see closest prior art alignments below).
Alignment of the instant anti-E3 ligase binding domain “RNF43-A4” HC (SEQ ID NO: 323) with WO2023060192-A2 (Anti-survivin antibody heavy chain variable region, SEQ 113 #1):
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Alignment of the instant anti-E3 ligase binding domain “RNF43-A6” HC (SEQ ID NO: 325) with WO2021077132-A1 (Cancer treating Fab heavy chain Z2G6 ZIKV LRT, SEQ 209):
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Alignment of the instant anti-E3 ligase binding domain “RNF43-A5” HC (SEQ ID NO: 333) with WO2017044308-A1 (Anti-BAX synthetic Fab antibody 2A6 heavy chain, SEQ ID:74):
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Conclusion
No claims are currently allowed.
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMY M CHATTIN whose telephone number is (571)270-0646. The examiner can normally be reached T-F 0600-1600 PST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Wu can be reached on (571) 272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/AMY M. CHATTIN/Examiner, Art Unit 1643
/GARY B NICKOL/Primary Examiner, Art Unit 1643
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