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 .
Claim Status
Claims 26-28, 30, 41-52 are pending in the instant application.
Claims 20-25 are cancelled.
Election/Restrictions
Applicant’s election without traverse of Group II, claims 26-28 and 30, and species election of: methods of treating blood cancer comprising administering to a subject in need thereof the binding protein comprising three polypeptide chains wherein:
the first polypeptide chain is comprised of VL1-CK-Hinge1-(CH2-CH3)A, wherein Hinge1 and (CH2-CH3)A comprises amino acid sequences SEQ ID NOs:74 and 69, respectively;
the second polypeptide chain is comprised of VH1-CH1-Hinge2-(CH2-CH3)B-L1-VH2-CH1-Hinge3, wherein Hinge2, (CH2-CH3)B, L1, and Hinge3 comprise amino acid sequences SEQ ID NOs:75, 70, 76, and 77, respectively;
the third polypeptide chain is comprised of VL2- CK;
wherein (1) the first antigen binding domain against human CD123 comprises VH1 comprising amino acid sequence SEQ ID NO:41 comprising CDR H1-H3 comprising SEQ ID NOs: 1-3, respectively, and VL1 comprising amino acid sequence SEQ ID NO:43 comprising CDR L1-L3 comprising SEQ ID NOs:7-9, respectively; (2) the second antigen binding domain against human NKp46 comprises VH2 comprising amino acid sequence SEQ ID NO:45 comprising CDR H1-H3 comprising SEQ ID NOs: 13-15, respectively, and VL2 comprising amino acid sequence SEQ ID NO:53 comprising CDR L1-L3 comprising SEQ ID NOs:27-29, respectively; and the Fc region binds to a human CD16A (Fc-γ RIII) polypeptide and comprises an N-linked glycosylation at residue N297, in the reply filed on 4/13/2026 is acknowledged.
Claims 26-28, 30, 41-52 are being examined on the merit.
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).
Information Disclosure Statement
The information disclosure statement filed 2/2/2024 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. It has been placed in the application file, but the information referred to therein has not been considered. This objection specifically refers to the following foreign documents and non-patent literature documents listed below:
<Foreign Patent Documents>
Cite No. 1-62 and 64
<Non-Patent Literature Documents>
Cite No. 1-28, 31-47, and 49.
The information disclosure statement filed 2/2/2024 fails to comply with 37 CFR 1.98(a)(1), which requires the following: (1) a list of all patents, publications, applications, or other information submitted for consideration by the Office; (2) U.S. patents and U.S. patent application publications listed in a section separately from citations of other documents; (3) the application number of the application in which the information disclosure statement is being submitted on each page of the list; (4) a column that provides a blank space next to each document to be considered, for the examiner’s initials; and (5) a heading that clearly indicates that the list is an information disclosure statement. The information disclosure statement has been placed in the application file, but the information referred to therein has not been considered. This objection specifically refers to the following foreign document listed below:
WO 2019/226617A1
Specification
The disclosure is objected to because of the following informalities:
Throughout the specification, SEQ ID NO:11 is used to describe the light chain CDR2 of the first ABD that binds specifically to human CD123 and it is a skipped sequence in the sequence listing. The sequence listing and CRF were entered under ST26 where sequence identifiers corresponding to 3 amino acids or less are shown as skipped sequences. Applicant is required to amend the specification of all the sequence identifiers corresponding to a skipped sequence with the specific sequences. See pages 6-7 and 54,-55.
On page 25, in regards to the definition of “preventing”, the end “)” is missing after i.e.
Appropriate correction is required.
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.
Claim 41 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.
SEQ ID NO:11 is a skipped sequence in the sequence listing and CRF. Page 87 of the specification recites sequence identifier SEQ ID NO:11 and the corresponding sequence as YAS. The sequence listing and CRF was entered under ST26 where sequences that are 3 amino acids or less are listed as skipped sequences. Currently,the corresponding sequences for the light chain CDR2 are disclosed in the Table under “Sequence Listing” in the instant specification. Applicant is required to amend SEQ ID NO:11 of claim 41 with ”YAS”.
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.
35 USC § 112(a): Written Description
Instant claim 41 and 50 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 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.
MPEP § 2163 states that 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, or it may be satisfied by the 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. “Functional” terminology may be used “when the art has established a correlation between structure and function” but “merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing one has invented a genus and not just a species. Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 598 F3d 1336, 94 USPQ2d 1161, 1171 (Fed Cir. 2010).
Scope of the Claimed Genus
Instant claim 41 is drawn to mixing and matching of VH and VL chains. Instant claim 41 define a structural genus of binding proteins comprising:
a first ABD that binds specifically to human CD123 based on the combination of a specific VH1 sequence comprising CDR-H1, H2, and H3 corresponding to the amino acid sequences SEQ ID NO:1 to 3 or SEQ ID NO:4 to 6, respectively, and a specific VL1 sequence comprising CDR-L1, L2, and L3 corresponding to the amino acid sequences SEQ ID NO:7 to 9 or SEQ ID NO:10, YAS, SEQ ID NO:12, respectively; and
a second ABD that binds specifically to human NKp46 based on the combination of a specific VH2 sequences comprising CDR-H1, H2, and H3 corresponding to the amino acid sequences SEQ ID NOs:13-15; 16-18; 19-21; 22-24; or 16, 25, and 26, respectively, and a specific VL2 sequence comprising CDR-L1, L2, and L3 corresponding to the amino acid sequences SEQ ID NO:27-29; 30-32; 33-35; 36-38; or 39, 31, and 40, respectively,
wherein all or part of the immunoglobulin Fc region or variant thereof binds to a human Fc-γ receptor.
Instant claim 50 is drawn to mixing and matching VH and VL chains. Instant claim 50 define a structural genus of binding proteins comprising:
VH1 and VL1 comprising the amino acid sequences of SEQ ID NO:41 and 43 respectively or comprise the amino acid sequences of SEQ ID NO:42 and 44 respectively; and/or
VH2 and VL2 comprise:
the amino acid sequences of SEQ ID NO: 45 and 53 respectively;
the amino acid sequences of SEQ ID NO: 46 and 54 respectively;
the amino acid sequences of SEQ ID NO: 47 and 55 respectively;
the amino acid sequences of SEQ ID NO: 48 and 56 respectively;
the amino acid sequences of SEQ ID NO: 49 and 57 respectively;
the amino acid sequences of SEQ ID NO: 50 and 58 respectively;
the amino acid sequences of SEQ ID NO: 51 and 59 respectively; or
the amino acid sequences of SEQ ID NO: 52 and 60 respectively.
One of ordinary skill in the art would understand that to mix and match heavy and light chains between antibodies, the CDR H1-H3 and CDR L1-L3 sequences must be identical (e.g., variability can only occur in non-CDR regions). Furthermore, the claim is directed to a subgenus of binding proteins comprising mixing and matching the recited CDR sequences with the ability of binding to human CD123 and human NKp46.
The instant specification describes the F25 format, or its variants, as illustrated in Figures 1 and 2, and comprising three polypeptide chains, wherein the NKp46-CD123_F25 binding protein comprises three polypeptide chains including a human CD123 binding domain and a human NKp46 binding domain, respectively including hypervariable regions comprising polypeptide sequences SEQ ID NO: 1, 2, 3, 7, 8, 9 and SEQ ID NO: 13, 14, 15, 27, 28, 29 (pages 110-111, section B.1). The instant specification or examples does not test mixing and exchanging of the binding protein VH and VL chains that possess the recited function of binding human CD123 and human NKp46.
State of the Relevant Art
At the time of the filing of the instant application, it was well established in the art that the formation of an intact antigen-binding site in an antibody usually required the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three “complementarity determining regions” (“CDRs”) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro & Fransson, Frontiers in Bioscience 2008; 13:1619-33; (see Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1). Almagro et al (Front. Immunol, 2018, 8:1751, Pages 1-19) also taught that while affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody (page 3 “The IgG Molecule”, second and third paragraphs), those techniques involve trial-and-error testing and the changes that maintain or improve affinity are not predictable a priori. E.g., id., (page 6 ending paragraph onto page 7). Chiu ML et al (Antibodies, 2019 8(4):55, Pages 1-80) taught the antigen binding of antibodies often results in conformational changes in the contact surface areas of both the antibody and the antigen (page 5, first paragraph). Thus, the prediction of CDR binding to the epitope is difficult to predict. Chiu further taught antibody modeling has been shown to be accurate for the framework region sequences, but CDR modeling requires further development and improvements (page 6, second paragraph). Prediction of the structure of CDR-H3 could not be accurately produced when given the Fv structures without their CDR-H3s (page 6, second paragraph). Chiu taught the quality of antibody structure prediction, particularly regarding CDR-H3, remains inadequate, and the results of antibody–antigen docking are also disappointing (page 11, paragraph 2).
In addition to changes within the CDR altering target binding, alterations to the CDR have been shown to dramatically alter antibody secretion. Hasegawa et al. (mAbs, 2017, 9(5): 854-873) taught a pair of human IgG clones with a single amino acid substitution in the variable region was sufficient to alter the efficiency of immunoglobulin biosynthesis (page 866, last sentence left column). Hasegawa taught the two mAbs differed only by one amino acid in the LC's CDR1 and that despite the near-identity of their primary sequences, the parental mAb secreted copious amounts of IgG to the culture media, while the variant mAb induced RB phenotypes extensively and secreted 20-fold less IgG (page 866, right column, first paragraph). Importantly, the two model IgGs were by no means abnormal or defective as mAbs, but demonstrated a profound impact of a single amino acid substitution on immunoglobulin biosynthesis (page 866, right column, first paragraph).
Furthermore, at the time of the instant application, there is no guidance in the art regarding a binding protein comprising a first ABD that binds specifically to human CD123, a second ABD that binds specifically to human NKp46, and wherein all or part of the immunoglobulin Fc region or variant thereof binds to a human Fc-γ receptor.
Summary of Species Disclosed in the original specification
MPEP § 2163 states that 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.
The specification discloses that the binding proteins comprise three polypeptide chains, including a human CD123 binding domain and a human NKp46 binding domain, respectively including hypervariable regions comprising polypeptide sequences SEQ ID NO: 1, 2, 3, 7, 8, 9 and SEQ ID NO: 13, 14, 15, 27, 28, 29 (pages 110-111, section B.1). The instant specification also describes the binding affinity of the F25 binding protein to NKp46 and CD123 in section B.4 and Tables 1 and 2 (page 113). However, the instant specification or examples do not test mixing and exchanging of the binding protein VH and VL chains that possess the recited function of binding human CD123 and human NKp46.
As noted above, the art generally accepted that the combination of the CDRs within the VH and VL pair of an antibody were essential for binding specificity. But the specification does not describe what residues within the CDRs confer the binding activity claimed, and the claim language permits changes of the VH and VL that contain the CDRs. Accordingly, the skilled artisan would not be able to discern a structure or function correlation for peptides other than those comprising all six CDRs or antibody or antigen fragment of the human CD123 and NKp46 bispecific binding protein.
Given the lack of shared structural properties of the CDR regions, the description of the species of separate bispecific binding proteins that comprise of a human CD123 binding domain and a human NKp46 binding domain, and the fact that the species that were described cannot be considered representative of the broad genus, Applicant was not in possession of the invention as claimed.
Summary
A genus of species is not present in the specification or prior art that would demonstrate a structure activity relationship would be known for antibody CDR residues for the recited function of binding the protein target human CD123 and human NKp46. There is a lack of an appropriate number of species with identical or alternative amino acid residues within the CDR binding determinant region that indicate which amino acid residues: i) are essential for binding; ii) can be changed and still allow protein target binding; and iii) disrupt protein target binding. Therefore, one of skill in the art would reasonably conclude that applicant was not in possession of the required genus of VH and VL substitutions of the bispecific binding protein at the time of filing.
35 USC § 112(a): Scope of Enablement
Claims 26-28, 30, and 41-52 are 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 cancer treatment comprising administering to a subject in need a binding protein comprising a first and a second antigen binding domain (ABD) and all or part of an immunoglobulin Fc region or variant thereof, wherein the first ABD binds specifically to human CD123, the second ABD binds specifically to human NKp46, and wherein all or part of the immunoglobulin Fc region or variant thereof binds to a human Fc-γ receptor, does not reasonably provide enablement for blood cancer prevention comprising administering to a subject in need a binding protein comprising a first ABD that binds specifically to human CD123, a second ABD that binds specifically to human NKp46, and wherein all or part of the immunoglobulin Fc region or variant thereof binds to a human Fc-γ receptor. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Claims 26-28, and 30 are for a method of treating or preventing blood cancer, e.g. myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) or CD64-positive AML, but the specification and the state of the art do not teach a method to prevent blood cancer by administering a binding protein comprising a first ABD that binds specifically to human CD123, a second ABD that binds specifically to human NKp46, and wherein all or part of the immunoglobulin Fc region or variant thereof binds to a human Fc-γ receptor. Claims 41-52 are further dependent on claim 26 without requiring treatment.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." These
factors include, but are not limited to:
The breadth of the claims;
The nature of the invention;
The state of the prior art;
The level of one of ordinary skill;
The level of predictability in the art;
The amount of direction provided by the inventor;
The existence of working examples; and
The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Scope of the claimed genus and nature of the invention.
Claims 26-28, 30, and 41-52 are for a method of treating or preventing blood cancer, e.g. MDS, AML, or CD64-positive AML, comprising administering a binding protein comprising a first ABD that binds specifically to human CD123, a second ABD that binds specifically to human NKp46, and wherein all or part of the immunoglobulin Fc region or variant thereof binds to a human Fc-γ receptor.
State of the Relevant Art; level of one of ordinary skill; and level of predictability of the art.
Cancer has a wide variety of causes, from environmental and/or developmental exposure to ionizing radiation and/or chemical exposure in addition to some types viral and bacterial exposure (Lichtman, 2017, The Oncologist, 22(5): 542–548). Even though cancer is featured by the infinite cell proliferation, its pathogenesis is extremely complex and related to many mechanisms. In general, the hallmarks of cancer consist of ten biological capabilities during the development of cancers, namely sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, tumor-promoting inflammation, genome instability and mutation, evading immune destruction and reprogramming energy metabolism (Hanahan et al, 2011, Cell, 144(5): 646-674, Figures 1 and 3). More than 100 types of cancer have been identified which are typically termed for the organs or tissues where they occur. Hanahan taught over the past decade, tumors have increasingly been recognized as organs whose complexity approaches and may even exceed that of normal healthy tissues (page 661, right column second to last paragraph). Hanahan taught many human tumors are histopathologically diverse, containing regions demarcated by various degrees of differentiation, proliferation, vascularity, inflammation, and/or invasiveness (page 662, left column, first paragraph).
Clinical trials aimed at proving preventative cancer activity attributable to a specific intervention are largely infeasible, due to the impossibly large number of subjects and an equally impossible long timeframe. Although cancer is a common disease, specific types of cancer are still relatively infrequent events in an otherwise healthy population. Therefore, trials with cancer incidence as endpoints would necessarily involve several thousands of subjects followed for several decades. Such logistic difficulties have precluded cancer prevention trials with cancer incidence as an endpoint in all but a selected few malignancies for treatments such as tamoxifen and finasteride (Lee et al, 2011, Nature Reviews Cancer, 11: 211-218; page 211, left column last paragraph) Lee further taught although many reports have suggested benefits and targets of phytochemicals, these reports mainly rely on cell and animal models (page 216, right column last paragraph). Lee taught that in order to apply phytochemicals as personalized cancer preventive agents, the effects of phytochemicals in humans will need to be assessed (page 216, right column last paragraph).
At the time of filing, it was known that CD123 (IL-3Rα) is frequently expressed by malignant Hodgkin lymphoma (HL) cells; however, naked monoclonal antibodies (mAb) against HL lack clinical benefit, partially due to absence of natural killer (NK) cells in the tumor microenvironment (Ernst et al, 2019, Blood Cancer J., 9(6):1-11; page 1, Abstract). Ernst et al teaches that the combination of a fully humanized anti-CD123 mAb (CSL362) and high-affinity Fcγ-receptor NK-92 cells (haNK) effectively target and kill HL cells in vitro. As a genetically engineered version of the NK-92 cell line, Ernst teaches that haNK was developed to express the high-affinity polymorphism (158V) of the IgG Fc-receptor (FcγRIIIa, CD16), with additional capacity for self-production of interleukin-2 (IL-2). Moreover, in combination with the selected mAbs, the haNK cells demonstrated an ability to undergo ADCC in contrast to the parental CD16-negative NK-92 line and kill tumor cells (page 2, left column, first paragraph). Ernst further teaches that targeting CD123 on HL cells with a humanized anti-CD123 mAb (CSL362) and NK cells capable of engaging in ADCC is highly effective in vitro and demonstrated that this enhanced cytotoxicity occurs via ARF6–PLD-1 activation, suggesting that the combination of the high-affinity CD16+NK line, haNK, and a humanized anti-CD123 mAb, CSL362, suggests a novel approach to investigate in the treatment of patients with relapsed/resistant CD123+ HL (page 10, left column, last paragraph). However, there is no guidance in the instant disclosure or the art regarding the prevention of cancer, e.g. blood cancer, comprising administering a binding protein comprising a first ABD that binds specifically to human CD123, a second ABD that binds specifically to human NKp46, and wherein all or part of the immunoglobulin Fc region or variant thereof binds to a human Fc-γ receptor.
Summary of Species disclosed in the original specification; the amount of direction provided by the inventor, existence of working examples; and quality of experimentation needed to make or use the invention based on the content of the disclosure.
The specification only identifies cancer treatment in Figures 8, and 18-19 dose-dependent anti-tumor activity with the muNKp46- huCD123_F25 binding protein (carrying anti-murine NKp46 and anti-human CD123 binding domains and also known as moNKp46-huCD123) against MOLM-13 human cells in a Severe Combined Immuno Deficient mice (SCID) mouse model (page 118, section B.8; Table 3; Figure 8). The treated groups already had cancer before treatment. There are no cancer prevention studies in the instant specification.
The instant specification teaches anti-tumor activity against MOLM-13 human AML injected in SCID mice (page 105, section A.9). The instant specification teaches three experiments:
In the first experiment, mice were randomized in 4 groups (n = 10 mice in treated groups and 20 mice in control group) on day 1 post tumor implantation. muNKp46-huCD123_F25 was administered at 0.5, 0.25 and 0.05 mg/kg following intra-parenteral administrations on day 1 (page 106; Figure 8). This experiment confirmed that the NK cell engagers were efficient for treatment of proliferative disorders in vivo in an animal model (page 119, lines 1-2).
In the second experiment, muNKp46-IC was administered at 0.5 mg/kg. muNKp46-huCD123_F25 and Reference-1 were administered at 5, 0.5, 0.25 and 0.05 mg/kg wherein the control group was left untreated (page 106; Figure 18). This experiment was performed for further evaluation of efficacy as shown in the first experiment and demonstrated the benefit of co-engaging NK cells with NKp46/FcγRs, leading to an improved in vivo efficacy relative to an anti-CD123 antibody (pages 119-120).
In the third experiment, mice were randomized into the 4 groups (untreated control group; untreated control group + anti-asialoGMi; NKCE control; or NKCE + anti-asialoGMi). A day before tumor implantation (day -1) as well as at day 5 post- tumor implantation the experimental groups received NK cell depletion antibody, anti-asialo GM1. Treatments (Vehicle or NKCE) were administered intraperitoneally on day 1 post tumor implantation at a single dose of 0.5 mg/kg. NKCE included Nkp46-CD123_F25, muNKp46-IC, an isotype control antibody binding huCD123 and murine FcyRs but not murine NKp46 (IC-huCD123) (Figure 19). The primary efficacy endpoints were the Median Survival Time (MST) in day, the percent Increased Lifespan (%ILS), and the long-term survivor rate (pages 105-106; Figure 19). This experiment showed that the NK depletion impacted the anti-tumoral activity of muNKp46-huCD123_F25, confirming the NK involvement as effector cells in muNKp46-huCD123_F25 NKCE in vivo efficacy (page 124-125 and Table 5).
The instant specification concludes that NKp46-CD123_F25 at different concentrations (1, 10, and 100ng/mL) enhances the cytotoxic activity of HD NK cells against THP1 GFP AML cells over time at the effector:target cells ratio of 1:1 (page 130, “Conclusion” section)
Conclusion
The Applicant does not have enablement for a method of preventing blood cancer, e.g. myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) or CD64-positive AML, comprising administering a binding protein comprising a first ABD that binds specifically to human CD123, a second ABD that binds specifically to human NKp46, and wherein all or part of the immunoglobulin Fc region or variant thereof binds to a human Fc-γ receptor. Claims 41-52 are further dependent on claim 26 without requiring treatment.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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 26-28, 30, and 42, 44-46, and 48-49 are rejected under 35 U.S.C. 103 as being unpatentable over Gauthier et al (US Patent No.10,113,003 B2, ; hereinafter Gauthier) and further in view of Albrecht et al (US Patent No.10,906,978 B2 hereinafter Albrecht).
Regarding instant claims 26-28, 30, and 42, 44-49, Gauthier teaches a multispecific protein comprising a first antigen binding domain and a second antigen binding domain, wherein one of the first or second antigen binding domains binds to a human NKp46 polypeptide and the other binds an antigen of interest, wherein the multispecific protein is capable of directing an NKp46-expressing NK cell to lyse a target cell expressing the antigen of interest, and an Fc domain that binds to human CD16A, (page 20, column 2, line 51-page 21, column 3, line 10; page 21, column 4, lines 45-50). Gauthier also discloses that the multispecific protein comprises at least a portion of a human Fc domain (page 21,column 3, lines 8-10), wherein the multispecific protein is designed to retain substantial FcγR binding, and wherein the multispecific protein binds via its Fc domain to a human CD16 or CD16A, CD32A, CD32B and/or CD64 polypeptide (page 21, column 3, lines 17-41). Gauthier further teaches that the multispecific polypeptide can be used to treat a cancer such as hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias (page 49, column 59, lines 4-16).
Gauthier also teaches a multispecific protein that has the structure of Format 5 (Figure 2D and also shown below).
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410
550
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Format 5 shows a tripeptide structure and has the structural components described in instant Figure 2B of instant application, wherein:
The top peptide (polypeptide chain I described in instant application) comprises Vκ-Cκ-(CH2-CH3), wherein Cκ corresponds to the constant domain of the kappa light chain, and Vκ corresponds to the variable kappa light chain, wherein Vκ corresponds to instant V1A of the instant application;
The middle peptide (polypeptide chain II described in instant application) comprises VH-CH1-(CH2-CH3)-VH-Cκ, wherein the first VH corresponds to instant V1B and the second VH corresponds to instant V2A of the instant application; and
The bottom peptide (polypeptide chain III described in instant application) comprises a Vκ-CH1 domain, wherein Vκ corresponds to instant V2B of the instant application;
(also see page 26, column 13, paragraph 4 – column 14, first paragraph). Furthermore, Gauthier teaches that an ABD (e.g. an immunoglobulin variable region) can optionally be linked to a constant domain or Fc domain via a flexible linker (e.g. polypeptide linker) that leads to less structural rigidity or stiffness (page 40, “Linker” section), optionally, the CH1 and/or Cκ domain are fused via a hinge region to the Fc domain (page 26, column 14, fourth paragraph).
Gauthier also teaches a multispecific protein that has the structure of Format 6 ( shown below) wherein the Fc domain comprises N-linked glycosylation at residue N297 (Kabat EU numbering) (page 35, column 32, lines 65-67; Figure 2D).
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406
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Furthermore, Gauthier teaches that the first and second polypeptide chains are bound by non-covalent bonds and further interchain disulfide bonds, e.g. formed between respective CH1 and Cκ domains and/or between respective hinge domains (page 25, column 12, lines 21-24). Gauthier also teaches that the second (and third, if present) polypeptide chains will also associate with the central polypeptide chain by CH1-Cκ heterodimerization, forming non-covalent bonds and further interchain disulfide bonds between complementary CH1 and Cκ domains (and interchain disulfide bonds between hinge regions), with a primary multimeric polypeptide being formed so long as CH/Cκ and VH/Vκ domains are chosen to give rise to a preferred dimerization configuration that results preferentially in the desired VH-VL pairings (page 37, column 35, lines 44-53).
However, Gauthier does not teach a binding protein wherein the other ABD binds specifically to human CD123.
The deficiency is resolved by Albrecht.
Albrecht teaches an antibody-like binding protein specifically binding to CD123 and binding specifically to at least one further antigen, wherein the invention also relates to pharmaceutical compositions comprising the antibody-like binding protein and their use to treat cancer (page 23, column 1, lines 18-24). Albrecht further teaches that the antibody-like binding protein binds to human CD123 (page 61, column 78, lines 48-49) and has an affinity (KD) for human CD123 of 0.01 nM to 5 nM, (page 61, column 78, line 66 – page 62, column 79, line 3). Albrecht also teaches hematological cancers associated with CD123 expression, wherein CD123 is a tumor antigen over-expressed in a variety of hematological neoplasms, wherein the majority of AML blasts express surface CD123 and this expression does not vary by subtype of AML (page 43, column 41, lines 46-50). Albrecht discloses that hematological cancers associated with CD123 expression include leukemias, such as acute myelogenous leukemia and myelodysplasia syndrome (page 72, column 100, line 65 – page 73, column 101, line 7; page 74, column 104, lines 8-22).
Regarding instant claims 26-28, 42, 45, and 48-49, it would have been obvious for a person having ordinary skill in the art at the time of filing to modify the CD19 binding domain of the multispecific protein comprising a first antigen binding domain that binds to NKp46, a second antigen binding domain that binds to CD19, and a Fc domain that binds to human CD16A of Gauthier, with the CD123 binding domain to treat MDS or AML of Albrecht, wherein the multispecific protein comprises three polypeptide chains that form two ABDs as described in Format 5 (see above or Figure 2D) of the multispecific protein taught by Gauthier. This is obvious because, Gauthier teaches a multispecific protein comprising an antigen binding domain that binds to a human NKp46 polypeptide and the other binds an antigen of interest, and an Fc domain that binds to human CD16A, wherein the multispecific protein comprises the structure of Format 5, wherein:
The top peptide (polypeptide chain I described in instant application) comprises Vκ-Cκ-(CH2-CH3), wherein Cκ corresponds to the constant domain of the kappa light chain, and Vκ corresponds to the variable kappa light chain, wherein Vκ corresponds to instant V1A of the instant application;
The middle peptide (polypeptide chain II described in instant application) comprises VH-CH1-(CH2-CH3)-VH-Cκ, wherein the first VH corresponds to instant V1B and the second VH corresponds to instant V2A of the instant application; and
The bottom peptide (polypeptide chain III described in instant application) comprises a Vκ-CH1 domain, wherein Vκ corresponds to instant V2B of the instant application;
wherein the ABD can optionally be linked to a constant domain or Fc domain via a flexible linker (e.g. polypeptide linker), and wherein the CH1 and/or Cκ domain are fused via a hinge region to the Fc domain, and wherein the multispecific polypeptide can be used to treat a cancer such as hematopoietic tumors of myeloid lineage, including AML, and Albrecht teaches an antibody-like binding protein specifically binding to CD123 and binding specifically to at least one further antigen, wherein the invention also relates to pharmaceutical compositions comprising the antibody-like binding protein and their use to treat cancer, e.g. hematological cancers associated with CD123 expression include leukemias, such as AML and MDS. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the method of treating MDS or AML comprised of administering a multispecific protein comprising a comprising a first antigen binding domain and a second antigen binding domain, wherein one of the first or second antigen binding domains binds to a human NKp46 polypeptide and the other binds an antigen of interest, and an Fc domain that binds to human CD16A, wherein the binding protein comprises three polypeptide chains (I), (II), and (III) that form two ABDs, as defined below:
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wherein:
V1A and V1B form a binding pair V1 (VH1/VL1);
V2A and V2B form a binding pair V2 (VH2/VL2);
C1A and C1B form a pair C1 (CH1/CL) and C2A and C2B form a pair C2 (CH1/CL) wherein CH1 is an immunoglobulin heavy chain constant domain 1 and CL is an immunoglobulin light chain constant domain;
Hinge1, Hinge2 and Hinge3 are identical or different and correspond to all or part of an immunoglobulin hinge region;
(CH2-CH3)A and (CH2-CH3)B are identical or different, and comprise an immunoglobulin heavy chain constant domain 2 (CH2) and an immunoglobulin heavy chain constant domain 3 (CH3); and
L1 is an amino acid linker.
Regarding instant claims 44 and 46, it would have been obvious for a person having ordinary skill in the art at the time of filing to take the method of treating hematological cancers comprising administering a multispecific protein comprising a first ABD that binds to human CD123, a second ABD that binds to human NKp46, and an Fc domain that binds to human CD16A as taught by the combined teachings of Gauthier and Albrecht and modify it wherein the residue N297 of the Fc region or variant thereof, according to EU numbering, comprises a N-linked glycosylation and a disulfide bond wherein the first and second polypeptide chains are bound by disulfide bonds formed between respective CH1 and Cκ domains and/or between respective hinge domains as taught by Gauthier. This is obvious because, the combined teachings of Gauthier and Albrecht teach a method of treating hematological cancers, such as AML or MDS, comprising administering a multispecific protein comprising a first ABD that binds to human CD123, a second ABD that binds to human NKp46, and an Fc domain that binds to human CD16A, wherein the multispecific protein is designed to retain substantial FcγR binding via its Fc domain to a human CD16 or CD16A, and Gauthier teaches that the Fc domain comprises N-linked glycosylation at residue N297, as shown in Figure 2D, Format 6 and disulfide bonds between the first and second polypeptide chains between respective CH1 and Cκ domains and/or between respective hinge domains. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the method of treating blood cancer comprising administering to a subject in need of a binding protein comprising a first ABD that binds specifically to human CD123, a second ABD that binds specifically to human NKp46, and all or part of an immunoglobulin Fc region or variant thereof that binds to a human Fc-γ receptor wherein the residue N297 of the instant Fc region or variant thereof according to EU numbering comprises a N-linked glycosylation and the instant binding protein comprises at least two polypeptide chains linked by at least one disulfide bridge.
Claim 30 is rejected under 35 U.S.C. 103 as being unpatentable over Gauthier et al (US Patent No.10,113,003 B2, ; hereinafter Gauthier) and Albrecht et al (US Patent No.10,906,978 B2 hereinafter Albrecht), as applied to claim 26 above, and further in view of Dunphy et al (Arch Pathol Lab Med, 2007, 131:748-754).
The combined teachings of Gauthier and Albrecht are discussed above.
The combined teachings of Gauthier and Albrecht do not teach a method of treating a CD64-positive AML comprising administering to a subject in need of a binding protein comprising a human CD123 ABD and human NKp46 ABD, wherein all or part of the immunoglobulin Fc region or variant thereof binds to a human Fc-γ receptor.
The deficiency is resolved by Dunphy.
Dunphy teaches that CD64 was expressed in AML subtypes M0 to M5 in varying intensities (page 748, Abstract; Figure 1).
Regarding instant claim 30, it would have been obvious for a person having ordinary skill in the art at the time of filing to modify the method of treating hematological cancers comprising administering a multispecific protein comprising a first ABD that binds to human CD123, a second ABD that binds to human NKp46, and an Fc domain that binds to human CD16A as taught by the combined teachings of Gauthier and Albrecht to include treating CD64 positive AML as taught by Dunphy. This is obvious because, the combined teachings of Gauthier and Albrecht teach a method of treating hematological cancers, such as AML or MDS, comprising administering a multispecific protein comprising a first ABD that binds to human CD123, a second ABD that binds to human NKp46, and an Fc domain that binds to human CD16A, wherein the multispecific protein is designed to retain substantial FcγR binding via its Fc domain to a human CD16 or CD16A, and Dunphy teaches that CD64 is expressed in AML subtypes M0 to M5 in varying intensities. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to form the method of treating CD64-positive AML comprising administering to a subject in need of a binding protein comprising a first ABD that binds specifically to human CD123, a second ABD that binds specifically to human NKp46, and all or part of an immunoglobulin Fc region or variant thereof that binds to a human Fc-γ receptor.
Claim 43 is rejected under 35 U.S.C. 103 as being unpatentable over Gauthier et al (US Patent No.10,113,003 B2; hereinafter Gauthier) and Albrecht et al (US Patent No.10,906,978 B2 hereinafter Albrecht), as applied to claim 26 above, and further in view of Sun et al (US Patent No. 8,410,043B2; hereinafter Sun), Chang and Moreb (US Patent No. 11,041,021B2; hereinafter Chang), and Humphreys and Peters (US Patent No. 10,221,251B2, hereinafter Humphreys).
The combined teachings of Gauthier and Albrecht are discussed above. Gauthier also discloses Format 16 of the multispecific protein, wherein the second polypeptide chain comprises of two CH1 domains, which correspond to instant C1B and instant C2A of the instant binding protein, and the immunoglobulin light chain domains are immunoglobulin kappa light chain constant domains, Cκ (Figure 2E, Format 16). Gauthier further teaches three variants of F10 proteins wherein the first and second variants comprised amino acid residues DKTHTCPPCP (SEQ ID NO: 205) in the hinge, which is identical to the instant Hinge1 amino acid sequence comprising instant SEQ ID NO:74 (page 55, column 71, lines 35-45). Gauthier also teaches the domain structure of a trimeric T5 polypeptide, GA101-T5-Ritux-NKp46, wherein the first polypeptide comprising amino acid sequence SEQ ID NO:188 comprises a hinge sequence identical to the instant Hinge2 amino acid sequence instant SEQ ID NO:75 (page 57, column 75, lines 30). Gauthier also teaches the domain structure of F2 polypeptide, wherein the second polypeptide chain comprises a linker, wherein the DNA sequence coded for a CH3/VH linker peptide having the amino acid sequence STGS was designed in order to insert a specific SaII restriction site at the CH3-VH for cloning, production, and purification purposes (page 54, column 69, lines 26-34), which is identical to the instant amino acid sequence instant SEQ ID NO:76, which corresponds to instant L1.
However, the combined teachings of Gauthier and Albrecht do not teach the method of treating hematological cancers comprising administering a multispecific protein comprising a first ABD that binds to human CD123, a second ABD that binds to human NKp46, and an Fc domain that binds to human CD16A wherein:
(CH2-CH3)A corresponds to the amino acid sequence of SEQ ID NO:69;
(CH2-CH3)B corresponds to the amino acid sequence of SEQ ID NO:70;
Hinge3 corresponds to the amino acid sequence SEQ ID NO:77; and
The deficiency is resolved by Sun, Chang, and Humphreys.
Sun teaches svActRIIB, a stabilized activin IIB receptor polypeptides and proteins capable of binding and inhibiting the activities of activin A, myostatin, or GDF-11 (page 6, column 2, lines 29-33), wherein scActRIIB further comprises a heterologous protein which is a human IgG Fc domain comprising the amino acid sequence SEQ ID NO:47 (page 7, column 3, lines 25-39), comprising the instant amino acid sequences instant SEQ ID NO:69 and 70, which are identical to each other as shown in the sequence alignment below.
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To further support Gauthier’s teachings of the amino acid sequences of Hinge1 and Hinge2, Chang also teaches hinge sequences comprising amino acid sequences VEPKSCDKTHTCPPCP (SEQ ID NO:7) and LDKTHTCPPCP (SEQ ID NO:10) (page 22, column 14, lines 9-44). SEQ ID NO:7 is identical to the instant amino acid sequence instant SEQ ID NO:75 that corresponds to Hinge2, and SEQ ID NO:10 is identical to the instant amino acid sequence instant SEQ ID NO:74, that corresponds to Hinge1.
Humphreys teaches symmetric bispecific antibody of the class IgG4, wherein the upper hinge in an IgG4 heavy chain consists of an IgG1-type hinge i.e. EPKSCDKTHTCPPC or a derivative of, such as an amino acid sequence comprising SEQ ID NO:128 (page 47, column 13), which aligns with the instant amino acid sequence instant SEQ ID NO:77 as shown below.
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Regarding instant claim 43, it would have been obvious for a person having ordinary skill in the art at the time of filing to take the method of treating hematological cancers comprising administering a multispecific protein comprising a first ABD that binds to human CD123, a second ABD that binds to human NKp46, and an Fc domain that binds to human CD16A as taught by the combined teachings of Gauthier and Albrecht and modify it to comprise Format16 of Gauthier wherein: (i) (CH2-CH3)A and (CH2-CH3)B comprise amino acid sequence SEQ ID NO:47 of Sun; (ii) Hinge1, Hinge2 comprise amino acid sequences SEQ ID NO: 10 and 7 of Chang; (iii) Hinge3 comprises amino acid sequence SEQ ID NO:128 with Humphreys; and (iv) L1 comprises the amino acid sequence STGS for cloning, production, and purification purposes as taught by Gauthier. This is obvious because, the combined teachings of Gauthier and Albrecht teach a method of treating hematological cancers, such as AML or MDS, comprising administering a multispecific protein comprising a first ABD that binds to human CD123, a second ABD that binds to human NKp46, and an Fc domain that binds to human CD16A, wherein the multispecific protein is designed to retain substantial FcγR binding via its Fc domain to a human CD16 or CD16A, Gauthier teaches Format 16 of the multispecific protein, wherein the second polypeptide chain comprises of two CH1 domains, which correspond to instant C1B and instant C2A of the instant binding protein, and the immunoglobulin light chain domains are immunoglobulin kappa light chain constant domains, Cκ, Sun teaches svActRIIB comprising a heterologous protein which is a human IgG Fc domain comprising the amino acid sequence SEQ ID NO:47, Chang teaches hinge sequences comprising amino acid sequences SEQ ID NO:7 and SEQ ID NO:10, wherein Gauthier uses these hinge sequences in the domain structure of a trimeric T5 polypeptide, GA101-T5-Ritux-NKp46, and Humphreys teaches symmetric bispecific antibody of the class IgG4, wherein the upper hinge in an IgG4 heavy chain consists of an IgG1-type hinge i.e. EPKSCDKTHTCPPC or a derivative of, such as an amino acid sequence comprising SEQ ID NO:128. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to form the instant method of treating blood cancer comprising administering to a subject in need of a binding protein comprising a first ABD that binds specifically to human CD123, a second ABD that binds specifically to human NKp46, and all or part of an immunoglobulin Fc region or variant thereof that binds to a human Fc-γ receptor, wherein the instant binding protein comprises the three polypeptide chain as defined below:
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, wherein:
Instant C1B is an immunoglobulin heavy chain constant domain 1 (CH1);
Instant C2A is an immunoglobulin heavy chain constant domain 1 (CH1);
Instant CL corresponds to an immunoglobulin kappa light chain constant domain (Cκ);
Instant (CH2-CH3)A corresponds to the amino acid sequence of SEQ ID NO: 69;
Instant (CH2-CH3)B corresponds to the amino acid sequence of SEQ ID NO: 70;
Instant Hinge1 corresponds to the amino acid sequence of SEQ ID NO:74;
Instant Hinge2 corresponds to the amino acid sequence of SEQ ID NO:75;
Instant Hinge3 corresponds to the amino acid sequence of SEQ ID NO: 77; and
Instant L1 corresponds to the amino acid sequence of SEQ ID NO: 76.
Claim 47 is rejected under 35 U.S.C. 103 as being unpatentable over Gauthier et al (US Patent No.10,113,003 B2; hereinafter Gauthier) and Albrecht et al (US Patent No.10,906,978 B2 hereinafter Albrecht), as applied to claim 26 above, and further in view of Wypych et al (J. Biol. Chem, 2008, 283(23):16194-16205; hereinafter Wypych).
Regarding instant claim 47, the combined teachings of Gauthier and Albrecht are discussed above.
However, the combined teachings of Gauthier and Albrecht do not teach the method of treating hematological cancers comprising administering a multispecific protein comprising a first ABD that binds to human CD123, a second ABD that binds to human NKp46, and an Fc domain that binds to human CD16A, wherein the binding protein comprises at least two polypeptide chains linked by at least one disulfide bridge wherein the polypeptide chains (I) and (II) are linked by at least one disulfide bridge between C1A and Hinge2 and/or wherein the polypeptide chains (II) and (III) are linked by at least one disulfide bridge between Hinge3 and C2B.
The deficiency is resolved by Wypych.
Wypych teaches studies of the covalent structure of human IgG2 molecules, wherein Wypych discloses the novel IgG2 structural isoform, IgG2-B and IgG2-A/B, wherein IgG2-B has a structure with both of the Fab arms disulfide bonded to the dimeric hinge through Cys136 in the heavy chains (HCs) and Cys215 in the light chains (LCs), and IgG2-A/B has one Fab arm connected to the dimeric hinge via Cys136 in HC and Cys215 in LC as in isoform IgG2-B, whereas the other Fab arm has the expected HC-LC disulfide linkage as in isoform IgG2-A (Figure 8; page 16202, left column, second paragraph). Wypych further teaches that although the functional significance of the disulfide bond heterogeneity is not fully known, with respect to the functional aspects of the phenomenon, the disulfide isoforms can, in principle, impact both effector functions and antigen binding affinity/avidity and thereby lead to some level of physiological control (page 16204, right column, last paragraph).
Regarding instant claim 47, it would have been obvious for a person having ordinary skill in the art at the time of filing to modify the method of treating hematological cancers comprising administering a multispecific protein comprising a first ABD that binds to human CD123, a second ABD that binds to human NKp46, and an Fc domain that binds to human CD16A, wherein the binding protein comprises at least two polypeptide chains linked by at least one disulfide bridge as taught by the combined teachings of Gauthier and Albrecht wherein the first and second polypeptide chains are bound by disulfide bonds formed between respective CH1 and Cκ domains as taught by Gauthier, and the second and third polypeptide chains are linked by a disulfide bridge between the hinge and light chain domains, wherein the disulfide bridge between the hinge and light chain domains may impact antigen binding affinity/avidity as taught by Wypych. This is obvious because, the combined teachings of Gauthier and Albrecht teach a method of treating hematological cancers, such as AML or MDS, comprising administering a multispecific protein comprising a first ABD that binds to human CD123, a second ABD that binds to human NKp46, and an Fc domain that binds to human CD16A, wherein the multispecific protein is designed to retain substantial FcγR binding via its Fc domain to a human CD16 or CD16A, wherein the binding protein comprises at least two polypeptide chains linked by at least one disulfide bridge, and Wypych teaches the novel IgG2 isoform, IgG2-A/B, which has one Fab arm connected to the dimeric hinge via Cys136 in HC and Cys215 in LC as in isoform IgG2-B, whereas the other Fab arm has the expected HC-LC disulfide linkage as in isoform IgG2-A, wherein with respect to the functional aspects of the disulfide isoforms, the disulfide linkage between the hinge and light chain domains may impact both effector functions and antigen binding affinity/avidity and thereby lead to some level of physiological control. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant method of treating blood cancer comprising administering to a subject in need of a binding protein comprising a first ABD that binds specifically to human CD123, a second ABD that binds specifically to human NKp46, and all or part of an immunoglobulin Fc region or variant thereof that binds to a human Fc-γ receptor wherein the instant binding protein comprises at least two polypeptide chains linked by at least one disulfide bridge wherein polypeptide chains (II) and (III) are linked by a disulfide bridge between Hinge3 and C2B.
Claim 50 is rejected under 35 U.S.C. 103 as being unpatentable over Gauthier et al (US Patent No.10,113,003 B2; hereinafter Gauthier) and Albrecht et al (US Patent No.10,906,978 B2 hereinafter Albrecht) as applied to claim 26 above, and further in view of Gauthier et al (US Patent No. 11,001,629B2, IDS entered on 2/2/2024; hereinafter Gauthier ‘629).
Regarding instant claim 50, the combined teachings of Gauthier and Albrecht are discussed above.
However, the combined teachings of Gauthier and Albrecht do not teach the method of treating hematological cancers comprising administering a multispecific protein comprising a first ABD that binds to human CD123, a second ABD that binds to human NKp46, and an Fc domain that binds to human CD16A wherein VH2 and VL2 comprises the amino acid sequences of SEQ ID NO:45 and 53, respectively.
The deficiency is resolved by Gauthier ‘629.
Gauthier ‘629 teaches NKp46-binding immunoglobulin variable regions, and proteins such as antibodies and multispecific proteins (page 1, Abstract), wherein the NKp46-1 antibody comprising a H1 heavy chain variable region comprising amino acid sequence SEQ ID NO:199 (page 35, column 40, lines 60-66; Table C) and a L1 light chain variable region comprising amino acid sequence SEQ ID NO:201 (page 36, column 41, lines 1-9; Table C) was able to direct resting NK cells to their CD19-positive Daudi tumor target cells efficiently activate resting NK cells while full-length anti-CD19 antibodies only showed at best very low activation of NK cells (FIGS. 3 and 4; page 20, column 10, lines 43-62).
Regarding instant claim 50, it would have been obvious for a person having ordinary skill in the art at the time of filing to take the method of treating hematological cancers comprising administering a multispecific protein comprising a first ABD that binds to human CD123, a second ABD that binds to human NKp46, and an Fc domain that binds to human CD16A as taught by the combined teachings of Gauthier and Albrecht and substitute SEQ ID NO:199 and SEQ ID NO:201 of Gauthier ‘629 to comprise VH2 and VL2, respectively. This is obvious because, the combined teachings of Gauthier and Albrecht teach a method of treating hematological cancers, such as AML or MDS, comprising administering a multispecific protein comprising a first ABD that binds to human CD123, a second ABD that binds to human NKp46, and an Fc domain that binds to human CD16A, wherein the multispecific protein is designed to retain substantial FcγR binding via its Fc domain to a human CD16 or CD16A, and Gauthier ‘629 teaches the NKp46-binding multispecific protein, NKp46-1, comprising a H1 heavy chain variable region comprising amino acid sequence SEQ ID NO:199 and a L1 light chain variable region comprising amino acid sequence SEQ ID NO:201, wherein NKp46-1 effectively activated resting NK cells in Daudi tumor target cells. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant method of treating blood cancer comprising administering to a subject in need of a binding protein comprising a first ABD that binds specifically to human CD123, a second ABD that binds specifically to human NKp46, and all or part of an immunoglobulin Fc region or variant thereof that binds to a human Fc-γ receptor, wherein the VH2 and VL2 comprise the amino acid sequences of instant SEQ ID NOs:45 and 53, respectively.
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.
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Claims 26-28, 30, and 45, are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6-8, 10, and 14 of copending Application No. 18/283,385 (US20240199750 A1; hereinafter ‘385) and further in view of Gauthier et al (US Patent No.10,113,003 B2, ; hereinafter Gauthier), Albrecht et al (US Patent No.10,906,978 B2 hereinafter Albrecht) and Dunphy et al (Arch Pathol Lab Med, 2007, 131:748-754). This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding instant claims 26-28, 30, and 45, claims 1-3 of ‘385 teach a multispecific protein which is capable of binding to an antigen of interest expressed by a target cell, and which is further capable of binding to NKp46, a cytokine receptor and optionally CD16A at the surface of an NK cell, and which multispecific protein is capable of potentiating NK cell cytotoxicity toward a target cell expressing an antigen of interest, the multispecific protein comprising:
an antigen binding domain (ABD) that binds to an antigen of interest;
an ABD that binds to a human NKp46 polypeptide;
an Fc domain, or a portion an Fc domain capable of binding FcRn; and
an ABD that binds a human cytokine receptor present on NK cells,
wherein the ABD that binds to a human NKp46 polypeptide is connected to the Fc domain, optionally via an Ig-derived or non-Ig-derived polypeptide linker, and wherein the ABD that binds a human cytokine receptor is connected, via a polypeptide linker, to the ABD that binds to a human NKp46 polypeptide or to the Fc domain, wherein the protein has only one ABD that binds to an antigen of interest, such that the protein binds to the antigen of interest monovalently, optionally further wherein the protein has only one ABD that binds to a human NKp46 polypeptide, only one ABD that binds a cytokine receptor, and only one Fc domain dimer. Claim 10 of ‘385 teaches that each ABD comprises a VH and/or VL domain or fragment thereof, wherein a VH and/or VL comprises three complementary determining regions (CDR1, CDR2 and CDR-3). Claim 4 of ‘385 teach the multispecific protein described above that comprises the ABD that binds to a human NKp46 polypeptide and the ABD that binds a human cytokine receptor, and optionally further the Fc domain, wherein the ABDs and the Fc domain are positioned within the multispecific protein in series with respect to the N- and C-termini of the multispecific protein. Claims 6-8 of ‘385 also teach that the polypeptide linker comprising the multispecific protein described above comprises less than 15 amino acid residues. Finally, Claim 14 teaches that the multispecific protein is a heterotrimer comprising a first, second, and third polypeptide chain.
However, ‘385 does not teach a multispecific protein wherein the other ABD binds specifically to human CD123. Furthermore, ‘385 does not teach a method of treating blood cancer, such as AML, MDS, or CD64-positive AML, comprising administering to a subject in need of a binding protein comprising a human CD123 ABD and human NKp46 ABD, wherein all or part of the immunoglobulin Fc region or variant thereof binds to a human Fc-γ receptor.
The deficiency is resolved by Gauthier, Albrecht and Dunphy.
The combined teachings of Gauthier, Albrecht and Dunphy are discussed in the 103 rejection. Albrecht further teaches that “CD123” (Cluster of Differentiation 123) is also known as “Interleukin 3 receptor, alpha (IL3RA)” or “IL3R”, “IL3RX”, “IL3RY”, “IL3RAY”, “hIL-3Ra” and denotes an interleukin 3 specific subunit of a heterodimeric cytokine receptor (page 42, column 40, “Anti CD123 Antibodies” section). Furthermore, Albrecht teaches that the antibody-like protein may induce cytotoxicity by different mechanisms, such as antibody-dependent cell-mediated cytotoxicity or complement-dependent cytotoxicity (page 61, column 77, line 63-column 78, line 2).
Regarding instant claims 26-28, 30 and 45, it would have been obvious for a person having ordinary skill in the art at the time of filing to take the multispecific protein comprising a first antigen binding domain and a second antigen binding domain, wherein one of the first or second antigen binding domains binds to a human NKp46 polypeptide and the other binds an antigen of interest, and an Fc domain that binds to human CD16A of ‘385 and modify it comprise a first ABD to specifically bind to human CD123 and a second ABD to specifically bind to human NKp46 wherein the multispecific protein is used in a method of treating hematological cancers, such as AML, MDS, or CD64-positive AML as taught by the combined teachings of Gauthier, Albrecht, and Dunphy. This is obvious because, ‘385 teaches a multispecific protein which is capable of binding to an antigen of interest expressed by a target cell, and which is further capable of binding to NKp46, a cytokine receptor and optionally CD16A at the surface of an NK cell, and which multispecific protein is capable of potentiating NK cell cytotoxicity toward a target cell expressing an antigen of interest, the multispecific protein comprising:
an antigen binding domain (ABD) that binds to an antigen of interest;
an ABD that binds to a human NKp46 polypeptide;
an Fc domain, or a portion an Fc domain capable of binding FcRn; and
an ABD that binds a human cytokine receptor present on NK cells,
and the combined teachings of Gauthier, Albrecht and Dunphy teach a method of treating hematological cancers, such as AML, CD64-positive AML, or MDS, comprising administering a multispecific protein comprising a first ABD that binds to human CD123, a cytokine receptor, wherein the multispecific protein is capable of potentiating NK cell cytotoxicity toward a target cell expressing CD123, a second ABD that binds to human NKp46, and an Fc domain that binds to human CD16A. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant method of treating blood cancer, such as AML or MDS, comprising administering to a subject in need of a binding protein comprising a first ABD that binds specifically to human CD123, a second ABD that binds specifically to human NKp46, and all or part of an immunoglobulin Fc region or variant thereof that binds to a human Fc-γ receptor. Moreover, a claimed product is obvious over a method comprising the product. Therefore, although the claims at issue are not identical, the instant claims are not patentably distinct from the claims in the copending application.
Claims 26-28, and 30, are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of copending Application No. 18/432,126 (US20240174748 A1; hereinafter ‘126) and further in view of Gauthier et al (US Patent No.10,113,003 B2, ; hereinafter Gauthier), Albrecht et al (US Patent No.10,906,978 B2 hereinafter Albrecht) and Dunphy et al (Arch Pathol Lab Med, 2007, 131:748-754). This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding instant claims 26-28, and 30, claim 1 of ‘126 teach a method of treating a disease in a subject comprising administering to the subject a composition comprising protein or polypeptide comprising an antigen binding domain that binds a human NKp46 polypeptide, wherein the domain comprises a heavy chain variable region (VH) and a light chain variable region (VL) comprising a VH comprising an amino acid sequence of SEQ ID NO:199 (NKp46-1 H1 variable domain, which is identical to instant SEQ ID NO:45), and a VL comprising an amino acid sequence of the amino acid sequence of SEQ ID NO:201 (NKp46-1 L1 variable domain, which is identical to instant SEQ ID NO:53). Claims 2-3, and 9 of ‘126 teach a multispecific antigen binding protein, a protein, or polypeptide comprising an antigen binding domain that binds a human NKp46 polypeptide, wherein the domain comprises a VH comprising an amino acid sequence of SEQ ID NO:199, and a VL comprising an amino acid sequence of SEQ ID NO:201, wherein the multispecific protein is used in a method of treating a disease in a subject comprising administering to the subject the multispecific antigen binding protein, and wherein the multispecific protein further comprises a second antigen binding domain that binds to an antigen of interest, wherein the multispecific protein is capable of directing an NKp46-expressing NK cell to lyse a target cell expressing the antigen of interest. Furthermore, claims 4-5 of ‘126 teach the structures that comprise the multispecific antigen binding protein, comprising multiple polypeptides. Claims 6-8 of ‘126 teach an isolated nucleic acid encoding the multispecific antigen binding protein, a recombinant host cell comprising the nucleic acid, and a method of producing a protein comprising culturing the recombinant host cell under conditions suitable for expression of the protein and recovering the protein.
However, ‘126 does not teach a multispecific protein wherein the other ABD binds specifically to human CD123. Furthermore, ‘126 does not teach a method of treating blood cancer, such as AML, MDS, or CD64-positive AML, comprising administering to a subject in need of a binding protein comprising a human CD123 ABD and human NKp46 ABD, wherein all or part of the immunoglobulin Fc region or variant thereof binds to a human Fc-γ receptor.
The deficiency is resolved by Gauthier, Albrecht and Dunphy.
The combined teachings of Gauthier, Albrecht and Dunphy are discussed in the 103 rejection and above.
Regarding instant claims 26-28, and 30, it would have been obvious for a person having ordinary skill in the art at the time of filing to take the method of treating a disease comprising administering to the subject a multispecific antigen binding protein comprising an antigen binding domain that binds a human NKp46 polypeptide, wherein the domain comprises a VH comprising an amino acid sequence of SEQ ID NO:199, and a VL comprising an amino acid sequence of SEQ ID NO:201, and a second antigen binding domain that binds to an antigen of interest, wherein the multispecific protein is capable of directing an NKp46-expressing NK cell to lyse a target cell expressing the antigen of interest of ‘126 and modify it comprise a first ABD to specifically bind to human CD123 and a second ABD to specifically bind to human NKp46 wherein the multispecific protein is used in a method of treating hematological cancers, such as AML, MDS, or CD64-positive AML as taught by the combined teachings of Gauthier, Albrecht, and Dunphy. This is obvious because, ‘126 teaches a method of treating a disease comprising administering to the subject a multispecific antigen binding protein comprising an antigen binding domain that binds a human NKp46 polypeptide, wherein the domain comprises a VH comprising amino acid sequence SEQ ID NO:199, and a VL comprising amino acid sequence SEQ ID NO:201, and a second antigen binding domain that binds to an antigen of interest, wherein the multispecific protein is capable of directing an NKp46-expressing NK cell to lyse a target cell expressing the antigen of interest, and the combined teachings of Gauthier, Albrecht and Dunphy teach a method of treating hematological cancers, such as AML, CD64-positive AML, or MDS, comprising administering a multispecific protein comprising a first ABD that binds to human CD123, a cytokine receptor, wherein the multispecific protein is capable of potentiating NK cell cytotoxicity toward a target cell expressing CD123, a second ABD that binds to human NKp46, and an Fc domain that binds to human CD16A. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant method of treating blood cancer, such as AML or MDS, comprising administering to a subject in need of a binding protein comprising a first ABD that binds specifically to human CD123, a second ABD that binds specifically to human NKp46, and all or part of an immunoglobulin Fc region or variant thereof that binds to a human Fc-γ receptor. Moreover, a claimed product is obvious over a method comprising the product. Therefore, although the claims at issue are not identical, the instant claims are not patentably distinct from the claims in the copending application.
Conclusion
No claims are allowed.
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/J.H./Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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