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 .
Summary
Claims 1-20 are pending in this office action. All pending claims are under examination in this application.
Priority
The current application was filed on July 22, 2024 is a 371 of PCT/US2023/011458 filed January 24, 2023, which in turn claims domestic priority to provisional patent application 63/302,290 filed January 24, 2022.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 3-4, 6, 13-16, and 18-19 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Bam et al. (Bioconjugate Chemistry, 2019).
Bam et al. is considered the closest prior art to the present invention as it teaches affibody-indocyanine green based contrast agent for photoacoustic and fluorescence molecular imaging of B7-H3 expression in breast cancer (see title). Also, Bam et al. disclose spectroscopic photoacoustic (sPA) molecular imaging has high potential for identification of exogenous contrast agents targeted to specific markers. Antibody-dye conjugates have recently been used extensively for preclinical sPA and other optical imaging modalities for highly specific molecular imaging of breast cancer. However, antibody-based agents suffer from long circulation times that limit image specificity. Here, the efficacy of a small protein scaffold, the affibody (ABY), conjugated to indocyanine green (ICG), a near-infrared fluorescence dye, as a targeted molecular imaging probe is demonstrated. In particular, B7-H3 (CD276), a cellular receptor expressed in breast cancer, was imaged via sPA and fluorescence molecular imaging to differentiate invasive tumors from normal glands in mice. Administration of ICG conjugated to an ABY specific to B7-H3 (ABYB7-H3-ICG) showed significantly higher signal in mammary tumors compared to normal glands of mice. ABYB7-H3-ICG is a compelling scaffold for molecular sPA imaging for breast cancer detection (see abstract).
Regarding instant claim 1, Bam et al. teach an anti-B7-H3 compound comprising an anti-B7-H3 affibody. The necessary citations within Bam et al. that correspond to instant claim 1 are compiled within Table I.
Table I
Instant Claim 1
Bam et al. Citations
An anti-B7-H3 compound comprising an anti-B7-H3 affibody, the anti-B7-H3 affibody comprising: SEQ ID NO:2; an amino acid sequence having at least 90% sequence similarity to SEQ ID NO:2; or an amino acid sequence having at least 90% sequence identity to SEQ ID NO:2.
Bam et al. discloses affibody conjugates that bind to B7-H3 (see title). Experiments were conducted with a compound called ABYB7-H3 (see p1680, 1st column, 2nd and 3d paragraphs), which has the following sequence:
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(see page 6 within the Supporting Information of Bam et al.) This polypeptide meets the claim limitation where this sequence has at least 90% sequence identity to SEQ ID NO:2 in the instant application.
The terminal histidine rich sequence assists in the isolation and purification of the material (-GSHHHHHH) (see PTO-892 NPL X).
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Regarding instant claims 3-4 and 6, Bam et al. teach further comprising a first functional component operably coupled to the anti-B7-H3 affibody.
Bam et al. disclose that the polypeptide was conjugated to ICG, a fluorescence imaging agent, using NHS ester chemistry (see p1680, 2nd column, 2nd paragraph, continues to p1681, 1st column, 1st paragraph). The ABYB7-H3-ICG was examined via fluorescence imaging in transgenic (MMTV-PyMT) murine model of breast cancer (see p1680, 2nd column, 2nd paragraph, continues to p1681, 1st column, 1st paragraph).
Regarding instant claim 13, Bam et al. teach a composition comprising: the anti-B7-H3 compound of instant claim 1; and a pharmaceutically acceptable carrier.
Bam et al. disclose that after purification, the labeled sequence was dissolved in bicarbonate buffer (see p1685, 2nd column, 3rd paragraph), a pharmaceutically acceptable carrier.
Regarding instant claims 14-16, Bam et al. teach a method comprising administering the composition of instant claim 13 to a subject having cancer.
Bam et al. disclose that this labeled sequence was used to image a mouse model of B7-H3 positive breast cancer (p1681, 2nd column, 1st paragraph).
Regarding instant claims 18-19, Bam et al. teach further comprising detecting the imaging component to detect anti-B7-H3 compound bound to B7-H3 expressed by a cell and wherein the cell is a cancer cell that expressed B7-H3.
Please see the citations and discussion within instant claims 1, 3-4, 6, and 14-16 for the necessary rejection text.
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 non-obviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3-5, 7-14, 17-18, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Bam et al. in view of Benatuil et al. (US2020/0338209A1), Kruziki (Ph.D. Dissertation, 2017), and Loss et al. (WO2020/148542A1).
[The Examiner is going to introduce each new reference and then combine them in the rejection of the instant claims.]
1. Benatuil et al.
Benatuil et al. teach anti-B7-H3 antibodies and antibody drug conjugates (see title). Furthermore, Benatuil et al. disclose that the invention relates to B7 homology 3 (B7-H3) antibodies and antibody drug conjugates (ADCs), including compositions and methods of using said antibodies and ADCs (see abstract).
2. Kruziki
Kruziki teaches engineering of a 45-amino acid protein scaffold for molecular cancer imaging (see title). Additionally, Kruziki discloses that cancer is the second leading cause of death in the United States. Molecularly targeted cancer treatments, including monoclonal antibodies and kinase inhibitors, exhibit strong performance on a small subset of patients but are inconsistent due to tumor heterogeneity. Biopsy-based genetic and protein tumor characterization provide value but cannot address spatial or temporal variations in heterogeneity. Non-invasive methods, such as molecular imaging, to characterize cancer cells will allow for easier patient stratification and treatment monitoring. Currently, molecular imaging is limited by the modest availability of quality probes that efficiently distribute throughout the body and quantitatively localize at the site of the cancer biomarker. Engineering effective diagnostic molecular probes would provide a substantial advance in cancer characterization and personalized medicine.
Protein scaffolds, which comprise a large stabilizing framework and a randomized region onto which binding interactions can be engineered, offer an efficient platform for probe engineering. More broadly, engineered binding proteins are useful in many aspects of biotechnology and medicine.
In this thesis, we mined ~100,000 known protein topologies to identify candidate
small protein scaffolds. We developed the 45-amino acid Gp2 scaffold and evolved multiple Gp2 variants that strongly (as strong as 0.2 nM) and specifically (greater than 50:1 target:control) bind their respective target while also retaining high thermal stability (65-80 °C thermal desaturation midpoint).
A Gp2 variant that was evolved to bind with strong affinity to epidermal growth
factor receptor (EGFR), a cell surface biomarker overexpressed in multiple cancer types, was more thoroughly investigated in pre-clinical studies. This variant exhibited strong (18 nM), selective binding, and was passive on normal EGFR signaling pathways, which is important to reduce off-target side effects. PET imaging of subcutaneously xenografted tumors in mice revealed effective probe localization to EGFR-high tumors while low signal was observed in EGFR-low tumors and from non-targeted control Gp2.
Gp2 evolution was studied by comparing the efficacy of different combinatorial
library amino acid diversity based on high throughput sequencing data, natural Gp2 homologs, structural data, and computed stability. Multiple library designs elucidated amino acid diversity that was beneficial or detrimental in different sections of the Gp2 protein, and will aid future evolution and developability of Gp2. From these libraries, high affinity Gp2 variants targeting an additional clinically-relevant cancer biomarker, programmed death-ligand 1 (PD-L1), were evolved, isolated, and characterized. Collectively this work identifies and validates Gp2 as a new potential tool for biomarker-based cancer detection and sets a strong foundation for future optimization (see abstract).3. Loss et al.
Loss et al. teach sortase-labelled clostridium neurotoxins (see title). In addition, Loss et al. disclose that the present invention relates to a method for preparing a labelled polypeptide, the method comprising: a. providing a polypeptide comprising: i. a sortase acceptor site or a sortase donor site; ii. a non-cytotoxic protease or a proteolytically inactive mutant thereof; iii. a Targeting Moiety (TM) that is capable of binding to a Binding Site on a target cell; and iv. a translocation domain; b. incubating the polypeptide with: a sortase; and a labelled substrate comprising a sortase donor site or a sortase acceptor site, respectively, and a conjugated detectable label; wherein the sortase catalyses: conjugation between an amino acid of the sortase acceptor site of the polypeptide and an amino acid of the sortase donor site of the labelled substrate; or conjugation between an amino acid of the sortase acceptor site of the labelled substrate and an amino acid of the sortase donor site of the polypeptide; thereby labelling the polypeptide; and c. obtaining the labelled polypeptide. The invention also relates to polypeptides for labelling, labelled polypeptides, nucleic acids encoding said polypeptides, and methods of using and manufacturing said polypeptides (see abstract).
The teachings of Bam et al. are disclosed within the 35 U.S.C. §102 Section (above).
Ascertaining the Difference
The Bam et al. reference was unable to map successfully against all of the instant claim limitations. However, Benatuil et al., Kruziki, and Loss et al. are able to fill-in the citation gaps left by Bam et al.
Combination of Bam et al., Benatuil et al., and Kruziki
Regarding claim 5, Bam et al., Benatuil et al., and Kruziki teach wherein the targeting component binds to the extracellular domain of a protein displayed on a natural killer cell or a T cell.
Benatuil et al. disclose that in one aspect, anti-B7-H3 antibodies of the invention may be conjugated to at least one immunomodulating agent. As used herein, the term "immunomodulating agent" refers to an agent that can stimulate or modify an immune response [bind to a T cell or natural killer cell]. In one embodiment, an immunomodulating agent is an immunostimulator that enhances a subject's immune response. In another embodiment, an immunomodulating agent is an immunosuppressant that prevents or decreases a subject's immune response. An immunomodulating agent may modulate myeloid cells (monocytes, macrophages, dendritic cells, megakaryocytes and granulocytes) or lymphoid cells (T cells, B cells and natural killer (NK) cells) and any further differentiated cell thereof. Representative examples include, but are not limited to, bacillus calmette-guerin (BCG) and levamisole (Ergamisol). Other examples of immunomodulating agents that may be used in the ADCs of the invention include, but are not limited to, cancer vaccines, cytokines, and immunomodulating gene therapy (see paragraph [0977] within Benatuil et al.).
A skilled artisan (POSITA; person of ordinary skill in the art) would substitute the affibody of instant claim 1 for the antibody disclosed within Benatuil et al. This methodology is applied to the remainder of the instant claims taught by Benatuil et al.
Regarding claim 8, Bam et al., Benatuil et al., and Kruziki teach wherein the small molecule drug includes one or more radioisotopes.
Kruziki discloses the EGFR-targeted Gp2 (Gp2-EGFR) and a non-binding control were site specifically labeled with 1,4, 7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelator. In this particular experiment, the radioisotope used was 64Cu (see p59 within Kruziki). This conjugation methodology is synthetically known and could be applied by a skilled artisan (POSITA) to the anti-B7-H3 compound of instant claim 1.
Regarding claims 9-11, Bam et al., Benatuil et al., and Kruziki teach further comprising a second functional component operably coupled to anti-B7-H3 affibody.
Benatuil et al. disclose the anti-B7-H3 antibodies described herein are conjugated to at least one antiangiogenic agent (small molecule) (see paragraph [0990] within Benatuil et al.).
Regarding claim 12, Bam et al., Benatuil et al., and Kruziki teach wherein the first functional component is directly linked to the anti-B7-H3 affibody and the second functional component is directly linked to the first functional component.
Despite the fact that Benatuil et al. does not disclose this specific type of linkage with the functional components attached to the anti-B7-H3 affibody, a skilled artisan (POSITA) could link the two functional components together based on the available reactive groups (amide, ether, amine, etc.). This claim limitation is straightforward.
Regarding claim 17, Bam et al., Benatuil et al., and Kruziki teach wherein the composition is administered prior to, simultaneously with, or following chemotherapy, surgical resection of a tumor, or radiation therapy.
Benatuil et al. disclose that the term "combination therapy" or "combination" in the context of a therapeutic method (e.g., a treatment method), as used herein, refers to the administration of two or more therapeutic substances, e.g., an anti-B7-H3 antibody or ADC and an additional therapeutic agent [such as a chemotherapeutic agent]. The additional therapeutic agent may be administered concomitant with, prior to, or following the administration of the anti-B7-H3 antibody or ADC (see paragraph [0220] within Benatuil et al.).
Regarding claim 20, Bam et al., Benatuil et al., and Kruziki teach wherein the imaging component can be detected by positron emission tomography.
Kruziki discloses a 64Cu-labeled Gp2 domain for PET imaging of epidermal growth factor receptor within instant claim 8 (see p59 within Kruziki). The argument within instant claim 8 describes implementation of this instant claim limitation to the anti-B7-H3 compound of instant claim 1.
Combination of Bam et al., Benatuil et al., and Loss et al.
Regarding instant claim 7, Bam et al., Benatuil et al., and Loss et al. teach the anti-B7-H3 compound of instant claim 4, wherein the enzyme comprises sortase A.
Loss et al. disclose the conjugation of sortase A with a polypeptide (see p15, line 14 within Loss et al.) Sortase conjugation of the polypeptide and the fluorescent peptides was performed overnight at 4 °C using a ratio of 1 to 2 to 20 equivalents of polypeptide to sortase A (SrtA) to fluorescent peptide, respectively. Therefore, a skilled artisan (POSITA) could apply this to the anti-B7-H3 compound of instant claim 1 under routine experimental conditions to obtain a SrtA conjugated anti-B7-H3 compound.
Analogous Art
The Bam et al., Benatuil et al., Kruziki, and Loss et al. references are directed to the same field of endeavor as the instant claims, that is, an anti-B7-H3 compound comprising an anti-B7-H3 affibody, as disclosed within instant claim 1.
Obviousness Analysis
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the affibody conjugate disclosed by Bam et al., using the teachings of Benatuil et al., Kruziki, and Loss et al. in order to arrive at the subject matter of the instant claims.
The Bam et al., Benatuil et al., Kruziki, and Loss et al. references all have considerable overlap in the polypeptide arts. In this instance, Bam et al. supplies the template for the B7-H3 binding affibody, Benatuil et al. supplies the conjugation of chemotherapeutic agents to the base polypeptide (antibodies which can be substituted by affibody), while Kruziki, and Loss et al. supply support for the use of a chelator in PET imaging, and the linking of sortase A, respectively. All references are directed to the polypeptide arts. These citations therefore constitute analogous art under MPEP §2141.01(a). A POSITA would have reasonably consulted the four references when seeking to develop an anti-B7-H3 affibody.
Given these teachings, a POSITA would have been motivated to combine the B7-H3 binding affibody as disclosed by Bam et al., the conjugation of chemotherapeutic agents to the base polypeptide disclosed by Benatuil et al., and the support for the use of a chelator in PET imaging, and the linking of sortase A, disclosed by Kruziki and Loss et al., respectively.
The modification constitutes a simple substitution of one known element for another to obtain a predictable result [MPEP §2143(I)(B)].
The combination represents the use of a known technique to improve a similar composition in the same way [MPEP §2143(I)(C)].
The art provides a finite number of identified, predictable solutions, and the POSITA would have pursued the claimed configuration with a reasonable expectation of success [MPEP §2143(I)(E); KSR].
The combination of the B7-H3 binding affibody taught by Bam et al. along with the use of the necessary claim limitations taught by Benatuil et al., Kruziki, and Loss et al. would allow a research and development scientist (POSITA) to develop the invention taught in the instant application.
Furthermore, the additional claim limitations taught by Benatuil et al., Kruziki, and Loss et al. would have been viewed by a POSITA as routine design optimizations or known modifications for conjugated B7-H3 binding affibody compositions. The motivation to combine the four references would be to create a unique anti-B7-H3 affibody for therapeutic use within the medical arena. Implementing these features in Bam et al.’s polypeptide B7-H3 binding affibody would not require more than ordinary skill or routine experimentation.
Accordingly, the combination of Bam et al., Benatuil et al., Kruziki, and Loss et al. provides all the elements of the claimed invention. The resulting anti-B7-H3 binding affibody, constitutes no more than the predictable outcome of combining familiar prior art components, and therefore the claimed subject matter would have been obvious to a POSITA prior to the effective filing date of the invention.
Allowable Subject Matter
Claim 2 is objected to as being dependent upon a rejected base claim but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The amino acid sequences in the prior art did not match:
any one of SEQ ID NO:3 through SEQ ID NO:20 or SEQ ID NO:22 through SEQ ID NO:34;
an amino acid sequence having at least 90% sequence similarity to any one of SEQ ID NO:3 through SEQ ID NO:20 or SEQ ID NO:22 through SEQ ID NO:34; or
an amino acid sequence having at least 90% sequence identity to any one of SEQ ID NO:3 through SEQ ID NO:20 or SEQ ID NO:22 through SEQ ID NO:34.
Motivation is lacking to add any of these claim limitations to the closest reference of Bam et al. because the prior art provides no guidance to modify amino acid sequence of the B7-H3 binding affibody.
Conclusion
No claims are allowed.
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/JOHN W LIPPERT III/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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