DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election of Group I (claims 1-17, 19-23, 26-27, and 30) and the below-listed species in the reply filed on 08/20/2026 is acknowledged.
Elected Species:
A linker-payload corresponding to SYNtecan E (see Page 40 of the instant specification for full structure).
A HER3 binding moiety comprising: HCDRs 1-3 corresponding to SEQ ID NOs: 38, 42, and 45, respectively; LCDRs 1-3 corresponding to SEQ ID NOs: 63, 67, and 70, respectively; VH corresponding to SEQ ID NO: 33; VL corresponding to SEQ ID NO: 58; HC corresponding to SEQ ID NO: 80; and a LC corresponding to SEQ ID NO: 76
Additionally, because Applicant did not distinctly and specifically point out any errors in the restriction requirement, the election has been treated as an election without traverse (MPEP 818.03(a)).
Claim Status
Claims 3-17 and 20-30 have been amended, as requested in the preliminary amendment filed on 02/08/2024. Following the amendment, claims 1-30 are pending in the instant application.
Claims 18, 24-25, and 28-29 stand as withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention in the Response filed 08/20/2026, there being no allowable generic or linking claim.
Claims 1-17, 19-23, 26-27, and 30 are under examination in the instant office action.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Claims 1-17, 19-23, 26-27, and 30 have an effective filing date of January 03, 2023 corresponding to PRO 63/436,730.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 02/03/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The drawings are objected to because Figure 3A comprises text/labels that are blurry and difficult to read, and Figure 13 comprises scale bars and corresponding labels which are difficult to see/read. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
Applicant is reminded of the proper content of an abstract of the disclosure.
A patent abstract is a concise statement of the technical disclosure of the patent and should include that which is new in the art to which the invention pertains. The abstract should not refer to purported merits or speculative applications of the invention and should not compare the invention with the prior art.
If the patent is of a basic nature, the entire technical disclosure may be new in the art, and the abstract should be directed to the entire disclosure. If the patent is in the nature of an improvement in an old apparatus, process, product, or composition, the abstract should include the technical disclosure of the improvement. The abstract should also mention by way of example any preferred modifications or alternatives.
Where applicable, the abstract should include the following: (1) if a machine or apparatus, its organization and operation; (2) if an article, its method of making; (3) if a chemical compound, its identity and use; (4) if a mixture, its ingredients; (5) if a process, the steps.
Extensive mechanical and design details of an apparatus should not be included in the abstract. The abstract should be in narrative form and generally limited to a single paragraph within the range of 50 to 150 words in length.
See MPEP § 608.01(b) for guidelines for the preparation of patent abstracts.
The abstract of the disclosure is objected to because it is less than 50 words in length. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
The disclosure is further objected to because of the following informalities: SEQ ID NOs: 67 and 69 are Appropriate correction is required.
The disclosure is further objected to for the use of the terms, for example, anticalin, avimer, fynomer, atrimer, DARPin, affibody, nanobody, and affilin, which are trade names or marks used in commerce, have been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Interpretation
With regard to the sequence language in the instant claims, the following are noted:
The recitation of, for example, “having the amino acid sequence of SEQ ID NO: 40” is being interpreted such that a reference sequence meets the limitation when the reference sequence comprises or consists of an exact match to full-length SEQ ID NO: 40. This interpretation pertains to claims 13-14.
The recitation of, for example, “comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 33” is being interpreted such that a reference sequence meets the limitation when the reference sequence comprises a sequence having at least 70% overall sequence identity to full-length SEQ ID NO: 33, wherein the reference sequence may comprise mutations (e.g., additions, deletions, substitutions, and/or truncations) relative to SEQ ID NO: 33. This interpretations pertains to claims 15-17.
Claim Objections
Claims 13-14 are objected to because of the following informalities: SEQ ID NO: 69 of claim 13 and SEQ ID NO: 67 of claim 14 are indicated as "000" in the sequence listing. Applicants must delete references to the above-listed SEQ ID NOs and spell out the sequences in the claims. Appropriate correction is required.
Claim 17 is objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim should refer to other claims in the alternative only. See MPEP § 608.01(n). For the purpose of examination, claim 17 is being interpreted as depending from claim 1.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-17, 19-23, 26-27, and 30 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a WRITTEN DESCRIPTION rejection.
The claims are all generally drawn to the antigen-binding molecule that binds HER3 of claim 1, which comprising (i) a HER3-binding moiety and (ii) a linker-payload moiety comprising exatecan or a derivative thereof.
Thus, the claims identify the antigen-binding molecule only by the function of binding HER3, and a partial structure that comprises exatecan or a derivative thereof. Thus, the claims encompass a vast genus of antigen-binding molecules, comprising a vast subgenus of HER3 antigen-binding moieties defined by function only and vast subgenus of linker-payload moieties comprising exatecan or a derivative thereof.
Regarding the linker-payload subgenus, it is specifically noted that at Page 30 of the specification a linker moiety is generally defined as referring to a moiety that connects two or more elements of a compound (i.e., the linker may, by definition, be cleavable or non-cleavable). Exemplified linker components are provided at Pages 31-32, wherein Page 32 of the instant specification provides a complete, exemplary generic payload-linker structure (comprising a cleavable linker) comprising exatecan as the payload and Page 39 provides the corresponding generic antigen-binding molecule structure. The specification does not disclose any exatecan derivatives nor does the specification provide any other exemplary, generic linker structures. The only fully-specified linker structure of the instant specification is that of SYNtecan E (see Page 40 of the specification).
Regarding the binding moiety subgenus, it is noted that the instant specification discloses 17 structurally similar HER3 antibodies that function to bind HER3 (see Table of Sequences at Pages 77-85), wherein said antibodies are adequately described by all six parental CDRs (3 HCDRs and 3 LCDRs) and corresponding HCVR, LCVR, HC, and LC sequences. Thus, the instant specification discloses making 17 structurally similar antibodies that function to bind HER3 and their respective complete sets of sequences. The specification fails to sufficiently disclose any other HER3-binding moieties that possess the function of binding to HER3.
To provide adequate written description and evidence of possession of the claimed antibody genus, the instant specification can structurally describe representative HER3-binding moieties that function to bind HER3, or describe structural features common to the members of the genus, which features constitute a substantial portion of the genus. Alternatively, the specification can show that the claimed invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics (see University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) and Enzo Biochem, Inc. V. Gen-Probe Inc.).
In this case, the only factor present in the claims is a recitation of the HER3-binding moiety function, “binds HER3”. The instant specification fails to describe structural features common to the members of the HER3-binding moiety genus, which features constitute a substantial portion of the genus. A definition by function does not suffice to define the genus because it is only an indication of what the binding moiety does, rather than what it is. Other than for the 17 antibodies disclosed at Pages 77-85, the specification fails to provide the structural features coupled to the claimed functional characteristics. The instant specification fails to describe a representative number of HER3-binding moieties for the genus that functions as claimed. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus required to make the claimed antigen-binding molecule that binds HER3.
The claims broadly encompass any binding moiety that functions to bind HER3. It is specifically noted that at Page 9 of the specification, acceptable binding moieties are defined as comprising, or being derived from, antibodies and antigen-binding fragments of antibodies (which can include single domain antibodies), antigen-binding aptamers, antigen-binding peptides/polypeptides. Applicants have not established any reasonable structure-function correlation with regards to the sequences that confer the ability to bind HER3, outside of the six CDRs of the 17 adequately described HER3 antibodies. Given the well-known high level of polymorphism of antibody CDR sequences and structure, and the lack of description of any single domain antibodies, antigen-binding aptamers, or antigen-binding peptides/polypeptides, the skilled artisan would not have been in possession of the vast repertoire of HER3-binding moieties encompassed by the claimed invention.
Although Applicants may argue that it is possible to screen for HER3-binding moieties that bind HER3 and function as claimed, the court found in (Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004) that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention. “As we held in Lilly, “[a]n adequate written description of a DNA … ‘requires a precise definition, such as by structure, formula, chemical name, or physical properties,’ not a mere wish or plan for obtaining the claimed chemical invention.” 119 F.3d at 1566 (quoting Fiers, 984 F.2d at 1171). For reasons stated above, that requirement applies just as well to non-DNA (or RNA) chemical inventions.” Knowledge of screening methods provides no information about the structure of any future antibodies yet to be discovered that may function as claimed. The HER3 antigen provides no information about the structure of a binding moiety that binds to it.
Given the lack of representative examples to support the full scope of the claimed antigen-binding molecules that bind HER3, lack of reasonable structure-function correlation with regards to the HER3-binding moiety that functions to bind HER3, and the vast genus of payload-linkers, the present claims lack adequate written description. Thus, the specification does not provide an adequate written description of antigen-binding molecules comprising (i) HER3-binding moieties that function to bind HER3 and payload-linkers comprising exatecan or a derivative thereof that together yield an antigen-binding molecule that functions to bind HER3.
Claim 30 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. This is an ENABLEMENT rejection.
The Breadth of the Claims
Claim 30 is drawn to the use of an antigen-binding molecule according to claim 1 as an in vitro or in vivo diagnostic or prognostic agent. It is particularly noted that the antigen-binding molecule of claim 1 comprises a payload-linker and a HER-binding moiety, and is therefore generally directed to an antigen-binding molecule drug conjugate, which is not enabled for use in diagnostic and/or prognostic methods.
The State of the Prior Art/Level of Predictability in the Art
It is noted that there is no evidence in the prior art that antigen-binding molecule drug conjugates (e.g., ADCs) on their own are useful in diagnostic and/or prognostic methods. The field of theranostics applies, for example, ADCs in methods of predicting treatment efficacy, which is neither diagnostic nor prognostic, but requires additional products to predict treatment efficacy. Moek et. al. (The Journal of Nuclear Medicine, 2017, 58(9), 83S-90S) teaches that in theranostics, radiolabeled compounds are used to determine a treatment strategy by combining therapeutics and diagnostics in the same agent; monoclonal antibodies (mAbs) and antibody-related therapeutics represent a rapidly expanding group of cancer medicines, and theranostic approaches using these drugs in oncology are particularly interesting because antibodies are designed against specific targets on the tumor cell membrane and immune cells as well as targets in the tumor microenvironment (Abstract). In addition, these drugs are relatively easy to radiolabel, and noninvasive molecular imaging techniques, such as SPECT and PET, provide information on the whole-body distribution of radiolabeled mAbs and antibody-related therapeutics (Id.). The only molecular imaging study performed with a radiolabeled ADC involved brentuximab vedotin (Page 88S, Column 1, Third Full Paragraph). Radiolabeling of ADCs themselves is considered to increase the risk of instability of the molecule, therefore radiolabeling of the naked antibody that is part of an ADC for PET imaging is a safe alternative; naked antibody uptake is assumed to reflect ADC uptake and thus may predict whether a patient will respond to ADC therapy (Page 88S, Column 1, Last Paragraph). Biodistribution and tumor uptake were also investigated with an 89Zr-labeled anti-mesothelin naked antibody in patients subsequently treated with a mesothelin-directed ADC; the results showed uptake of the radiolabeled naked antibody in pancreatic and ovarian tumors (Page 88S, Column 2, First Partial Paragraph). A carcinoembryonic cell adhesion molecule 6–directed ADC was administered to monkeys and assessed biodistribution with a 64Cu-labeled anti–carcinoembryonic cell adhesion molecule 6 naked mAb; the highest tracer uptake was seen in the bone marrow, and neutropenia and anemia occurred in all animals treated with this ADC, suggesting that tissue-specific toxicity can be predicted by antibody tracer uptake (Id.). In 2 clinical studies, radiolabeled trastuzumab is being evaluated as a biomarker for predicting the response to T-DM1 treatment for HER2-positive metastatic breast cancer; the ZEPHIR trial is designed to prospectively investigate the role of pretreatment 89Zrtrastuzumab PET combined with early response assessment using 18F-FDG PET in the selection of patients who have metastatic HER2-positive tumors and are unlikely to benefit from T-DM1 treatment, and the same approach is being used to evaluate whether 64Cu-labeled trastuzumab can predict a response to T-DM1 therapy (Page 88S, Column 2, First Full Paragraph).
The Amount of Direction Provided by the Inventor/Existence of Working Examples
It is specifically noted that the instant specification provides no working examples, nor does the specification disclose any methods detailing using an antigen-binding molecule of the invention, on its own, as either a diagnostic or a prognostic agent. Examples, 3.1, 3.2, 3.3, 3.5, and 3.6 are all generally drawn to detecting antigen-binding molecules of the invention (e.g., to evaluate binding and/or internalization as part of characterizing the antigen-binding molecules, but theses methods of detection all require additional agents (e.g., detectable labels, detectable secondary antibodies, etc.) and are not diagnostic and/or prognostic methods.
In view of the lack of the predictability of the art to which the invention pertains as evidenced by the art above, the lack of guidance and direction provided by Applicant, and the absence of working examples, undue experimentation would be required to use an antigen-binding molecule according to instant claim 1 as an in vitro or in vivo diagnostic and/or prognostic agent as claimed.
Claims 21-23 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 using antigen-binding molecules for medical treatment (i.e., treatment of HER3-expressing cancer), does not reasonably provide enablement for use in the prophylaxis/prevention of cancer, diagnostic or prognostic methods, nor the treatment of any cancer. 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. This is a SCOPE OF ENABLEMENT rejection.
The Breadth of the Claims
Claim 21 is drawn to an antigen-binding molecule according to claim 1, for use in a medical treatment or prophylaxis, or in a method of diagnosis or prognosis. Claim 22 is drawn to an antigen-binding molecule of claim 1 for use in treating or preventing a cancer. Claim 23 is drawn to use of an antigen-binding molecule according to claim 1, in the manufacture of a medicament for treating or preventing a cancer. The full scope of these claims is not enabled.
The State of the Prior Art/Level of Predictability in the Art
It is noted that there is no evidence in the prior art that antigen-binding molecule drug conjugates (e.g., ADCs) on their own are useful in diagnostic and/or prognostic methods. The field of theranostics applies, for example, ADCs in methods of predicting treatment efficacy, which is neither diagnostic nor prognostic, but requires additional products to predict treatment efficacy. Moek et. al. (The Journal of Nuclear Medicine, 2017, 58(9), 83S-90S) teaches that in theranostics, radiolabeled compounds are used to determine a treatment strategy by combining therapeutics and diagnostics in the same agent; monoclonal antibodies (mAbs) and antibody-related therapeutics represent a rapidly expanding group of cancer medicines, and theranostic approaches using these drugs in oncology are particularly interesting because antibodies are designed against specific targets on the tumor cell membrane and immune cells as well as targets in the tumor microenvironment (Abstract). In addition, these drugs are relatively easy to radiolabel, and noninvasive molecular imaging techniques, such as SPECT and PET, provide information on the whole-body distribution of radiolabeled mAbs and antibody-related therapeutics (Id.). The only molecular imaging study performed with a radiolabeled ADC involved brentuximab vedotin (Page 88S, Column 1, Third Full Paragraph). Radiolabeling of ADCs themselves is considered to increase the risk of instability of the molecule, therefore radiolabeling of the naked antibody that is part of an ADC for PET imaging is a safe alternative; naked antibody uptake is assumed to reflect ADC uptake and thus may predict whether a patient will respond to ADC therapy (Page 88S, Column 1, Last Paragraph). Biodistribution and tumor uptake were also investigated with an 89Zr-labeled anti-mesothelin naked antibody in patients subsequently treated with a mesothelin-directed ADC; the results showed uptake of the radiolabeled naked antibody in pancreatic and ovarian tumors (Page 88S, Column 2, First Partial Paragraph). A carcinoembryonic cell adhesion molecule 6–directed ADC was administered to monkeys and assessed biodistribution with a 64Cu-labeled anti–carcinoembryonic cell adhesion molecule 6 naked mAb; the highest tracer uptake was seen in the bone marrow, and neutropenia and anemia occurred in all animals treated with this ADC, suggesting that tissue-specific toxicity can be predicted by antibody tracer uptake (Id.). In 2 clinical studies, radiolabeled trastuzumab is being evaluated as a biomarker for predicting the response to T-DM1 treatment for HER2-positive metastatic breast cancer; the ZEPHIR trial is designed to prospectively investigate the role of pretreatment 89Zrtrastuzumab PET combined with early response assessment using 18F-FDG PET in the selection of patients who have metastatic HER2-positive tumors and are unlikely to benefit from T-DM1 treatment, and the same approach is being used to evaluate whether 64Cu-labeled trastuzumab can predict a response to T-DM1 therapy (Page 88S, Column 2, First Full Paragraph).
No material has been found to date that has been shown to or would be expected to prevent cancer, and there is no working example, prior art, or any evidence that would provide the skilled artisan with any predictable guidance to use the claimed invention. It would be reasonable to conclude the claimed invention is not enabled.
Reasonable guidance with respect to preventing any cancer relies on quantitative analysis from defined populations that have been successfully pre-screened and are predisposed to particular types of cancer. This type of data might be derived from widespread genetic analysis, cancer clusters, or family histories. The essential element towards the validation of a preventive therapeutic is the ability to test the drug on subjects monitored in advance of clinical cancer and link those results with subsequent histological confirmation of the presence or absence of disease. This irrefutable link between antecedent drug and subsequent knowledge of the prevention of the disease is the essence of a valid preventive agent. Further, a preventive administration also must assume that the therapeutic will be safe and tolerable for anyone susceptible to the disease.
The vaccine art teaches that compositions comprising some tumor associated antigens are effective in treatment of cancer through generation of immunogenic response to the tumor antigen (see for example, Komenaka et. al., Clinics in Dermatology, 2004, Vol. 22, Pg. 251-265, specifically page 257). However, nowhere in the art does it show that tumor antigens are effective at preventing cancer. Evans et. al. (Q. J. Med 1999: 92: 299-307) teach that vaccines against cancer are not fully established, and it is stated that adjuvant therapy to prevent or delay disease still needs experimentation. Evans et. al. further state that such cancer vaccines are at best used as a therapeutic and not as a prophylactic and that “the notion that cancer vaccines will replace standard therapeutic strategies in malignant disease still belongs to the realm of fiction” (see page 303 last paragraph).
In some cases, it is known that certain cancers arise from a single cause. This cause can be viral as in the case of cervical cancer, caused predominantly by persistent cervical infection with human papillomavirus (HPV) (Schiffman et. al., The New England Journal of Medicine, Vo. 353, No. 20, Pg. 2101-2104, 2005). Schiffman et. al. teach that primary prevention through vaccination against HPV might be possible in young women (Pg. 2101, Column 3, Paragraph, first partial). However, they also teach that vaccine evaluations are ongoing (Pg. 2103, Column 3, Paragraph, first full). In addition, the most promising vaccines designed against HPV types 16 and 18 would only prevent 70 percent of cervical cancer cases at best (Pg. 2103, Column 2, Paragraph, first full). Therefore, there is still no vaccine that can definitively prevent a cancer. Current evidence points only to the potential of future prophylactic agents.
The art of small molecule chemotherapeutics teach that some molecules successful at treating cancers can also reduce risk. Cuzick et. al. (The Lancet, Vol. 361, Pg. 296-300, 2003) teach that tamoxifen can reduce the risk of ER-positive breast cancer but cannot be recommended as a preventive agent (Pg. 299, Column 2, Paragraph, first). The reason it cannot be recommended centers around the need for continued research into specific subgroups of high-risk but healthy women for whom the risk-benefit ratio is sufficiently positive to recommend prophylactic tamoxifen treatment (Pg. 299, Column 2, Paragraph, first).
With respect to peptide-based cancer prevention agents, the art currently does not recognize a definitive example though promising candidates are present. Hernandez-Ledesma (Peptides, Vol. 30, Pg. 426-430, 2009) teaches that lunasin, a peptide discovered in soy has demonstrated cancer-preventative capacity in vitro and mouse models (Abstract). The authors define it as a perfect candidate to exert an in vivo cancer-preventive activity but more research is required to establish it in this role (Pg. 429, Column 2, Paragraph, first partial).
Therefore, the art has only recognized the treatment of a cancer.
Furthermore, cancer treatment is highly unpredictable. Even though the EGFR was identified in some cancers as a drug target, the in vitro (i.e., in a test tube) effectiveness of a drug in inhibiting the EGFR turned out to be a poor proxy for how effective that drug actually was in treating cancer in vivo (i.e., in the body). Numerous EGFR inhibitors that showed promising in vitro activity failed for a variety of reasons. These included poor pharmacokinetics due to poor absorption or rapid metabolism ( [**2]or both), undesirable drug-drug interactions, drug toxicity due to drug binding onto healthy cells, drug toxicity due to binding onto other receptors, and metabolite toxicity. Some drug candidates were limited by one or more of these shortcomings, further underscoring the unpredictable nature of cancer treatment. OSI Pharmaceuticals , LLc, v. Apotex Inc, 939 F.3d 1375, 2019.
The state of the art at the time of filing was such that the functionality of an anti-tumor antibody was dependent on both its action on the intended target and whether or not the modulation of said target had an effect on any particular cancer cell. Baxevanis (Expert Opinion: Drug Discovery, Vol. 3, No. 4, Pg. 441-452, 2008) teaches that, depending on the epitope against which an antibody is directed, antibody-antigen binding may neutralize circulating targets or cell surface receptors (Pg. 444, Column 1, Paragraph, first full). They teach that presently available monoclonal antibodies (mAbs) are directed against molecular targets that are expressed on tumor cells or play an important role in the tumor microenvironment (Pg. 444, Column 1, Paragraph, first full; Table 1). Table 1 lists currently available antibodies for use in clinical oncology and illustrates that each antibody has a specific target (Table 1, Column 2) and a specific set of cancers for which it has therapeutic utility (Table 1, Column 4). Taken together, the art does not recognize a single antibody that is an effective therapy against all tumors.
To further illustrate this point, Baxevanis goes on to explain the functionality of the more commonly used therapeutic antibodies. Trastuzumab targets the receptor HER-2 (HER-2/neu) which is overexpressed in some breast cancers and so is a viable treatment for said breast cancers (Pg. 444, Column 2, Lines 19-24). The basis of this variability in treatment response is due to the fact that the growth inhibitory effect of anti-HER-2 is dependent on the extent of HER-2 overexpression (pg. 443, Column 1, Paragraph, first partial). Because only a portion of breast cancer patients overexpress HER-2 and respond to trastuzumab, the selection of suitable patients is important (Pg. 445, Column 1, Lines 13-15).
Rituximab is an antibody against CD20 antigen, which is expressed on most B cells including B-cell lymphomas (Pg. 445, Column 1, Lines 36-38). Therefore, it is used to treat B-cell lymphomas (Pg. 444, Table 1). It has been used to treat patients with relapsed or refractory low-grade non-Hodgkin's lymphoma (a B-cell lymphoma) (Pg. 445, Column 1, Lines 41-50).
In contrast to trastuzumab and rituximab, some therapeutic antibodies show efficacy in treating multiple cancers. This stems from the fact that their target antigen is associated with multiple cancers. Cetuximab is an anti-EGFR antibody (Pg. 445, Column 1, Lines 19-20). EGFR is overexpressed in many epithelial cell tumors (Pg. 445, Column 1, Lines 20-21). The association of EGFR overexpression with multiple cell types gives cetuximab a broader therapeutic applicability than trastuzumab (Pg. 444, Table 1) as it is used to treat both renal and head and neck cancers.
As a final point, the art also recognizes that the function of the therapeutic antibody must correlate with an effect on its target conducive to tumor growth inhibition or tumor lysis, resulting in patient benefit. Anti-HER-2 antibodies, like Trastuzumab, disrupt HER-2 catalytic activity (Pg. 443, Column 1, Paragraph, first partial, Sentence, ultimate; Table 1, Column 3, (S) referring to decreased protein signaling (activity); and Pg. 444, Column 2, Lines 19-22). Cetuximab also inhibits its target’s activity as it prevents EGFR dimerization and subsequent activation via phosphorylation (Pg. 445, Column 1, Lines 23-25). Since both HER-2 and EGFR activity support growth of cancer cells in which they are overexpressed, their inhibition is therapeutic to patients. Rituximab causes tumor cell lysis by antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) (Pg. 445, Column 1, Lines 38-39) and so its therapeutic benefit is provided by specifically inducing cancer cell death.
The teachings of Baxevanis discussed above underline the requirement of a link between an inhibitory antibody’s target and specific cancers to make therapy of said cancer predictable to one of ordinary skill in the art.
The Amount of Direction Provided by the Inventor/Existence of Working Examples
It is specifically noted that the instant specification provides no working examples, nor does the specification disclose any methods detailing using an antigen-binding molecule of the invention, on its own, as either a diagnostic or a prognostic agent. Examples, 3.1, 3.2, 3.3, 3.5, and 3.6 are all generally drawn to detecting antigen-binding molecules of the invention (e.g., to evaluate binding and/or internalization as part of characterizing the antigen-binding molecules, but these methods of detection all require additional agents (e.g., detectable labels, detectable secondary antibodies, etc.) and are not diagnostic and/or prognostic methods. Furthermore, the specification provides no working examples of prophylactic treatment/prevention of, for example, cancer. The only working examples provided are for medical treatments, specifically in HER3-expressing cancers/tumors, as provided in Example 4.
In view of the lack of the predictability of the art to which the invention pertains as evidenced by the art above, the lack of guidance and direction provided by Applicant, and the absence of working examples, undue experimentation would be required to use an antigen-binding molecule according to instant claim 1 in methods of (i) treating any cancer, (ii) prophylaxis/prevention, (iii) diagnostics, (iv) prognosis, and/or (v) manufacturing a medicament for treating any cancer/preventing cancer commensurate in scope with the instant claims.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 2, 4, 6, 8-9, 23, 26, and 30 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
With regard to claims 2, 4, 6, and 8-9, the claims are considered to be indefinite as it is unclear what the recited structures (i.e., structures A, B, E, D, and E, respectively) are connected to and therefor how they are incorporated into the antigen-binding molecule of claim 1. For example, the recited structures in each claim comprise wavy lines, which one of ordinary skill in the art would understand as being a point of connection to another atom/structural element. Thus, one of ordinary skill in the art could not reasonably ascertain the metes and bounds of claims 2, 4, 6, and 8-9 because it is unclear as to what the recited structures are connected to at all indicated points of connection, and therefore it is unclear how they are incorporated into the antigen-binding molecule of claim 1.
With regard to claims 23, 26, and 30, it is noted that the claims are “use” claims, which attempt to claim a process/processes without setting forth any steps involved in the process; because the claims merely recite a use without any active, positive steps delimiting how this use is actually practiced. Ex parte Erlich, 3 USPQ2d 1011 (Bd. Pat. App. & Inter. 1986). See MPEP 2173.05(q). Thus, claims 23, 26, and 30 are considered to be indefinite.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 21-22 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claims 21-22 each fail to further limit claim 1 from which they depend; each of claims 21-22 recite an antigen-binding molecule of claim 1 for use in, respectively: (i) a method of medical treatment or prophylaxis, or in a method of diagnosis or prevention and (ii) in treating or preventing a cancer. The recited uses are merely intended uses, which do not serve to further limit the antigen-binding molecule of claim 1. The recited intended uses do not impart a structural difference on the antigen-binding molecule of claim 1 and thus claims 21-22 are not further limiting. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 23, 26, and 30 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter. The claim(s) does/do not fall within at least one of the four categories of patent eligible subject matter because they are “use” claims. MPEP 2173.05(q) recites that “use” claims that do not purport to claim a process, machine, manufacture, or composition of matter fail to comply with 35 U.S.C. 101. In re Moreton, 288 F.2d 708, 709, 129 USPQ 227, 228 (CCPA 1961)("one cannot claim a new use per se, because it is not among the categories of patentable inventions specified in 35 U.S.C. § 101"). The claims attempt to claim a process/processes without setting forth any steps involved in the process, and as such are not proper process claims under 35 U.S.C. § 101, failing to fall within at least one of the four categories of patent eligible subject matter.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 21-23 and 26-27 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by non-patent literature by Hashimoto et. al. (Clin Cancer Res, 2019, 25(23), 7151-7161; herein after referred to as "Hashimoto").
Hashimoto teaches that HER3 is a compelling target for cancer treatment, wherein at the time the reference was published there was no HER3-targeted therapy clinically available; the authors produced U3-1402 (also known in the art as HER3-DXd and patritumab deruxtecan), an anti-HER3 antibody–drug conjugate with a topoisomerase I inhibitor exatecan derivative (DXd), and systematically investigated its targeted drug delivery potential and antitumor activity in preclinical models (Abstract, Purpose). The structure of U3-1402 is shown in Figure 1A at Page 7154, and is reproduced below:
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U3-1402 is an ADC comprising the fully human anti-HER3 monoclonal IgG1 antibody patritumab, tetra-peptide based linker, and an exatecan-derivative topoisomerase I inhibitor DXd
(Fig. 1A), wherein patritumab was conjugated with our linker-payload system that is designed to be cleaved by lysosomal enzymes (i.e., the linker comprises a cleavable linker moiety) resulting in release of the payload DXd; theoretically, eight cysteine residues of antibody are available for linker conjugation, and hydrophobic interaction chromatography showed a homogeneous drug distribution and the DAR of synthesized U3-1402 was observed to be approximately eight (Fig. 1B) (Page 7153, Column 2, Results, HER3-Targeting ADC U3-1402). To confirm the target specificity of U3-1402, the authors assessed its binding activity against human HER family proteins; the results of ELISA revealed that U3-1402 bound to human HER3 recombinant proteins, while there was no binding detected against other human HER family proteins EGFR, HER2, and HER4 (Fig. 1C) (Id.). Furthermore, the cytotoxic activity of U3-1402 was evaluated
under three-dimensional cell culture conditions using HER3-positive human cancer HCC1569 and HER3-negative human cancer C-33A cells (Supplementary Fig. S1A); both HCC1569 and
C-33A cells were susceptible to DXd with IC50 of 1.3 nmol/L and 4.2 nmol/L, respectively, whereas U3-1402 markedly decreased cell viability in only HCC1569 cells with IC50 of 0.4 nmol/L (Fig. 1D), indicating that U3-1402 exerts HER3-dependent cytotoxic activity (Page 7154, Column 1, First Paragraph). To assess the targeted delivery potential of U3-1402, cell surface binding, internalization, trafficking, and payload release were investigated in eight cancer cell lines with various HER3 expression levels, along with cell growth inhibition activity; among all of the data obtained for internalization, trafficking, and payload release, the mean values at 6 hours were representatively plotted against cell surface binding level, as shown in Fig. 3A–C. U3-1402 bound to the cell surface in HER3-positive cell lines (HCC1569, SK-BR-3, MDA-MB-175VII, MDA-MB-453, MDA-MB-361, OVCAR-8, and JIMT-1), but not in the HER3-negative cell line MDA-MB-231 (Fig. 3A), and overall each of the intracellular processes tended to be correlated with the surface binding level, although MDA-MB-175VII tended to be an outlier in the linear regression (Fig. 3A–C) (Page 7154, Column 2, HER3-Mediated Molecular Dynamics of U3-1402 in Eight Cancer Cell Lines). To determine whether U3-1402 exerts antitumor activity in vivo, the authors used a human breast cancer cell line MDA-MB-453 xenograft model, featuring tumors with high HER3 expression (Fig. 6B); mice bearing tumors were administered intravenously with an escalating dose of U3-1402 at 0.375, 0.75, 1.5, 3, and 6 mg/kg, and the treatment with U3-1402 at 0.75, 1.5, 3, and 6 mg/kg significantly inhibited tumor growth with TGI indices of 45%, 68%, 82%, and 94%, respectively, compared with the control group at 21 days after administration (P < 0.001; Fig. 5A) (Page 7156, Column 1, In Vivo Antitumor Activity of U3-1402). U3-1402 demonstrated potent antitumor activity against HER3-expressing tumors through HER3-specific payload delivery via efficient intracellular internalization. U3-1402 may
offer a promising treatment option for patients with HER3-expressing tumors (Page 7160, Column 1, Second Paragraph). Thus. Hashimoto teaches an antigen-binding molecule that comprises a HER3-binding moiety and a linker-payload comprising exatecan and a cleavable linker moiety, wherein said antigen-binding molecule, its use in the manufacture of medicament, notably for treating HER3-expressing cancers, killing HER3-expressing cells, and forming an in vitro complex comprising the antigen-binding molecule bound to HER3. Thus, Hashimoto anticipates claims 21-23 and 26-27.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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 1-17, 19-23, and 26-27 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2022/058395 A1 (herein after referred to as "Hoogenboom") in view of non-patent literature by Hashimoto et. al. (Clin Cancer Res, 2019, 25(23), 7151-7161; herein after referred to as "Hashimoto") and US 2019/0300624 A1 (herein after referred to as "Boyd-Kirkup").
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Hoogenboom teaches that linkers with a cleavable peptide-PABC system are highly suitable for metal-free click or thiol conjugation of exatecan to antibodies, resulting in antibody-exatecan conjugates that show no or negligible aggregation propensity; the resulting antibody-drug conjugates (ADCs) were found to display significant in vivo efficacy, and as such, the inventors have for the first time been able to prepare an ADC with exatecan payloads that exhibits efficacy in the same order of magnitude as the most efficacious known antibody-camptothecin conjugates, while showing no aggregation at all (Paragraph 0025). The invention is drawn to an antibody-drug conjugate, having structure (1) (Paragraph 0073, Pages 15-16):
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The ADCs according to the invention may more specifically be of structure (1a) (Page 18):
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The ADCs of the invention may also be of structure (1b) (Page 19):
An especially preferred embodiment includes ADCs of structure (1d) (Pages 43-44):
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It is specifically noted that (Z38) corresponds to the structure reproduced below (Page 36):
Regarding structures (1b) and (1d), it is specifically noted that Z connects antibody AB with the exatecan payload, via a linker, and connecting group Z is a moiety that is obtainable by a metal-free click reaction or by thiol ligation wherein the skilled person understands that the exact nature
of Z depends on the nature of F and Q (which react to form Z) (Paragraph 0096). In an especially preferred embodiment, Q contains a cyclic alkyne moiety and F is an azide, and Z contains a triazole moiety that is formed by 1,3-dipolar cycloaddition of the alkyne moiety with
the azide moiety (Paragraph 0099); Su is a monosaccharide containing F (Paragraph 0115) wherein F is reactive towards a cyclic alkene, cyclic alkyne, and is typically selected
from the group consisting of azide, tetrazine, triazine, nitrone, nitrile oxide, nitrile imine, diazo
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compound, ortho-quinone, dioxothiophene and sydnone (Paragraph 0172). Thus, in the especially preferred embodiment of structure (1d), Su is GalNAc that further comprises an azide reactive group, which is capable of reacting with a click probe Q (i.e., Q38; R15, R18, and R19 defined above):
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to yield connecting group Z (i.e., Z38); this mode of conjugation is exemplified in Figure 9 as reproduced below:
which specifically shows the structures of ADCs obtained by enzymatic remodeling of N-glycan (for introduction of azido-sugar) followed by metal-free click conjugation with linker-drugs 1 or 2, wherein remodeling and conjugation with 1 or 2 at the native N297 glycan only, provides ADC1a or ADC2, respectively, both DAR4, and remodeling and conjugation with 1 at the native N297 glycan plus an additionally engineered N-glycosylation site (e.g. HC-L201 N), provides ADC1b, DAR8 (Paragraph 0037). It is specifically noted that the ADC1a reads directly on the drug-linker structures of instant claims 1-11 and 19 (wherein the drug-linker corresponds to SYNtecan E and wherein the antigen binding domain (i.e., antibody) comprises an Fc region and is conjugated to the drug-linker at an azido group provided in a 6-azido-6-deoxy-N-acetylgalactosamine residue of an N-glycan linked to N297 of a CH2 domain of the Fc region). Furthermore, it is noted that Hoogenboom also teaches that the invention further concerns a method for the treatment of a specific disease in a subject in need thereof (i.e., using the conjugates of invention in methods of treatment), comprising the administration of the conjugate according to the invention; the specific disease may be selected from cancer and an autoimmune disease, preferably the disease is cancer, and the subject in need thereof is typically a cancer patient (Paragraph 0178). The use of antibody-drug conjugates is well-known in such treatments, especially in the field of cancer treatment, and the conjugates according to the invention are especially suited in this respect; in the method according to this aspect, the conjugate is typically administered in a therapeutically effective amount (Id.). The invention further concerns a pharmaceutical composition comprising the antibody-payload conjugate according to the invention and a pharmaceutically acceptable carrier (i.e., using the conjugates of the invention in the manufacture of a medicament for treatment) (Paragraph 0180).
However, while Hoogenboom teaches that ADCs based on deruxtecan may be beneficial in treating tumors with target heterogeneity, and ADCs derived by cysteine conjugation with deruxtecan showed high stability, enabling high drug loading up to DAR8, as has been applied in three ADC programs, i.e. DS-8201 a (ADC targeting HER2, currently marketed as Enhertu), U3-1402a (ADC targeting HER3) and DS-6157a (ADC targeting GRP20), Hoogenboom does not explicitly disclose (i) conjugating the drug-linkers of the invention to a HER3 antigen binding domain, specifically a HER3 antigen binding domain comprising the instantly claimed sequences, nor compositions/uses of a conjugate thereof (ii) in vitro complexes comprising the conjugate bound to HER3, nor (iii) the use of such a conjugate for depleting/killing HER3 expressing cells. These deficiencies are remedied by Hashimoto and Boyd-Kirkup.
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Hashimoto teaches Hashimoto teaches that HER3 is a compelling target for cancer treatment, wherein at the time the reference was published there was no HER3-targeted therapy clinically available; the authors produced U3-1402 (also known in the art as HER3-DXd and patritumab deruxtecan), an anti-HER3 antibody–drug conjugate with a topoisomerase I inhibitor exatecan derivative (DXd), and systematically investigated its targeted drug delivery potential and antitumor activity in preclinical models (Abstract, Purpose). The structure of U3-1402 is shown in Figure 1A at Page 7154, and is reproduced below:
U3-1402 is an ADC comprising the fully human anti-HER3 monoclonal IgG1 antibody patritumab, tetra-peptide based linker, and an exatecan-derivative topoisomerase I inhibitor DXd
(Fig. 1A), wherein patritumab was conjugated with our linker-payload system that is designed to be cleaved by lysosomal enzymes (i.e., the linker comprises a cleavable linker moiety) resulting in release of the payload DXd; theoretically, eight cysteine residues of antibody are available for linker conjugation, and hydrophobic interaction chromatography showed a homogeneous drug distribution and the DAR of synthesized U3-1402 was observed to be approximately eight (Fig. 1B) (Page 7153, Column 2, Results, HER3-Targeting ADC U3-1402). To confirm the target specificity of U3-1402, the authors assessed its binding activity against human HER family proteins; the results of ELISA revealed that U3-1402 bound to human HER3 recombinant proteins, while there was no binding detected against other human HER family proteins EGFR, HER2, and HER4 (Fig. 1C) (Id.). Furthermore, the cytotoxic activity of U3-1402 was evaluated
under three-dimensional cell culture conditions using HER3-positive human cancer HCC1569 and HER3-negative human cancer C-33A cells (Supplementary Fig. S1A); both HCC1569 and
C-33A cells were susceptible to DXd with IC50 of 1.3 nmol/L and 4.2 nmol/L, respectively, whereas U3-1402 markedly decreased cell viability in only HCC1569 cells with IC50 of 0.4 nmol/L (Fig. 1D), indicating that U3-1402 exerts HER3-dependent cytotoxic activity (Page 7154, Column 1, First Paragraph). To assess the targeted delivery potential of U3-1402, cell surface binding, internalization, trafficking, and payload release were investigated in eight cancer cell lines with various HER3 expression levels, along with cell growth inhibition activity; among all of the data obtained for internalization, trafficking, and payload release, the mean values at 6 hours were representatively plotted against cell surface binding level, as shown in Fig. 3A–C. U3-1402 bound to the cell surface in HER3-positive cell lines (HCC1569, SK-BR-3, MDA-MB-175VII, MDA-MB-453, MDA-MB-361, OVCAR-8, and JIMT-1), but not in the HER3-negative cell line MDA-MB-231 (Fig. 3A), and overall each of the intracellular processes tended to be correlated with the surface binding level, although MDA-MB-175VII tended to be an outlier in the linear regression (Fig. 3A–C) (Page 7154, Column 2, HER3-Mediated Molecular Dynamics of U3-1402 in Eight Cancer Cell Lines). To determine whether U3-1402 exerts antitumor activity in vivo, the authors used a human breast cancer cell line MDA-MB-453 xenograft model, featuring tumors with high HER3 expression (Fig. 6B); mice bearing tumors were administered intravenously with an escalating dose of U3-1402 at 0.375, 0.75, 1.5, 3, and 6 mg/kg, and the treatment with U3-1402 at 0.75, 1.5, 3, and 6 mg/kg significantly inhibited tumor growth with TGI indices of 45%, 68%, 82%, and 94%, respectively, compared with the control group at 21 days after administration (P < 0.001; Fig. 5A) (Page 7156, Column 1, In Vivo Antitumor Activity of U3-1402). U3-1402 demonstrated potent antitumor activity against HER3-expressing tumors through HER3-specific payload delivery via efficient intracellular internalization. U3-1402 may offer a promising treatment option for patients with HER3-expressing tumors (Page 7160, Column 1, Second Paragraph).
Boyd-Kirkup teaches an antigen-binding molecule, optionally isolated, which is
capable of binding to HER3 in extracellular region subdomain II (Paragraph 0005). In some embodiments, the antigen-binding molecule is capable of binding to a polypeptide comprising or consisting of SEQ ID NO: 16 (Paragraph 0007); it is specifically noted that Boyd-Kirkup SEQ ID NO: 16 residues 35-52 are an exact match to instant SEQ ID NO: 77. In some embodiments the antigen-binding molecule of the present invention comprises one or more regions of an immunoglobulin heavy chain constant sequence; in some embodiments the immunoglobulin heavy chain constant sequence is, or is derived from, the heavy chain constant sequence of an IgG (e.g. IgG1, IgG2, IgG3, IgG4), IgA (e.g. IgA1, IgA2), IgD, IgE or IgM (Paragraph 0659). In particular embodiments the antigen-binding molecule comprises: (i) a VH region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:36; and a VL region comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO:83 (Paragraphs 0224-0226). It is noted that Boyd-Kirkup SEQ ID NOs: 36 and 83 (i) are exact matches to instant SEQ ID NOs: 33 and 58, respectively, and (ii) read on instant SEQ ID NOs: 40/43/48 and 66/69/74, respectively, such that they comprise exact matches to instant SEQ ID NOs: 38/42/45 and 63/67/70, respectively. In some embodiments, the antigen-binding molecule comprises or consists of (i) two polypeptides comprising, or consisting of, an amino acid sequence having at least 70%, preferably one of 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to the amino acid sequence of NO:206; and (ii) two polypeptides comprising, or consisting of, an amino acid sequence having at least 70%, preferably one of 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to the amino acid sequence of NO:207 (Paragraphs 0832-0834). It is noted that Boyd-Kirkup SEQ ID NO: 207 is an exact match to instant SEQ ID NO: 76, and Boyd-Kirkup SEQ ID NO: 206 reads on instant SEQ ID NO: 75 wherein it is a 99.6% match to instant SEQ ID NO: 80. The alignment of Boyd-Kirkup SEQ ID NO: 206 (designated as Db) with instant SEQ ID NO: 80 (designated as Qy) is shown below:
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However, it is noted that Boyd-Kirkup teaches that In embodiments in accordance with the present invention in which one or more amino acids are substituted with another amino acid, the substitutions may conservative substitutions, for example according to the table reproduced below, wherein in some embodiments amino acids in the same block in the middle column are substituted and in some embodiments, amino acids in the same line in the rightmost column are substituted (Paragraph 0656):
In some embodiments, substitution(s) may be functionally conservative, wherein the substitution may not affect (or may not substantially affect) one or more functional properties (e.g., target binding) of the antigen-binding molecule comprising the substitution as compared to the equivalent unsubstituted molecule (Paragraph 0657). Thus, one of ordinary skill in the art would recognize that L237 and L238 of Boyd-Kirkup SEQ ID NO: 206 could each reasonably be substituted for alanine to arrive at A237 and A238, and thus the exact sequence of instant SEQ ID NO: 80, wherein such a substitution would reasonably be expected to be functionally conservative as suggested by Boyd-Kirkup. The invention also provides: (i) an antigen-binding molecule, a CAR, a nucleic acid or a plurality of nucleic acids, an expression vector or a plurality of expression vectors, a cell, or a composition according to the present invention for use in a method of treatment of a cancer (Paragraph 0245); (ii) the use of an antigen-binding molecule, a CAR, a nucleic acid or a plurality of nucleic acids, an expression vector or a plurality of expression vectors, a cell, or a composition according to the present invention in the manufacture of a medicament for use in a method of treatment of a cancer (Paragraph 0246); and (iii) a method of treating or preventing a cancer, comprising administering to a subject a therapeutically or prophylactically effective amount of an antigen-binding molecule, a CAR, a nucleic acid or a plurality of nucleic acids, an expression vector or a plurality of expression vectors, a cell, or a composition according to the present invention (Paragraph 0247). The invention further comprises an in vitro complex, optionally isolated, comprising an antigen-binding molecule according to the present invention bound to HER3 (Paragraph 0250). In some embodiments the antigen-binding molecules of the invention are conjugated to a chemical moiety, wherein the chemical moiety may be a moiety for providing a therapeutic effect and, in some embodiments, the chemical moiety may be a drug moiety (e.g. a cytotoxic agent) (Paragraph 0797). In some embodiments, the antigen-binding molecule of the invention is capable of increasing killing of HER3-expressing cells (Paragraph 0937).
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It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify conjugate structure (1d) of Hoogenboom, wherein e = 0, Su is GalNAc, Z is (Z38), m = 2, p = 1, q = 1, R17 is CH3, A is 1,4-phenyl, R21 is H (reading directly on the instantly elected SYNtecan E structure):
such that the antibody of the conjugate is a HER3-specific antibody comprising the instantly claimed sequences, as taught by Boyd-Kirkup, wherein one of ordinary skill in the art would have been motivated to make such a modification based on the teachings of both Hoogenboom and Hashimoto that HER3-directed exatecan-comprising ADCs are known and established in the art, and are useful as pharmaceutical compositions/medicaments in therapeutic methods for treating HER3-expressing cancer. One of ordinary skill in the art would have a reasonable expectation of success that the resulting ADC would be (i) HER3-specific, (ii) capable of releasing the drug via cleavage of the linker, and (iii) be useful in the treatment of HER3-expressing cancers as suggested by Hoogenboom, Hashimoto, and Boyd-Kirkup.
Conclusion
Claims 1-30 are pending. Claims 18, 24-25, and 28-29 are withdrawn. Claims 1-17, 19-23, 26-27, and 30 are rejected. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALYSSA RAE STONEBRAKER whose telephone number is (571)270-0863. The examiner can normally be reached Monday-Thursday 7:00 am - 5:00 pm.
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/ALYSSA RAE STONEBRAKER/Examiner, Art Unit 1642
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