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 1-21 are pending in the instant application. Claims 1-21 are under examination in the instant office action.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. Additionally, it is noted that the certified copies of the foreign priority documents are in English, and as such the claim to foreign priority has been perfected.
Claims 1-21 have an effective filing date of October 18, 2022 corresponding to EP22202240.2.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 03/29/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
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 it contains an embedded hyperlink and/or other form of browser-executable code at Page 3. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code (e.g., https://, www., .org, .com, .gov, .html, etc.); references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The disclosure is further objected to for the use of the terms, for example, PROTACs, nanobodies, XEVO, FACS, ÄKTA Pure, pHrodo, and Tween, 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 term should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms.
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 application, the following are noted:
The recitation of, for example, “having an amino acid sequence with at least 80% identity to SEQ ID NO: 3” is being interpreted such that in order for a reference sequence to meet the limitation, said reference sequence must comprise or consist of a sequence that is at least 80% identical to full-length SEQ ID NO: 3. Thus, truncations and/or mutations are permissible at any position relative to SEQ ID NO: 3 so long as overall the reference sequence is at least 80% identical to full-length SEQ ID NO: 3. This interpretation pertains to claim 2.
The recitation of, for example, “a light chain comprising SEQ ID NO: 5” is being interpreted such that in order for a reference sequence to meet the limitation, said reference sequence must comprise or consist of an exact match to full-length SEQ ID NO: 5. This interpretation pertains to claim 2.
The recitation of, for example, “having the amino acid sequence as set forth in SEQ ID NO: 7” is being interpreted such that in order for a reference sequence to meet the limitation, said reference sequence must comprise or consist of a sequence that is an exact match to full-length SEQ ID NO: 7. This interpretation pertains to claim 2.
Art-Free Subject Matter
It is noted that an anti-TPBG antibody comprising (i) a heavy chain variable region having at least 80% identity to SEQ ID NO: 3 and a light chain variable region having at least 80% identity to SEQ ID NO: 4; (ii) a heavy chain comprising SEQ ID NO: 5 and a light chain comprising SEQ ID NO: 6; and/or (iii) a heavy chain variable region comprising heavy chain CDRs 1-3 having the amino acid sequences set forth in SEQ ID NOs: 7-9, respectively, and a light chain variable region comprising light chain CDRs 1-3 having the amino acid sequences set forth in SEQ ID NOs: 10-12, respectively, have been thoroughly searched.
The closest prior art made of record but not relied upon, specifically with regard to the anti-TPBG antibody, is US 2017/0342160 A1 (herein after referred to as “Mertens”). Mertens teaches a bispecific binding molecule comprising three binding domains, wherein a first and/or a second binding domain are capable of binding to the extracellular 5T4 antigen (i.e., TPBG) and the remaining binding domain(s) is (are) capable of binding to the CD3 receptor complex on T cells (Abstract; emphasis added). More specifically, Mertens teaches sequences for combined VH/VL binding domains (i.e. also called combined VH/VL) as given in SEQ ID NO: 42 (scFv5T4); SEQ ID NO 43: (scFvhu5T4); and SEQ ID NO: 44 (dsFvhu5T4) for 5T4 binders (Paragraph 0146). Notably, Mertens SEQ ID NO: 43 residues 1-120 and 140-246 comprise exact matches to the instant claimed heavy chain and light chain CDRs, respectively, and have 99.5% identity with instant SEQ ID NO: 3 and 95.5% identity with instant SEQ ID NO: 4, respectively. Mertens SEQ ID NO: 44 residues 1-120 and 140-246 comprise exact matches to the instant claimed heavy chain and light chain CDRs, respectively, and have 92.9% identity with instant SEQ ID NO: 3 and 97.8% identity with instant SEQ ID NO: 4, respectively. However, Mertens does not teach or render obvious an anti-TPBG antibody that comprises Fc silencing mutations nor having the functions of binding human TPBG, having cross-reactivity with white-tufted-ear marmoset TPBG, and internalization. Thus, anti-TPBG antibodies, and subsequently antibody-drug conjugates thereof, comprising the instantly claimed sequences, Fc silencing mutations, and the functions of binding human TPBG, having cross-reactivity with white-tufted-ear marmoset TPBG, and internalization are considered to be free of the prior art.
Claim Objections
Claim 1 is objected to because of the following informalities: lines 1-2 currently read "wherein said anti-TPBG antibody comprising Fc silencing mutations", but should read "wherein said anti-TPBG antibody comprises Fc silencing mutations". Appropriate correction is required.
Claim 2 is objected to because of the following informalities: lines 6-7 currently read, respectively, "a light chain comprising SEQ ID NO: 5" and "a heavy chain comprising SEQ ID NO: 6", but it is noted that SEQ ID NO: 5 corresponds to a heavy chain sequence and SEQ ID NO: 6 corresponds to a light chain sequence (see Figure 21 and sequence listing). Appropriate correction is required.
Claim 17 is objected to because of the following informalities: line 1 currently reads "[t]he antibody drug conjugate (ADC) according to any one of claims 11", but should read "[t]he antibody drug conjugate (ADC) according to claim 11". Appropriate correction is required.
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 1-21 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 drawn to an anti-TPBG antibody, wherein the anti-TPBG antibody generally comprises Fc silencing mutations and is capable of: (a) binding to human Trophoblast glycoprotein (TPBG); (b) having cross-reactivity with white-tufted-ear marmoset TPBG; and (c) internalization. Claim 2 is further drawn to the anti-TPBG antibody above, wherein said anti-TPBG antibody is an antibody comprising, generally: (i) a heavy chain variable region having an amino acid sequence with at least 80% identity to SEQ ID NO: 3 and a light chain variable region having an amino acid sequence with at least 80% identity to SEQ ID NO: 4, optionally comprising a light chain comprising SEQ ID NO: 5 a heavy chain comprising SEQ ID NO: 6; and/or (ii) comprising a heavy chain variable region comprising heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 7, heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 8, and heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 9 and a light chain variable region comprising light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 10, light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 11, and light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 12. Further regarding claim 5, the claim is drawn to various genera of cytotoxic moieties, including fragments, analogues, and/or prodrugs thereof of the cytotoxic moieties listed.
Thus, the claims identify the antibody by the functions of (a) binding to human Trophoblast glycoprotein (TPBG); (b) having cross-reactivity with white-tufted-ear marmoset TPBG; and (c) internalization, and a partial sequence structure that comprises (i) a heavy chain variable region having an amino acid sequence with at least 80% identity to SEQ ID NO: 3 and a light chain variable region having an amino acid sequence with at least 80% identity to SEQ ID NO: 4; and/or (ii) heavy chain CDRs 1-3 and light chain CDRs 1-3 having the amino acid sequences as set forth in SEQ ID NOs: 7/8/9 and 10/11/12, respectively. Claim 5 further identifies cytotoxic moieties of the claimed antibody-drug conjugate by their function(s). Thus, the claims encompass a vast genus of (i) antibody variants, wherein said antibody variants comprise no defined sequence structure, or comprise a partial sequence structure having any undefined variations within the CDR sequences, which are required to bind human TPBG and perform the claimed functions and (ii) cytotoxic moiety variants (i.e., fragments, analogues, and/or prodrugs thereof) which are required to be cytotoxic, wherein some agents further require more specific functions (e.g., kinase inhibitors, MEK inhibitors, KSP inhibitors).
Example 1, Paragraph 00344 of the instant specification details the synthesis and expression of a monoclonal anti-TPBG antibody, wherein the resultant antibody is depicted in Figure 21. The heavy chain of said monoclonal anti-TPBG antibody comprises heavy chain CDRs 1-3 having the amino acid sequences as set forth in SEQ ID NOs: 7/8/9 and a heavy chain variable region consisting of SEQ ID NO: 3; the full heavy chain (without signal peptide) corresponds to SEQ ID NO: 5. The light chain of said monoclonal anti-TPBG antibody comprises light chain CDRs 1-3 having the amino acid sequences as set forth in SEQ ID NOs: 10/11/12 and a light chain variable region consisting of SEQ ID NO: 4; the full light chain (without signal peptide) corresponds to SEQ ID NO: 6. It is noted that Example 3 further discloses two additional anti-TPBG antibodies for comparison to the monoclonal anti-TPBG antibody described above, but these comparison antibodies are structurally distinct from the monoclonal anti-TPBG antibody above; comparison antibody 1 comprises a heavy chain corresponding to SEQ ID NO: 16 and a light chain corresponding to SEQ ID NO: 15 whereas comparison antibody 2 comprises a heavy chain corresponding to SEQ ID NO: 20 and a light chain corresponding to SEQ ID NO: 19 (see Pages 128-130). It is specifically noted that only the monoclonal anti-TPBG antibody, not comparison antibodies 1 and 2, was demonstrated to have cross-reactivity in marmosets. With regard to the cytotoxic moieties, other than the genera recited in claim 5, no specific examples falling within said genera are provided; notably no fragments, analogues, or prodrugs falling within the recited genera having the required functions are provided.
Thus, the instant specification discloses making only one monoclonal anti-TPBG antibody that has the functions of (a) binding to human Trophoblast glycoprotein (TPBG), (b) having cross-reactivity with white-tufted-ear marmoset TPBG, and (c) internalization; the specification describes the complete heavy chain CDR 1-3, light chain CDR 1-3, heavy chain variable, light chain variable, full heavy chain, and full light chain sequences for said monoclonal anti-TPBG antibody. The specification fails to disclose any other heavy chain CDR 1-3 and light chain CDR 1-3 sequence variants that possess the functions above.
To provide adequate written description and evidence of possession of the claimed antibody genus, the instant specification can structurally describe representative antibody variants that have the functions of (a) binding to human Trophoblast glycoprotein (TPBG), (b) having cross-reactivity with white-tufted-ear marmoset TPBG, and (c) internalization, or describe structural features common to the members of the genus, which features constitute a substantial portion of the genus. To provide adequate written description and evidence of possession of the claimed genera of cytotoxic moieties, the instant specification can structurally describe representative variants that have the function being cytotoxic and/or having specific inhibitory activities (e.g., kinase inhibitors, MEK inhibitors, KSP inhibitors), 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 (i) a recitation of the antibody function, “anti- TPBG” wherein said antibody is capable of binding to human Trophoblast glycoprotein (TPBG), having cross-reactivity with white-tufted-ear marmoset TPBG, and internalization; and (ii) partial sequence structure as stated above. The instant specification fails to describe structural features common to the members of the antibody genus, which features constitute a substantial portion of the genus because the instant specification fails to disclose representative antibody variant sequences that function as claimed. A definition by function does not suffice to define the genus because it is only an indication of what the antibody does, rather than what it is. Other than for the antibody disclosed in Example 1 (see Figure 21), the specification fails to provide the heavy chain CDR 1-3 and light chain CDR 1-3 structural features coupled to the claimed functional characteristics. The instant specification fails to describe a representative number of antibody sequence variants for the genus of antibodies that function 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 antibodies. With regard to the cytotoxic moieties, the only factor present in the claims is the recitation of function (i.e., cytotoxic and/or inhibitory functions). A definition by function does not suffice to define the genera because it is only an indication of what the cytotoxic moieties do, rather than what they are.
The claims broadly encompass any sequence variant that comprises heavy chain variable region and light chain variable region pairings with any amino acid sequences having at least 80% identity to SEQ ID NOs: 5 and 6, respectively (see claim 2) that have the functions of (a) binding to human Trophoblast glycoprotein (TPBG), (b) having cross-reactivity with white-tufted-ear marmoset TPBG, and (c) internalization. Furthermore, the claims broadly encompass any structure/sequence variant regarding the recited cytotoxic moieties (i.e., fragments, analogues, and/or prodrugs) that have cytotoxic and/or specific inhibitory functions. Applicants have not established any reasonable structure-function correlation with regards to the sequences in the CDRs that can be altered and still maintain the above-recited functions, nor any reasonable structure-function correlation with regards to fragments, analogues, and/or prodrugs of the recited genera of cytotoxic moieties that still maintain the recited function(s). Given the well-known high level of polymorphism of antibody CDR sequences and structure, and the criticality of therapeutic agent sequence/structure with pharmacokinetic properties and function, the skilled artisan would not have been in possession of the vast repertoire of antibodies encompassed by the claimed invention. One could not reasonably or predictably extrapolate (i) the structure of a single anti-TPBG antibody to the structure of any variants required to function as broadly as currently claimed nor (ii) the structure/sequence of a single recited cytotoxic moiety to the structure/sequence any variants (i.e., fragments, analogues, and/or prodrugs thereof) required to function as broadly as currently claimed. Therefore, one could not readily envision members of the broadly claimed genera.
Although Applicants may argue that it is possible to screen for antibodies that bind TPBG and/or cytotoxic agent fragments, analogues, and/or prodrugs thereof that 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 TPBG antigen provides no information about the structure of an antibody that binds to it.
Given the lack of representative examples to support the full scope of the claimed variant antibodies and cytotoxic moieties, and lack of reasonable structure-function correlation with regards to (i) the unknown variable sequences in the CDRs that provide the recited functions and (ii) the unknown structural/sequence variability in the recited cytotoxic moieties that provide the recited function(s), the present claims lack adequate written description. Thus, the specification does not provide an adequate written description of (i) any antibody sequence variants that comprise heavy chain variable region and light chain variable region pairings with any amino acid sequences having at least 80% identity to SEQ ID NOs: 5 and 6, respectively (see claim 2) that have the functions of (a) binding to human Trophoblast glycoprotein (TPBG), (b) having cross-reactivity with white-tufted-ear marmoset TPBG, and (c) internalization (see claim 1) nor (ii) any structure/sequence variants regarding the recited cytotoxic moieties (i.e., fragments, analogues, and/or prodrugs) that have cytotoxic and/or specific inhibitory functions that are required to practice the claimed invention. Claims 3-21 are also included in this rejection as they all depend from and/or incorporate the anti-TPBG antibody of claim 1.
Claim 21 is 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 treatment, amelioration, and/or diagnostics of cancers in which TPBG is implicated, does not reasonably provide enablement for the . 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 a method for treatment, amelioration, prophylaxis, and/or diagnostics of cancer. Thus, under broadest reasonable interpretation (BRI), the claim is drawn to (i) the prevention of any and all cancers and/or (ii) the treatment, amelioration, and/or diagnosis of any and all cancers, the full scope of which is not enabled.
The State of the Prior Art/Level of Predictability in the Art
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
The instant specification further fails to provide any working examples regarding prophylaxis/prevention of any kind of cancer. Moreover, the instant specification discloses that oncofetal antigen 5T4 (interchangeably referred to as trophoblast glycoprotein (TPBG)), is a 72-kDa glycoprotein that is typically only expressed during embryonic development, whereas expression in normal adult tissues is very limited; expression of 5T4, however, is reported to be significantly upregulated in many types of carcinomas, including, but not limited to, cancers of the lung, breast, stomach, prostate, colon, and ovaries, and its expression has been correlated with poor prognosis in multiple indications (Paragraph 005). Example 1, Paragraph 00360 discloses evaluating the binding of the disclosed anti-TPBG antibody to 5T4 expressing MDA-MB-468 cells (breast cancer). Paragraph 00369 evaluates the direct cytotoxicity of ADCs comprising the anti-TPBG antibody on 5T4 expressing MDA-MB-468 cells (breast cancer), BXPC-3 cells (pancreatic cancer), and DU-145 cells (prostate cancer) (see Figure 5). Paragraphs 00374-00375 provide in vivo evaluation of anti-TPBG ADC efficacy on a variety of 5T4 expressing cancer cells (see Figure 8). Example 2, Paragraphs 00417-00423 also evaluates in vivo efficacy of anti-TPBG ADCs in patient derived xenograft models (i.e., 5T4 expressing patient derived xenografts) (see Figures 23-24). Notably, Example 3, Paragraphs 00438-00453 provides both in vitro and in vivo experiments evaluating anti-TPBG ADCs, wherein responses are only noted in 5T4 expressing cancer cells, not 5T4 negative cells (i.e., SW-620 colorectal adenocarcinoma) (see Figures 27-29). Thus, the instant specification indicates that TPBG is an ideal target for specific cancers, wherein differential expression of 5T4 is implicated; there is no evidence in the specification that any and all cancers are associated with TPBG (see data regarding 5T4 negative SW-620 cells in Example 3).
In view of the of the breadth of the claims, the level of predictability in 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 anti-TPBG antibody drug conjugates (ADCs) in (i) the prevention of any and all cancers and/or (ii) the treatment, amelioration, and/or diagnosis of any and all cancers with a reasonable expectation of success, absent a specific and detailed description in Applicant’s specification of how to effectively practice this and absent working examples providing evidence which is reasonably predictive that the claimed antibodies are functional, commensurate in scope with the claimed invention.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
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 1-21 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.
Regarding claim 1, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). The claim recites “comprising Fc silencing mutations such as leucine (L) to alanine (A) substitution at the position 234 and 235 (LALA mutations)”. Thus, it is unclear if the recitation of leucine (L) to alanine (A) substitution at the position 234 and 235 (LALA mutations) is intended to be limiting, or if the recitation is merely intended as exemplary Fc silencing mutations.
Further regarding claim 1, a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 1 recites the broad recitation “internalization”, and the claim also recites “optionally by the means of the antigen-mediated antibody internalization” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Regarding claim 2, a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 2 recites the broad recitation “an antibody comprising a heavy chain variable region having an amino acid sequence with at least 80% identity to SEQ ID NO: 3 and a light chain variable region having an amino acid sequence with at least 80% identity to SEQ ID NO: 4”, and the claim also recites “optionally said anti-TPBG antibody comprising: a) a light chain comprising SEQ ID NO: 5 and b) a heavy chain comprising SEQ ID NO: 6” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Regarding claims 4 and 18, the claims are considered to be indefinite as the claims fail to define what the structural element
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corresponds to in the context of the claims. As such, absent a clear definition of said structural element, one of ordinary skill in the art cannot reasonably determine the metes and bounds of the claims and the claims are therefore considered to be indefinite.
Further regarding claim 4, the recitation that R1, R3, R4, R5, R6, and/or R7 may be “an optionally substituted aliphatic residue or an optionally substituted aromatic residue” renders the instant claim indefinite. It is specifically noted that Page 26 of the instant specification defines “substituted” or “optionally substituted” wherein one or more hydrogen atoms are replaced with a substituent, wherein some exemplary, but not limiting, substituents are provided. It is noted that even the specific exemplary substituents listed vary significantly in physiochemical properties, and it is unclear as to (i) how many substitutions can be made within a single R group and across various R groups, and (ii) what possible combinations of substituents within a single R group or across R groups would still yield an antibody drug conjugate (ADC) that is both functional and possess desirable physiochemical properties. As such, claim 4 is considered to be indefinite.
Regarding claim 5, the claim contains the trademark/trade name PROTACs. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe pharmaceutical products for degrading disease-causing cellular proteins and, accordingly, the identification/description is indefinite.
Regarding claim 17, a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 17 recites the broad recitation “wherein n ranges from 2 to 10”, and the claim also recites “optionally wherein n is 4 or 8” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claims 3, 6-16, and 19-21 are included in this rejection as they each depend from and/or incorporate at least one of the claims rejected above.
Conclusion
Claims 1-21 are pending. Claims 1-21 are rejected. No claims are allowed.
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/ALYSSA RAE STONEBRAKER/Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
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