DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. 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
2. The amendment filed June 30, 2026 has been entered. Claims 14-17 were cancelled. Claims 1-13 are under consideration in this Office Action.
Election/Restrictions
3. Claims 14-17 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on July 30, 2026.
Applicant’s election of Group I in the reply filed on June 30, 2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Information Disclosure Statement
4. The information disclosure statement (IDS) submitted on July 2, 2024 was filed. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
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.
5. Claims 1-13 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 a method of treating cancer in a patient in need thereof, comprising the step of administering to the patient a therapeutically effective amount of a cell-targeting molecule or a pharmaceutical composition thereof, wherein the cell-targeting molecule comprises: (i) a binding region capable of specifically binding an extracellular target biomolecule physically coupled to the surface of a cell, and
(ii) a Shiga toxin effector polypeptide comprising an amino acid sequence having at least 90% identity to amino acids 1 to 251 of SEQ ID NO: 1; wherein the amino acid sequence comprises at least four endogenous B-cell epitope regions, and comprises: amino acid substitutions V54I, R55L, 157F, P59F, E60T, and E61L in SEQ ID NO: 1, wherein the endogenous B-cell epitope regions are natively positioned in a wild-type Shiga toxin A Subunit within amino acid residues: 39-48 of SEQ ID NO:1; 94-115 of SEQ ID NO:1; 179-190 of SEQ ID NO:1; and 243-251 of SEQ ID NO:1; wherein the amino acid sequence comprises an asparagine at the amino acid residue corresponding to position 75 of SEQ ID NO: 1, a tyrosine at the amino acid residue corresponding to position 77 of SEQ ID NO: 1, a tyrosine at the amino acid residue corresponding to position 114 of SEQ ID NO: 1, a glutamate at the amino acid residue corresponding to position 167 of SEQ ID NO: 1, an arginine at the amino acid residue corresponding to position 170 of SEQ ID NO: 1, an arginine at the amino acid residue corresponding to position 176 of SEQ ID NO: 1, and a tryptophan at the amino acid residue corresponding to position 203 of SEQ ID NO: 1; and wherein the amino acid sequence has at least 95% sequence identity to SEQ ID NO: 16
The instant specification fails to provide any experiments that show that a method of treating cancer in a patient in need thereof, comprising the step of administering to the patient a therapeutically effective amount of a cell-targeting molecule or a pharmaceutical composition thereof, wherein the cell-targeting molecule comprises: (i) a binding region capable of specifically binding an extracellular target biomolecule physically coupled to the surface of a cell, and (ii) a Shiga toxin effector polypeptide comprising an amino acid sequence having at least 90% identity to amino acids 1 to 251 of SEQ ID NO: 1 as instantly claimed.
The treatment of cancer art is highly unpredictable and the instant specification fails to provide any information that the recited cell targeting molecule will treat all types of cancers. There are no immunological experiments provided to demonstrate that a single claimed composition would treat every type of cancer effectively. More importantly, there are no challenge experiments to demonstrate that a subject was administered the claimed composition would treat any type of cancers.
There are no protocols provided which demonstrate that the administered composition would treat lymphomas, carcinomas, sarcomas, leukemias, germ cell tumors and/or blastomas. There is no teaching as to what the most effective route of administration for the claimed compositions. There is merely a general outline of compositions that do not apply directly to the instant invention. Example 10 recites Iin this example, the Shiga toxin effector region is a CD8+ T-cell hyper-immunized and B-cell/CD4+ T-cell de-immunized Shiga toxin effector polypeptide derived from the A subunit of Shiga-like Toxin 1 (SLT-1A) as described above. An immunoglobulin-type binding region αNeurotensin-Receptor is derived from the DARPin™ (GenBank Accession: 2P2C_R) or a monoclonal antibody (Ovigne J et al., Neuropeptides 32:247-56 (1998)) which binds the human neurotensin receptor. The neurotensin receptor is expressed by various cancer cells, such as breast cancer, colon cancer, lung cancer, melanoma, and pancreatic cancer cells. However, this example does not provide a written description because there is no teaching of a method of treating cancer in a patient in need thereof, comprising the step of administering to the patient a therapeutically effective amount of a cell-targeting molecule or a pharmaceutical composition thereof, wherein the cell-targeting molecule as instantly claimed. At best, the specification describes a composition for administration to treat cancer. The specification does not provide substantive evidence that the claimed method will actually treat any type of cancer.
This demonstration is required for the skilled artisan to be able to use the claimed vaccines for their intended purpose of preventing any gram-negative infections. Without this demonstration, the skilled artisan would not be able to reasonably predict the outcome of the administration of the claimed vaccines, i.e. would not be able to accurately predict if protective immunity has been induced against a bacterium. The specification fails to teach the identity a vaccine with the claimed characteristics. Furthermore, the specification fails to adequately disclose a description of the claimed vaccines, thus a skilled artisan would be required to de novo locate, identify and characterize the claimed vaccines with the recited ability of providing a protective immune response. Accordingly, this would require undue experimentation given the fact that the specification is completely lacking in teachings as to attenuated live or whole cell vaccines with the broadly claimed protection characteristics. Thus, the art indicates that it would require undue experimentation to formulate and use a successful attenuated live vaccine without the prior demonstration of vaccine efficacy.
Factors to be considered in determining whether undue experimentation is required, are set forth in In re Wands, 8 USPQ2d 1400. They include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art and (8) the breadth of the claims.
Applying the above test to the facts of record, it is determined that 1) no declaration under 37 C.F.R. 1.132 or other relevant evidence has been made of record establishing the amount of experimentation necessary; 2) insufficient direction or guidance is presented in the specification with respect to the cancer treatment, 3) there is an absence of working examples showing treatment of any type of cancer in any types of patients and there are no challenge experiments. While the level of skill in the art is high, the unpredictability of the art, lack of guidance, broad scope of the claims and poorly developed state of the art would require that undue and excessive experimentation would have to be conducted by the skilled artisan in order to practice the claimed invention. With regard to (4) the nature of the invention has been discussed above along with (5) the state of the prior art. With regard to (6) the relative skill of those in the art is commonly recognized as quite high (post-doctoral level). With regard to predictability 7) the specification requires the skilled artisan to practice trial and error experimentation to show possession of the invention as claimed.
Given the above analysis of the factors which the courts have determined are critical in determining whether Applicant is in possession or the specification supports the claimed invention. Thus, Applicant has not satisfied the requirements as set forth under 35 U.S.C. 112 first paragraph.
Claim Rejections - 35 USC § 112
6. Claims 1-13 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 a method of increasing cytotoxicity, does not reasonably provide enablement for a method of treating every type of cancer in any type of patient in need thereof. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims. This is a scope of enablement rejection.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the inventions commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01 (A)). These include: nature of the invention, breadth of the claims, guidance of the specification, the existence of working examples, state of the art, predictability of the art and the amount of experimentation necessary. In re Fisher, 427 F.2d 833,839, 166 USPQ 18, 24 (CCPA 1970) states, "The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art." "The "amount of guidance or direction" refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictablethe art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling" (MPEP 2164.03). The MPEP further states that physiological activity can be considered inherently unpredictable. Thus, Applicant assumes a certain burden in establishing that inventions involving physiological activity are enabled. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the invention: The instant claims are drawn to a method of treating cancer in a patient in need thereof, comprising the step of administering to the patient a therapeutically effective amount of a cell-targeting molecule or a pharmaceutical composition thereof, wherein the cell-targeting molecule comprises
(i) a binding region capable of specifically binding an extracellular target biomolecule physically coupled to the surface of a cell, and (ii) a Shiga toxin effector polypeptide comprising an amino acid sequence having at least 90% identity to amino acids 1 to 251 of SEQ ID NO: 1; wherein the amino acid sequence comprises at least four endogenous B-cell epitope regions, and comprises: amino acid substitutions V54I, R55L, 157F, P59F, E60T, and E61L in SEQ ID NO: 1, wherein the endogenous B-cell epitope regions are natively positioned in a wild-type Shiga toxin A Subunit within amino acid residues: 39-48 of SEQ ID NO:1; 94-115 of SEQ ID NO:1; 179-190 of SEQ ID NO:1; and 243-251 of SEQ ID NO:1; wherein the amino acid sequence comprises an asparagine at the amino acid residue corresponding to position 75 of SEQ ID NO: 1, a tyrosine at the amino acid residue corresponding to position 77 of SEQ ID NO: 1, a tyrosine at the amino acid residue corresponding to position 114 of SEQ ID NO: 1, a glutamate at the amino acid residue corresponding to position 167 of SEQ ID NO: 1, an arginine at the amino acid residue corresponding to position 170 of SEQ ID NO: 1, an arginine at the amino acid residue corresponding to position 176 of SEQ ID NO: 1, and a tryptophan at the amino acid residue corresponding to position 203 of SEQ ID NO: 1; and wherein the amino acid sequence has at least 95% sequence identity to SEQ ID NO: 16.
Breadth of the claims: The claims encompass methods treating every type of cancer in any type of patient in need thereof, comprising the step of administering to the patient a single therapeutically effective amount of a cell-targeting molecule or a pharmaceutical composition thereof, wherein the cell-targeting molecule comprises
(i) a binding region capable of specifically binding an extracellular target biomolecule physically coupled to the surface of a cell, and (ii) a Shiga toxin effector polypeptide.
Guidance of the specification/The existence of working examples: In the specification there are no examples for treating any type of cancer in any patient in need thereof. There is no administration of a therapeutically effective amount of a cell-targeting molecule or a pharmaceutical composition thereof, wherein the cell-targeting molecule comprising (i) a binding region capable of specifically binding an extracellular target biomolecule physically coupled to the surface of a cell, and (ii) a Shiga toxin effector polypeptide as instantly claimed to any cancer cell lines, to any syngeneic tumor models or to any well-known animal models.
Furthermore there are no examples that show any type of treatment of any symptom or disease related action within any type of model. There are no protocols provided which demonstrate whether the treatment would not be effective in treating all types of cancers, nor are there protocols detailing the types binding regions and types of cancers necessary for treatment. There is merely a general scheme drawn to the treatment that does not apply directly to the instantly claimed method. It is unclear that one of skill in the art could follow these general guidelines and achieve treatment of every type of cancer in any type of patient in need thereof, comprising the step of administering to the patient a single therapeutically effective amount of a cell-targeting molecule or a pharmaceutical composition thereof, wherein the cell-targeting molecule comprises (i) a binding region capable of specifically binding an extracellular target biomolecule physically coupled to the surface of a cell, and (ii) a Shiga toxin effector polypeptide as instantly claimed.
The specification does not provide substantive evidence that the claimed treatment method is effective. This demonstration is required for the skilled artisan to be able to use the claimed method for their intended purpose of treating cancers. Without this demonstration, the skilled artisan would not be able to reasonably predict the outcome of the claimed treatment method. Accordingly, this would require undue experimentation given the fact that the specification is completely lacking in teachings as to method of treatment.
State of the art:
The instant specification fails to provide any experiments that show method steps which would be effective for broadly treating any or every type of cancer. The art of treating cancer is highly unpredictable and the instant specification fails to provide any information that the recited method would treat all types of cancers in any type of patient. It is unclear that one of skill in the art could not follow the general guidelines recited in the claims and achieve treatment using the claimed method.
The state of the art as exemplified by Danielewicz et al., (ACS Omega (2023) 8 (17):15406-15421) teach receptor-mediated drug delivery has gained major attention in the treatment of cancer. The pathogen-derived Shiga Toxin B subunit (STxB) can be used as a carrier that detects the tumor-associated glycosphingolipid globotriaosylceramide (Gb3) receptors. Furthermore, STxBAzK was clicked to the antineoplastic agent monomethyl auristatin E (MMAE) and evaluated in cell-killing assays for its ability to deliver the drug to Gb3-expressing tumor cells. The STxBAzK–MMAE conjugate induced uptake and release of the MMAE drug in Gb3-positive tumor cells, reaching 94% of HT-29 cell elimination at 72 h post-treatment and low nanomolar doses while sparing LS-174 (human colon adenocarcinoma) cells. STxBAzK is therefore presented as a well-functioning drug carrier, with a possible application in cancer therapy. the abundance and species diversity of the Gb3 antigen of HT-29 and LS-174 cells, among other model cancer cell lines. As a result, the amount of Gb3 isoforms was found to be very high in HT-29 cells, while LS-174 displayed low traces of the antigen. The treatment failed to distinguish between target and nontarget cells. LS-174 cells, expressing poor or no Gb3 at the surface, were equally eliminated by the standard MMAE treatment.
Thus, Treating all types of cancer with a single drug is considered medically impossible because cancer is not a single disease, but rather a collection of more than 200 distinct diseases defined by widely different genetic mutations, cellular origins, and survival mechanisms. See Plana et al., (Cancer Discov (2022) 12(3):606-624). Instead of a single "silver bullet" drug, modern oncology relies on multi-agent regimens, tumor-agnostic therapies, and drug repurposing to treat a broad spectrum of malignancies. Intra- and intertumor heterogeneity is evident at the level of genetics, histology, and disease progression, and single-cell sequencing has revealed rapid and diverse cancer genome evolution in response to therapy. Moreover, heterogeneity and evolvability, via genetic or nongenetic mechanisms, are two of the greatest obstacles to the successful treatment of cancers. Variability in drug response is observed in clinical trials of even highly successful precision therapies that target mutant or amplified oncogenes (the drugs that are ideal Ehrlich “magic bullets”. For example, fewer than half of biomarker-positive patients respond initially to trastuzumab (Herceptin) in HER2-overexpressing breast cancers or to MEK/BRAF inhibitors in BRAFV600E/K-mutant melanomas. However, such responses can be of sufficient magnitude in the patients in whom they occur to make trastuzumab and MEK/BRAF inhibitors practice-changing. Studies in genetically homogeneous mouse models of cancer suggest that, were all cancers biologically similar (and tumor evolution relatively limited), a single therapeutic vulnerability might be sufficient for tumor eradication. However, heterogeneity among cells within a single human cancer commonly promotes drug resistance and disease progression, and heterogeneity between cancers limits clinically meaningful responses (with rare exception) to a subset of patients. The molecular origins of variability could include patient-to-patient (or tumor-to-tumor) differences in cancer cell genetics, drug pharmacokinetics, or patient immune function. Among these possibilities, patient-specific differences in pharmacokinetics remain the least studied or understood. There is no teaching of any treatment methods as instantly claimed. In view of the lack of support in the art and specification for effective treatment methods, the methods would require undue experimentation on the part of the skilled artisan to make and use the claimed methods of treatment; therefore the full scope of the claims is not enabled.
Claim Rejections - 35 USC § 112
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.
7. Claim 1 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 1(i) recites the limitation "the surface" in the claim. There is insufficient antecedent basis for this limitation in the claim. Appropriate clarification is required.
Pertinent Art
8. The prior art made of record and not relied upon is considered pertinent to applicant’s disclosure. Johannes et al., (US Patent 8,313,731) teach Shiga Toxin B subunit compounds for cancer therapy or diagnosis and more specifically to the use of a non-toxic B subunit of Shiga toxin mutant as a vector for diagnostic products or drugs in over-expressing Gb3 receptor cells, and the treatment of intestinal tumors and more particularly for colorectal tumors.
Conclusion
9. No claims allowed.
10. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JA-NA A HINES whose telephone number is (571)272-0859. The examiner can normally be reached Monday thru Thursday.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor Peter Paras, can be reached on 571-272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JANA A HINES/Primary Examiner, Art Unit 1645
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