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 .
DETAILED ACTION
Election/Restrictions
Applicant’s election without traverse of species: 10 mg to 100 mg, dosage schedule of claim 5, 0.3 mg to 3 mg as the first dose, SEQ ID NO: 438, anti-inflammatory agent, a corticosteroid, extensive stage SCLC, and etanercept in the reply filed 07/21/2025 is acknowledged.
Claims 2, 4, 15, 41-42 and 53-54 are withdrawn from consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions and species, there being no allowable generic or linking claims. Election was made in the reply filed 07/21/2025.
Claims 1, 3, 5, 7-9, 16-21, 35-39, 43-52, and 55 are now under consideration in the instant Office Action.
Withdrawn Objections
Objections to the disclosure is objected due to minor informalities are hereby withdrawn in view of the submission of a substitute specification which corrects outstanding issues.
Objections to claims 36-38 for minor informalities are hereby withdrawn in view of amendments to the claims to correct the grammatical error and improper parenthetical references.
Modified Rejections Necessitated by Amendment
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.
Claims 1, 3, 5, 7-9, 16-21, 35-39, 43-52, and 55 are rejected under 35 U.S.C. 103 as being unpatentable over Raum et al. (WO 2017021349 A1, in IDS filed 10/30/2023), in view of Abel et al. (US20190151448 A1, in IDS filed 10/30/2023), and Dylla et al. (US20180243435A1, in IDS filed 10/30/2023).
Raum et al. teaches “a bispecific antibody construct comprising a first binding domain which binds to human DLL3 on the surface of a target cell and a second binding domain which binds to human CD3 on the surface of a T cell”, see Abstract. Raum et al. discuss that DLL3 was presently identified as an SCLC-specific tumor antigen by next-generation sequencing, comparing the prevalence of DLL3 mRNA in a panel of primary patient tumors and a large collection of normal tissues. The level of DLL3 expression in SCLC tumors was moderate, but highly prevalent, with approximately 90% of the tumors analyzed showing evidence of DLL3 expression by RNA-seq, see page 3. As such, a polypeptide was created to bind to DLL3 and be used in a treatment for small cell lung cancer. This polypeptide is comprised in SEQ ID NO: 438, which is a 100% match to instant SEQ ID NO: 438.
However, Raum et al. does not teach the dosage necessary to treat small cell lung cancer. Abel et al. remedies this deficiency.
Abel et al. teaches an antibody construct of the invention can bind to a tumor antigen, which is selected from the group consisting of CD19, CD33, EGFRvIII, MSLN, CDH19, FLT3, DLL3, CDH3, BCMA and PSMA, see paragraph 0252. Abel et al. discloses that the antibody is dosed at “(a) 0.5 to 200 μg/ml at a pH of 6.5 to 7.5, or (b) 0.5 to 1000 μg/ml at a pH of 4.0 to 6.0”, see paragraph 0016.
Abel also teaches the dosage for the antibody construct with an ““effective dosage” is defined as an amount sufficient to achieve or at least partially achieve the desired effect. The term “therapeutically effective dose” is defined as an amount sufficient to cure or at least partially arrest the disease and its complications in a patient already suffering from the disease. Amounts or doses effective for this use will depend on the condition to be treated (the indication), the delivered antibody construct, the therapeutic context and objectives, the severity of the disease, prior therapy, the patient's clinical history and response to the therapeutic agent, the route of administration, the size (body weight, body surface or organ size) and/or condition (the age and general health) of the patient, and the general state of the patient's own immune system. The proper dose can be adjusted according to the judgment of the attending physician such that it can be administered to the patient once or over a series of administrations, and in order to obtain the optimal therapeutic effect”, see paragraph 0351. Abel also teaches that a “typical dosage may range from about 0.1 μg/kg to up to about 30 mg/kg or more, depending on the factors mentioned above. In specific embodiments, the dosage may range from 1.0 μg/kg up to about 20 mg/kg, optionally from 10 μg/kg up to about 10 mg/kg or from 100 μg/kg up to about 5 mg/kg”, see paragraph 0352. Abel also teaches that “the pharmaceutical compositions and the antibody construct of this invention are particularly useful for parenteral administration, e.g., subcutaneous or intravenous delivery, for example by injection such as bolus injection, or by infusion such as continuous infusion. Pharmaceutical compositions may be administered using a medical device”, see paragraph 0345.
However, Raum and Abel do not teach the combination of a corticosteroid with the anti-DLL3 agent. Dylla et al. remedies this deficiency.
Dylla et al. teaches “methods of administering anti-DLL3 antibodies or immunoreactive fragments thereof, including antibody drug conjugates (ADCs), comprising the same for the treatment, diagnosis or prophylaxis of cancer and any recurrence or metastasis thereof”, see paragraph 0003. Dylla et al. also teaches that the “cancer will comprise a solid tumor including, but not limited to, adrenal, liver, kidney, bladder, breast, gastric, ovarian, cervical, uterine, esophageal, colorectal, prostate, pancreatic, lung (both small cell and non-small cell)”, see paragraph 0012. Dylla et al. also teaches the combination of the anti-DLL3 agent “with certain steroids to potentially make the course of treatment more effective and reduce side effects such as inflammation, nausea and hypersensitivity. Exemplary steroids that may be used on combination with the ADCs of the instant invention include, but are not limited to, hydrocortisone, dexamethasone, prednisone, methylprednisolone and prednisolone. In particularly preferred aspects the steroid will comprise dexamethasone”, see paragraph 0483. In regards to the method of administration, Dylla et al. makes the following recommendation in paragraph 0013 for use in the treatment of cancer wherein the treatment may comprise administering an effective amount of an anti-DLL3 antibody drug conjugate (DLL3 ADC):
at least once every week (QW), at least once every two weeks (Q2W), at least once every three weeks (Q3W), at least once every four weeks (Q4W), at least once every five weeks (Q5W), at least once every six weeks (Q6W), at least once every seven weeks (Q7W), at least once every eight weeks (08W), at least once every nine weeks (Q9W), at least once every ten weeks (Q10W), at least once every eleven weeks (Q11W) or at least once every twelve weeks (Q12W). In selected embodiments the DLL3 ADC will be administered at least every three weeks (Q3W), at least once every four weeks (Q4W), at least once every five weeks (Q5W) or at least once every six weeks (Q6W). In other selected embodiments the DLL3 ADC will be administered at a dose of about 0.01 mg/kg, 0.025 mg/kg, 0.05 mg/kg, 0.075 mg/kg, 0.1 mg/kg, 0.15 mg/kg, 0.2 mg/kg, 0.25 mg/kg, 0.3 mg/kg, 0.4 mg/kg, 0.5 mg/kg, 0.6 mg/kg, 0.7 mg/kg, 0.8 mg/kg, 0.9 mg/kg or 1.0 mg/kg. Selected embodiments will comprise treating the patient with a single administration of the DLL3 ADC. Certain other embodiments will comprise treating the patient at specified intervals (i.e. Q2W, 03W, Q4W, Q5W, Q6W, etc) for two cycles (×2), for three cycles (×3), for four cycles (×4), for five cycles (×5), for six cycles (×6), for seven cycles (×7), for eight cycles (×8), for nine cycles (×9), or for ten cycles (×10). In other embodiments the initial DLL3 ADC treatment (of x cycles) may be completed and no further DLL3 ADC treatment is undertaken until the cancer shows signs of progressing (treatment at progression). In yet other embodiments the initial DLL3 ADC treatment (of x cycles) may be completed and then the patient is put on maintenance therapy (e.g., 0.1 mg/kg DLL3 ADC Q6W indefinitely). In such maintenance settings the DLL3 ADC may be administered at relatively low levels as a continuous or periodic (e.g., every hour) infusion via a peristaltic pump. In still other embodiments the patient will receive the initial DLL3 ADC treatment (of x cycles) and then not be treated (with the disclosed ADCs or with another agent) for the same or related cancer again until progression (i.e., treat at progression). In such cases the second treatment cycle (e.g., with DLL3 ADCs) will not be effected until after four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen or sixteen or more weeks after conclusion of the first treatment cycle.
It would have been obvious to one of ordinary skill in the art at the time the invention to use the antibody construct taught by Raum et al. and modify the methods and dosages of Abel and Dylla to include administering a dosage of 10 to 100 mg on day 1 once every two weeks, a first dose from 0.3 mg to 3 mg on day 1, a second dose of from 10 to 100 mg on day 8, a third dose of from 10 to 100 mg on day 15 and once every two weeks thereafter in combination with a corticosteroid such as dexamethasone to treat small cell lung cancer. Since the general conditions of the claims are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. One of ordinary skill in the art would be motivated to do so to provide a dosing schedule to optimize therapeutic efficacy while minimizing adverse effects associated with said antibody.
Therefore, claims 1, 3, 5, 7-9, 16-21, 35-39, 43-52, and 55 are rejected as obvious over Raum et al., in view of Abel et al. and Dylla et al.
Response to Arguments
Applicant's arguments filed 12/10/2025 have been fully considered but they are not persuasive.
Applicant argues “the Office cited no disclosure in Abel relating to small cell lung cancer. As such, similar to Raum, the Office has not established that Abel “teaches the dosage necessary to treat small cell lung cancer”. This is not found persuasive.
Abel et al. discloses that the antibody construct of the invention can bind to a tumor antigen, which is selected from the group consisting of CD19, CD33, EGFRvIII, MSLN, CDH19, FLT3, DLL3, CDH3, BCMA and PSMA, see paragraph 0252. Abel et al. teaches that the antibody construct, which targets markers known to be implicated in cancer pathways, can be used as an anti-cancer treatment in addition to other “biologically active agents, depending on the intended use of the composition. Such agents might be drugs acting on the gastro-intestinal system, drugs acting as cytostatic, drugs preventing hyperuricemia, drugs inhibiting immunoreactions (e.g. corticosteroids), drugs modulating the inflammatory response, drugs acting on the circulatory system and/or agents such as cytokines known in the art. It is also envisaged that the antibody construct of the present invention is applied in a co-therapy, i.e., in combination with another anti-cancer medicament”, see paragraph 0309. As such, the antibody construct of Abel et al. teaches that cancers that implicate certain markers, such as DLL3, are adequate targets for this type of treatment. The dosages taught by Abel et al. are therefore optimized to reach a “therapeutically effective dose”, which is defined as an amount sufficient to cure or at least partially arrest the disease and its complications in a patient already suffering from the disease. The dosages can be varied under the guidance of a physician based upon a patient’s disease state and treatment plan.
The evidentiary reference of Saunders et al. 2015 (in instant PTO-892) teaches that pulmonary neuroendocrine tumors, such as small cell lung cancer, are marked by an increased expression in DLL3.
Saunders et al. have discovered that DLL3, a ligand in the Notch signaling pathway, is associated with the neuroendocrine cancer phenotype. Saunders et al. targeted DLL3 with an antibody conjugated to a cytotoxic drug, which proved to be much more effective than standard chemotherapy for treating patient-derived tumor xenografts, see Abstract. To further expand their analysis of tumor and normal tissue specimens, Saunders et al. examined DLL3 expression in whole transcriptome sequencing data sets from 29 primary SCLC biopsy specimens, 25 SCLC cell lines, and 25 normal lung biopsy specimens, whose analysis confirmed our initial observations, revealing a ~35-fold elevation in DLL3 mRNA in SCLC relative to normal lung, see Figure 1E. Given that increases in DLL3 mRNA expression is associated with small cell lung cancers, one of ordinary skill in the art would recognize that targeting DLL3 with an antibody could serve as a potential treatment against small cell lung cancer.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). While Raum et al. does not explicitly recite the dosage necessary, it teaches the same agent as claimed which would bind to the same target of DLL3. As such, the Abel et al. reference supplements what is known in the prior art at the time of filing to specify a treatment dosage that uses the claimed agent in a method of treatment it has already considered.
Applicant argues that the “Office cited nothing in the references pointing one of ordinary skill in the art to the particular combination of features required in the instant claims” and that “the disclosures cited by the Office relating to dosing and timing regimes are generic and encompass hundreds (if not thousands) of different combinations of patient populations, doses, and timing intervals.” This is not found persuasive.
This argument is not persuasive because optimization of a dosage regimen for an antibody (e.g., modification of antibody amount or timing) is considered routine and conventional within the art, and the argument that modification of the regimen renders the instant claims distinct from the prior art is not persuasive for nonobviousness. The art expressly recognizes that a particular range of dosages may be modified to treat a certain condition based on the characteristics of a disease state in a patient. It would have been obvious to the ordinary artisan to modify the composition to improve treatment outcomes and decrease the presence of disease because it was already known that such changes could be advantageous when treating cancer. One of ordinary skill in the art would argue that the improvement in disease state observed after modification and optimization of the regimen was expected, especially in the view of the art recognized need to develop antibody treatments against DLL3 cancers and to modify the regimen per patient to provide the best treatment course through routine optimization. Modifying the regimen to reach this endpoint is a part of routine optimization.
A person of ordinary skill in the art would have been motivated to combine treatment modalities of the prior art known to be useful for the same conditions, and would have expected the combination therapy to be at least as good as either therapy alone (see MPEP §2144.06). The instant claims are amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose in order to form a third composition that is to be used for the very same purpose since the idea of combining them flows logically from their having been individually taught in the prior art. Applying the same logic to the instant claims, given the teachings of the prior art, it would have been obvious to combine the agents and dosage regimens because the idea of doing so would have logically followed from their having been individually taught in the prior art to be useful as anti-cancer agents. One of ordinary skill in the art would have reasonably expected to obtain a therapeutic benefit upon the combination of the agents and regimens since they had been demonstrated in the prior art to be reasonably predictive of treating cancers that overexpress DLL3.
Applicant argues “the combination of teachings of the cited references does not point one of ordinary skill in the art to the particular dosing regimen recited in the claims, nor does the combination suggest the remarkable results”. This is not found persuasive.
Applicant provides data for a phase I trial using AMG 757 (tarlatamab) for patients with previously treated SCLC, and claims that this claimed invention provided a therapeutic benefit to SCLC patients that could not have been predicted prior to the study described in the instant application. It is unclear why this particular clinical trial is brought up in the arguments, as neither the instant specification nor prior art refer to the agent of the instant claims as “tarlatamab”.
Additionally, Applicant cites a failed clinical trial that “demonstrated no survival benefit” in SCLC patients using anti-DLL3 antibody-drug conjugates that were not deemed to be effective using rovalpituzumab. This was done to show the relative unpredictability of treating anti-DLL3 expressing cancers. It is unclear how this antibody, which is not the one recited in the prior art, would dictate the success of the antibody found in the instant application or prior art. Applicant is reminded that absolute predictability is not a necessary prerequisite to a case of obviousness. Rather, a degree of predictability that one of ordinary skill would have found to be reasonable is sufficient. “Good science and useful contributions do not necessarily result in patentability.” PharmaStem Therapeutics, Inc. v. Viacell, Inc., 491 F.3d 1342 (Fed. Cir. 2007).
The prior art references used in the obviousness rejection supra all outline a clear explanation of how targeting DLL3, which is expressed in small cell lung cancers, would aid in the treatment of the condition. The prior art teaches that the dosage regimen can be optimized to retrieve effective patient outcomes, thus teaching a range that encompasses the range of the instant claims. The prior art references also consider additional therapeutics that would enhance the efficacy of the antibody treatment, and provide reasoning as to why, for example, a corticosteroid would be beneficial to aid in the treatment of the cancer. Given that all of these references were available at the time of filing, one of ordinary skill in the art would recognize that there is a reasonable expectation of success in combining these treatments which all share an end result of treating cancer.
Therefore, the rejection is maintained.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/SELAM BERHANE/Examiner, Art Unit 1675
/AURORA M FONTAINHAS/Primary Examiner, Art Unit 1675