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 .
Application Status
The Response to the Restriction/Election of Species Requirement mailed on November 18, 2025 has been entered. Applicant’s election without traverse of the invention of Group I (claims 121-191 and 194-195), drawn to a dosing regimen, and to the species of follicular lymphoma (claims 125-139, 148-190, and 194), in the reply filed on January 16, 2026 is acknowledged.
The claims filed on January 16, 2026 are acknowledged. Claims 123-191 and 194-195 are pending. Claims 192-193 are canceled. Claims 140-147, 191, and 195 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 123-139, 148-190, and 194 are under examination herein.
Information Disclosure Statement
The information disclosure statements (IDSes) submitted on October 24, 2023 and January 16, 2026 are in compliance with the provisions of 37 CFR 1.97. The information disclosure statements are being considered by the examiner.
The NPL reference corresponding to Citation No. 394 (“Bannerji et al. ‘Emerging clinical activity of REGN1979, …’, Poster Presented at the 2018 American Society of Hematology, December 1-4, San Diego, GA, 1 page”) has not been considered because the scanned copy supplied by Applicant is illegible.
Claim Rejections - 35 USC § 112(b)
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 132-133 and 180-181 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.
Claim 132 recites the limitation “…wherein the two days are consecutive days” in lines 1-2. There is insufficient antecedent basis for this limitation in the claim. The claim depends from claim 123, which recites an initial dose that is administered “over two days during week 1” (see lines 6-7), a first intermediate dose that is administered “over two days during week 2” (see line 11), and a second intermediate dose that is administered “over two days during week 3” (see line 15). Accordingly, claim 132 is indefinite because it is unclear whether “the two days” is intended to refer to those corresponding to the initial dose, the first intermediate dose, or the second intermediate dose, or to a combination of these doses.
Claim 133 recites the limitation “…wherein the two days are no more than three days apart” in lines 1-2. There is insufficient antecedent basis for this limitation in the claim. The claim depends from claim 123, which recites an initial dose that is administered “over two days during week 1” (see lines 6-7), a first intermediate dose that is administered “over two days during week 2” (see line 11), and a second intermediate dose that is administered “over two days during week 3” (see line 15). Accordingly, claim 133 is indefinite because it is unclear whether “the two days” is intended to refer to those corresponding to the initial dose, the first intermediate dose, or the second intermediate dose, or to a combination of these doses.
Claim 180 recites the limitations that “administering a dose of antihistamine” or “administering a dose of acetaminophen” comprises instructing the subject to ingest the dose of antihistamine or acetaminophen, respectively. There is insufficient antecedent basis for these limitations in the claim. The claim depends from earlier claims 163 and 123, which do not recite administering either of an antihistamine or acetaminophen. There is not a clear nexus between the earlier recited steps in the claimed method and the subsequent step of instructing the subject to ingest (self-administer) a dose of antihistamine or acetaminophen in the same way that there is for administering the dose of steroid (which is earlier recited in claim 163).
Claim 181 recites the limitation that “administering a dose of antihistamine comprises intravenously administering …the dose of antihistamine”. There is insufficient antecedent basis for this limitation in the claim. The claim depends from earlier claims 163 and 123, which do not recite administering an antihistamine. There is not a clear nexus between the earlier recited steps in the claimed method and the subsequent step of intravenously administering a dose of antihistamine in the same way that there is for administering the dose of steroid (which is earlier recited in claim 163).
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.
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.
(1)
Claims 123-139, 148-159, 161-162, 187-190, and 194 are rejected under 35 U.S.C. 103 as being unpatentable over Brownstein (US 2020/0129617 A1; cited in IDS) in view of Hosseini (NPJ Systems Biology and Applications (2020) 6: 28) and Topp (Blood (2017) 130 (Suppl_1): 1495; cited in IDS).
Brownstein teaches administration regimens for therapeutic proteins (e.g., T cell-activating bispecific antibodies) that mitigate cytokine release syndrome (CRS) and infusion-related reaction (IRR) (e.g., Abstract). Brownstein teaches that CRS is characterized by the activation of bystander immune cells and non-immune cells to produce elevated levels of IL-6, IL-10, and IFN-γ (e.g., ¶ 0004). Relevant to claims 123-124, 126, 128-130, 132-133, 189-190, and 194, Brownstein discloses a method of administering said therapeutic protein to mitigate adverse effects of CRS or IRR (e.g., ¶ 0006-0024; claims 1-2, 4, 6, 10, 13, 18, 24-26, 30-33, 35, 39-43, 52, 54-56, 58, 60-62), said method comprising:
administering fractions of a primary dose (D1) comprising no more than 10 mg of the therapeutic protein in week 1 of the dosing regimen, wherein a first dose fraction (F1D1) comprises 40-60% of the total primary dose and is administered to the subject on day 1 of week 1 and a second dose fraction (F2D1) comprises the remaining 40-60% of the total primary dose and is administered to the subject from 12 to 96 hours following administration of the F1D1;
administering fractions of a secondary dose (D2) of the therapeutic protein comprising no more than one-half of a maximum weekly dose of the therapeutic protein in week 2 of the dosing regimen, wherein a first dose fraction (F1D2) comprises 40-60% of the total secondary dose, a second dose fraction (F2D2) comprises the remaining 40-60% of the total secondary dose, and the F2D2 is administered to the subject from 12 to 96 hours following administration of the F1D2;
administering fractions of a tertiary dose (D3) of the therapeutic protein comprising no less than one-half of the maximum weekly dose of the therapeutic protein in week 3 of the regimen, wherein a first dose fraction (F1D3) comprises 40-60% of the total tertiary dose, a second dose fraction (F2D3) comprises the remaining 40-60% of the total tertiary dose, and the F2D3 is administered to the subject from 12 to 96 hours following administration of the F1D3;
administering the maximum weekly dose of the therapeutic protein to the subject as a single dose in a subsequent week (or weeks) of the dosing regimen; and
further administering the maximum weekly dose of the therapeutic protein to the subject during a maintenance phase.
Brownstein teaches that the “primary dose”, “secondary dose”, and “tertiary dose” may also be referred to as the “initial dose”, “intermediate dose”, and “step-up dose”, respectively (e.g., ¶ 0106). Brownstein teaches that the primary dose of the therapeutic protein can range from 0.1 mg to 10 mg or more (e.g., ¶ 0077). Brownstein further discloses that the study design was based on a traditional 3+3 design in patients with non-Hodgkin lymphoma (e.g., ¶ 0274).
Brownstein further recites, “In one exemplary embodiment of the dosing regimen, the primary dose comprises 1 mg, each of the first dose fraction (F1D1) and the second dose fraction (F2D1) comprises 500 mcg, the secondary dose comprises 20 mg, each of the first dose fraction (F1D2) and the second dose fraction (F2D2) comprise 10 mg, the tertiary dose comprises 80 mg, each of the first dose fraction (F1D3) and the second dose fraction F2D3) comprise 40 mg, and the maximum weekly dose comprises 160 mg of the therapeutic protein, wherein the tertiary dose is administered as a single dose (i.e., 80 mg) weekly (QW) during weeks 4 to 12 of the dosing regimen, and the maximum weekly dose is administered as a single dose (i.e., 160 mg) once every two weeks (Q2VV) from week 14 onwards of the dosing regimen” (¶ 0100). See also ¶ 0289.
Regarding claims 125 and 131, the instantly claimed limitation that the full dose of the bispecific antibody is split into two equal fractions is conditional upon “if the subject experiences a grade 3 event of cytokine release syndrome when administered the initial dose, the first intermediate dose, or the second intermediate dose”. Brownstein teaches that “in any of the embodiments …, the incidence of grade 3 CRS and IRR is less than 10%. In some cases, the incidence of grade 3 CRS and IRR is less than 7.5% or less than 7%” (e.g., ¶ 0033). Based on the analysis set forth in Ex parte Schulhauser (attached in Office Action appendix), the broadest reasonable interpretation of the claim is that the split-dosing of the full dose does not need to be performed (i.e., is not required to meet the conditions of the claim) unless the conditional limitation is met. Looking to Brownstein, in the majority of cases, the subject does not experience a grade 3 event, therefore, it is not required that the full dose be split into two equal fractions.
Regarding claim 127, Brownstein teaches that more than one maintenance dose may be administered during a maintenance phase of the dosing regimen, following completion of the weekly phase of the regimen (e.g., ¶ 0014-0015, ). Brownstein teaches that said maintenance dose may be administered once every four weeks, and that the maintenance phase may be 24 weeks, or period of up to 86 weeks, or 87 weeks, or greater than 100 weeks, etc. (e.g., ¶ 0015). These ranges include a week 36 (24 weeks after week 12), relevant to the instant claim.
Pertinent to claims 134-139, Brownstein teaches that the subject treated in the method has been diagnosed with a B-cell malignancy such as follicular lymphoma, and that the full dose is 80 mg and the maintenance dose is 160 mg (e.g., ¶ 0018-0021, 0169-0179; claims 1, 39-45).
Relevant to claim 148, Brownstein describes a clinical study in which patients were treated with REGN1979 and inclusion criteria required that the subject has a documented CD20+ B-cell malignancy, with active disease not responsive to prior therapy, for whom no standard of care options exist and for whom treatment with an anti-CD20 antibody may be appropriate (e.g., Example 1, ¶ 0169-0215). Relevant to claims 149-153, patients with follicular lymphoma (grades 1-3a) must have received at least two prior lines of systemic therapy including an anti-CD20 antibody and an alkylating agent, and must be ≥ 18 years of age (e.g., Example 1, ¶ 0192-0215). Relevant to claim 154, the REGN1979 antibody is administered intravenously (e.g., ¶ 0171).
Relevant to claims 159 and 161-162, REGN1979 comprises an anti-CD20 binding arm comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 10 (which shares 100% sequence identity to instant SEQ ID NO: 16 and to residues 1-453 of instant SEQ ID NO: 1) and a common light chain comprising the amino acid sequence of SEQ ID NO: 12 (which shares 100% sequence identity to instant SEQ ID NO: 3), and an anti-CD3 binding arm comprising the heavy chain comprising the amino acid sequence of SEQ ID NO: 11 (which shares 100% sequence identity to instant SEQ ID NO: 17 and to residues 1-448 of instant SEQ ID NO: 2) and a common light chain comprising the amino acid sequence of SEQ ID NO: 12 (e.g., ¶ 0023-0024, 0114), and which comprises the respective heavy chain and light chain CDRs set forth in claim 123. The corresponding anti-CD20 heavy chain variable region (VH) comprises an amino acid sequence of SEQ ID NO: 13 (which shares 100% sequence identity to instant SEQ ID NO: 4) and a light chain variable region (VL) comprising the common amino acid sequence of SEQ ID NO: 15 (which shares 100% sequence identity to instant SEQ ID NO: 6), and the corresponding anti-CD3 VH comprises an amino acid sequence of SEQ ID NO: 14 (which shares 100% sequence identity to instant SEQ ID NO: 5) and a common VL comprising the amino acid sequence of SEQ ID NO: 15 (e.g., ¶ 0114), pertinent to claim 155. Pertinent to claims 156-158, Brownstein states that the bispecific antibody comprises a human IgG1 or human IgG4 heavy chain constant region (e.g., ¶ 0115).
Relevant to claims 187-188, Brownstein teaches that tocilizumab, an anti-IL-6 [receptor] antibody, has become a standard initial treatment for severe CRS (¶ 0005). Brownstein teaches administering an anti-IL-6 receptor antibody (e.g., sarilumab) in combination with the therapeutic protein (e.g., ¶ 0030, 0105; claims 74 and 79).
However, Brownstein does not expressly recite all of the specific doses of the initial, first intermediate, and second intermediate doses (including fractional doses thereof) as set forth in claim 123, in particular a dose corresponding approximately to the “first intermediate dose” of 4 mg set forth in the instant claim.
Hosseini describes the development of a model for understanding safety and efficacy of mosunetuzumab with the goal of mitigating the risk of cytokine release syndrome (e.g., Abstract; Introduction). Mosunetuzumab is a fully humanized full-length anti-CD20/CD3 T cell-dependent bispecific antibody that stimulates T cell-mediated killing of CD20-exressing B cells (e.g., patient-derived leukemia or lymphoma cells) in vitro and in vivo (e.g., Introduction). Hosseini teaches that the potent T cell activation induced by mosunetuzumab could trigger CRS and affect its therapeutic potential (e.g., Introduction). Hosseini modeled the dynamics of B- and T-lymphocytes and their interactions with mosunetuzumab using preclinical data (e.g., Introduction; Results; Figures 3 and 5). Hosseini teaches, “The model predictions for IL6 levels suggest that, as observed for blinatumomab, peak cytokine levels are driven primarily by the Cycle 1 Day 1 dose and that a higher dose on Cycle 1 Day 1 leads to higher peak cytokine levels (Fig. 5a–d); thus, the first cytokine peak for the non-fractionated dosing schedule is higher than that of the flat-fractionated dosing schedule, which in turn is higher than that of the step-fractionated dosing schedule. In addition, the model suggests that for the single- or double-step fractionated schedule, subsequent cytokine peaks are substantially lower than the first cytokine peak despite administration of a higher dose of mosunetuzumab, providing the opportunity to escalate to higher doses … With respect to the proportion of systemic activated T-cells arising from mosunetuzumab treatment (Fig. 5e–h), the model suggests that the first spike in Cycle 1 is dose-dependent (non-fractionated > flat-fractionated > step-fractionated dosing) and the subsequent spikes after each dose regardless of the time of administration are generally similar, suggesting that further fractionation has minimal impact on T-cell activation peaks. Importantly, to evaluate whether flat or step-up dose fractionation would significantly reduce antitumor efficacy, we compared the waterfall plots and found that percent change in tumor size on Day 84 is overall similar across the dosing regimens, despite the slight delay in reaching maximum doses and the relatively rapid growth of DLBCL tumors (Fig. 5i–l). Hence, the model predicts that step-fractionated dosing regimens mitigate the risk of high systemic cytokine peaks across the population of NHL patients, with minimal impact on antitumor efficacy, suggesting that this would be a safer option for administration of mosunetuzumab to patients” (Results, page 6). Hosseini reports that subsequent observations made using double-step fractionated dosing of mosunetuzumab during phase 1 clinical trials were consistent with those predicted by the model (e.g., Results, pages 6-7). Hosseini concludes, “Overall, the systems modeling presented here offered a novel and valuable approach for evaluation of clinical dosing strategies for mosunetuzumab and can potentially be extended to other related molecules and/or other B-cell malignancies” (Discussion, page 9).
Topp describes preliminary data evaluating the safety and efficacy of an anti-PD-1 antibody (REGN2810) alone or in combination with the anti-CD20/anti-CD3 bispecific antibody REGN1979 in patients with B-lymphoid malignancies. In the Arm 2 study, REGN2810 was administered in combination with REGN1979 at doses ranging from 2-4 mg (initial dose 1 mg). Topp teaches that 89% of the nine patients treated with this regimen experienced CRS, primarily grade 1 or grade 2, with the majority occurring after the initial dose (“Arm 2 …”). Topp states that “CRS/IRR events were similar in frequency and severity to those previously observed in single agent studies of REGN1979” (“Conclusion”).
Taken together, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to arrive at a dosing regimen for treating a B-cell malignancy with REGN1979 which comprises a split initial dose of 0.7 mg, a split first intermediate dose of 4 mg, a split second intermediate dose of 20 mg, a full dose administered weekly between weeks 4-12, and a maintenance dose thereafter, determined through the process of routine optimization. The skilled artisan would have been motivated to do so because Brownstein teaches that a similar regimen mitigates the adverse effects associated with cytokine release syndrome. Furthermore, Hosseini notes that step-fractionated dosing for an alternative anti-CD20/CD3 bispecific antibody reduces markers of CRS (e.g., IL-6 release) without sacrificing anti-tumor efficacy of the treatment regimen, and both REGN1979 and mosunetuzumab illicit peak release of IL-6 and other cytokines upon the first administration of the drug (as taught by Hosseini and Topp). There would have been a reasonable expectation of success because it was well within the skill of one of ordinary skill in the art at the time of filing to monitor patients for cytokine release syndrome when administering an anti-tumor therapy and to modify the dosing schedule as necessary to reduce or mitigate observed side effects.
Furthermore, with regard to the specific dosage and interval amounts recited in the instant claims, "[w]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955), and see M.P.E.P. § 2144.05 (II)(A). Moreover, it is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804,809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989). This is because, as is made clear from the prior art, the determination of the dosage regimen of a known drug is well within the purview of one of ordinary skill in the art at the time the invention was made, and it would have been obvious to one of ordinary skill in the art at the time Applicants' invention was made to determine all operable and optimal intervals of treatment because optimal intervals is an art-recognized result-effective variable which would have been routinely determined and optimized in the pharmaceutical art. Therefore, it would be conventional and within the skill of the art to identify the optimal dosages administered and optimal intervals to achieve target levels and therapeutically effective doses. Further, it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. It is clear that both the prior art and claimed method perform the same protocol to achieve the same results. It would be conventional and within the skill of the art to determine the optimal treatment regimens. Accordingly, one can see that the courts, over a period of over 50 years, have consistently held that dosage and treatment interval optimization is obvious.
(2)
Claims 123 and 160 are rejected under 35 U.S.C. 103 as being unpatentable over Brownstein (US 2020/0129617 A1; supra) in view of Hosseini (NPJ Systems Biology and Applications (2020) 6: 28; supra) and Topp (Blood (2017) 130 (Suppl_1): 1495; supra) as applied to claims 123-139, 148-159, 161-162, 187-190, and 194, further in view of Davis (U.S. Patent No. 9,359,437; published June 7, 2016).
The teachings of Brownstein are recited in the 35 U.S.C. § 103 rejection above.
However, Brownstein does not teach that the bispecific antibody administered in the dosing regimen of the invention comprises a first heavy chain constant region comprising the amino acid sequence of instant SEQ ID NO: 18 and a second heavy chain constant region comprising the amino acid sequence of instant SEQ ID NO: 19.
The teachings of Hosseini and Topp are discussed above.
Davis describes antibodies, antigen-binding proteins and Fc-fusion proteins comprising recombinant polypeptides having a chimeric heavy chain constant region that binds to certain Fc receptors (FcRs) but has reduced effector functions (e.g., Abstract). Davis teaches that designing antibodies with reduced effector function is desirable for bispecific antibodies, including those that combine an antigen-binding domain against a tumor-associated antigen with an antigen-binding domain that activates T cells, where the desired therapeutic properties are attributed to the different binding specificities of the bispecific antibody (e.g., Background, cols 1-2). Davis notes that for this scenario, “if the Fc portion binds to an Fc receptor, then potentially that could trigger undesirable killing of cells bearing Fc receptors by T cells, or killing of T cells by Fc receptor-bearing cells such as natural killer cells or macrophages” (col 2). Davis discloses bispecific antibodies comprising a first heavy chain constant region having the amino acid sequence of SEQ ID NO: 30 (which shares 100% sequence identity to instant SEQ ID NO: 18) and a second heavy chain constant region having the amino acid sequence of SEQ ID NO: 37 (which shares 100% sequence identity to instant SEQ ID NO: 19).
Based on the further teachings of Davis, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to incorporate into the bispecific anti-CD20/CD3 antibody administered in the dosing regimen of Brownstein the heavy chain constant regions comprising instant SEQ ID NO: 18 and 19, respectively. The skilled artisan would have been motivated to do so because Davis teaches that said heavy chain constant regions have reduced effector functions, which Davis notes is desirable for bispecific antibodies (including T cell engagers) where the binding specificities are the primary contribution to its therapeutic properties. There would have been a reasonable expectation of success because the REGN1979 antibody used in the method of Brownstein is a bispecific antibody that has specificity for a tumor-associated antigen (CD20) and for CD3, which activates T cells, and because the heavy chain constant regions described by Davis are expressly suited for use in a bispecific antibody.
(3)
Claims 123, 163-166, 169, 173-174, and 180-183 are rejected under 35 U.S.C. 103 as being unpatentable over Brownstein (US 2020/0129617 A1; supra) in view of Hosseini (NPJ Systems Biology and Applications (2020) 6: 28; supra) and Topp (Blood (2017) 130 (Suppl_1): 1495; supra) as applied to claims 123-139, 148-159, 161-162, 187-190, and 194, further in view of Zugmaier (US 2013/0287774 A1).
Teachings of Brownstein are recited in the 35 U.S.C. § 103 rejection above.
In addition, Brownstein teaches that premedication with steroids is among several strategies that have been used to effectively mitigate severe CRS, including when incremental dose escalation is implemented (e.g., ¶ 0005, 0279). Brownstein also sets forth embodiments in which the therapeutic protein (e.g., REGN1979) is administered in combination with a steroid such as dexamethasone, wherein the steroid “is administered prior to the administration of the therapeutic protein (e.g., about one to three hours prior to the F1D1, the F2D1, the F1D2, the F2D2, the F1D3 and/or the F2D3)”, as a pretreatment (¶ 0030, 0105). Brownstein sets forth that the pretreatments are discontinued with the single dose administration of the maximum weekly dose beginning at week 4. Brownstein also teaches, “Dexamethasone did not inhibit cytotoxicity of REGN1979, modestly affected upregulation of T-cell activation, and inhibited cytokine release” (¶ 0283).
However, Brownstein does not expressly teach that the dosing regimen further comprising the step of administering a dose of steroid to the subject from 12-24 hours prior to each of the first dose fraction of the initial dose, the first dose fraction of the first intermediate dose, and the first dose fraction of the second intermediate dose.
The teachings of Hosseini and Topp are summarized above.
Zugmaier teaches that GCs are widely used anti-inflammatory agents that suppress cytokines including IL-6 and IFN-γ (e.g., ¶ 0022). Zugmaier discloses the use of a glucocorticoid (GC) for mitigation, treatment, or prophylaxis of adverse side effects (e.g., cytokine release syndrome) caused by the administration of a CD3 binding domain, e.g., a bispecific antibody therapy, to a patient (e.g., Abstract; ¶ 0001-0009). In preferred embodiments, the GC is dexamethasone (e.g., ¶ 0028-0032), relevant to claim 182. Relevant to claims 180-181 and 183, the dose is 20 mg per day, administered intravenously or orally (e.g., ¶ 0037). Zugmaier discloses a three-stage administration scheme in which dexamethasone is administered (1) between 6-48 hours (preferably 12 hours) before administration of the first dose of the CD3 binding domain, (2) approximately 1 hour (60 minutes before) the first dose of the binding domain is administered, and (3) one day (i.e., about 24 hours, which is within the scope of 20-28 hours) after the first dose of the binding domain (e.g., ¶ 0085-0087), relevant to claims 163-166 and 1691. Zugmaier teaches that “in a further embodiment, dexamethasone is administered for a period of two, three, four or five days during which the dose of the binding domain is increased” (¶ 0087), reading on repeated administration of dexamethasone with increasing doses of an anti-CD3 antigen-binding domain-containing antibody during a step-up dosing regimen such as that set forth by Brownstein. Zugmaier also describes specific embodiments in which a patients having a B-cell malignancy (e.g., relapsed ALL or diffuse large B-cell lymphoma) were treated with the “early dexamethasone schedule” (20 mg at -12 hours to -6 hours, -1 hour, at start of infusion or dose increase, and during the following days) in combination with blinatumomab, which Zugmaier states was the “safest way” to administer blinatumomab to patients with DLBCL and allowed patients to continue receiving treatment without adverse events (e.g., ¶ 0093-0117).
Based on the further teachings of Zugmaier, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to modify the dosing regimen collectively taught by Brownstein, Hosseini, and Topp, by adding the additional step of administering a dose of steroid (e.g., 20 mg dexamethasone) to the subject 12-24 hours prior to administration of the first dose fractions at each step. The skilled artisan would have been motivated to do so because Zugmaier teaches that this early dexamethasone schedule decreases the frequency of dose-limiting toxicities (DLTs) and CRS-related events in patients being treated for a B-cell malignancy. There would have been a reasonable expectation of success because (1) Zugmaier teaches that dexamethasone suppresses cytokines such as IL-6 and IFN-γ, which Brownstein notes are elevated during CRS, and (2) the method of Zugmaier is carried out in combination with treatments comprising an anti-CD3 antigen-binding domain, and REGN1979 (the bispecific antibody administered in the dosing regimen of Brownstein) comprises an anti-CD3 binding domain.
(4)
Claims 123, 163, 167-168, 170-173, 175-179, and 184-186 are rejected under 35 U.S.C. 103 as being unpatentable over Brownstein (US 2020/0129617 A1; supra) in view of Hosseini (NPJ Systems Biology and Applications (2020) 6: 28; supra) and Topp (Blood (2017) 130 (Suppl_1): 1495; supra) and further in view of Zugmaier (US 2013/0287774 A1; supra) as applied to claims 123, 163-166, 169, 173-174, and 180-183 above in (3), further in view of Goodman (The Oncology Nurse (TON) – APNPA (2015) 8(5)) and Plante (Current Oncology (2021) 28: 4118-4128).
The teachings of Brownstein are recited in the 35 U.S.C. § 103 rejections above.
However, Brownstein does not expressly teach the steps of administering a dose of antihistamine (e.g., 25 mg diphenhydramine) 30-60 minutes prior to administering a dose of the therapeutic protein or administering a dose of acetaminophen (e.g., 650 mg) 30-60 minutes prior to administering a dose of the therapeutic protein in the dosing regimen.
The teachings of Hosseini, Topp, and Zugmaier are summarized above.
Goodman teaches that CRS can be observed following administration of immune-based therapies including antibodies such as rituximab (anti-CD20 antibody). Goodman relays tips for managing CRS in oncology settings as presented by an experienced inpatient oncology nurse, Anne Kolenic, at the 2015 annual meeting of the Oncology Nursing Society. Quoting Kolenic, Goodman recites, “Thirty minutes before receiving a first dose of rituximab, or any monoclonal antibody that can cause CRS, the nurse should give the patient Tylenol plus Benadryl”2.
Plante describes a retrospective observational study evaluating protocols for reducing infusion-related reactions (IRR) incidence in rituximab-treated patients with hematological cancer and high lymphocyte count (e.g., Abstract). Plante teaches that cytokine release syndrome is the most accepted mechanism for explaining rituximab-induced IRR, and that strategies including premedication consisting of an antihistamine, an antipyretic, and a glucocorticoid, as well as gradually increasing the infusion rate, are used to prevent IRR (e.g., Introduction). In the observational cohort, all patients received premedication consisting of an antihistamine, an antipyretic, and a glucocorticoid before each rituximab infusion (Section 2.1). Plante discloses that all patients received acetaminophen as the antipyretic, with over 96% receiving a dose of 650 mg (Section 3.2). Plante further teaches that most patients received diphenhydramine (25 mg or 50 mg), orally or intravenously, as the antihistamine.
Based on the further teachings of Goodman and Plante, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to further incorporate the step of administering 650 mg acetaminophen and/or 25 mg diphenhydramine about 30 minutes before each infusion of the therapeutic protein in the dosing regimen collectively taught by Brownstein, Hosseini, Topp, and Zugmaier. The skilled artisan would have been motivated to do so because Goodman and Plante teach that these measures reduce the incidence of CRS/IRR in patients with hematological cancers who are being treated with an anti-CD20 antibody. There would have been a reasonable expectation of success because the therapeutic protein used in the dosing regimen of Brownstein likewise comprises an anti-CD20 antigen-binding domain and seeks to treat hematological malignancies.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
(1)
Claims 123-139, 149, 151, 155-159, 161-162, 187-190, and 194 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-53 of U.S. Patent No. 11,590,223 (cited in IDS) in view of Hosseini (NPJ Systems Biology and Applications (2020) 6: 28; supra), Topp (Blood (2017) 130 (Suppl_1): 1495; supra), and Chu (US 2018/0134798 A1).
Relevant to claims 123-133, 136-137, and 189, patented claims 1-7, 10, and 51-53 recite a method of administering a therapeutic protein (i.e., a bispecific antibody that comprises a first antigen-binding domain that binds human CD3 and a second antigen-binding domain that binds human CD20, comprising identical CDRs to those recited in claim 123) in a dosing regimen to mitigate adverse effects of CRS in the treatment of a CD20-expressing B-cell malignancy. The method comprises the steps of:
administering fractions of a primary dose (D1) comprising no more than 10 mg of the therapeutic protein in week 1 of the dosing regimen, wherein a first dose fraction (F1D1) comprises 40-60% of the total primary dose and is administered to the subject on day 1 of week 1 and a second dose fraction (F2D1) comprises the remaining 40-60% of the total primary dose and is administered to the subject from 12 to 96 hours following administration of the F1D1;
administering fractions of a secondary dose (D2) of the therapeutic protein that is greater than the primary dose, comprising no more than one-half of a maximum weekly dose of the therapeutic protein, in week 2 of the dosing regimen, wherein a first dose fraction (F1D2) comprises 40-60% of the total secondary dose, a second dose fraction (F2D2) comprises the remaining 40-60% of the total secondary dose, and the F2D2 is administered to the subject from 12 to 96 hours following administration of the F1D2;
administering fractions of a tertiary dose (D3) of the therapeutic protein comprising no less than one-half of the maximum weekly dose of the therapeutic protein in week 3 of the regimen, wherein a first dose fraction (F1D3) comprises 40-60% of the total tertiary dose, a second dose fraction (F2D3) comprises the remaining 40-60% of the total tertiary dose, and the F2D3 is administered to the subject from 12 to 96 hours following administration of the F1D3;
administering the maximum weekly dose of the therapeutic protein to the subject as a single dose in a subsequent week (i.e., week 4, or any one of weeks 4-36 (which includes weeks 4-12)) of the dosing regimen.
Patented claims 16 and 21 further recite that the method further comprises administering the maximum weekly dose (from 80 mg to 320 mg) once every two weeks or once every four weeks during a maintenance phase of the dosing regimen, following completion of a weekly phase of the dosing regimen.
Pertinent to claim 187-188, patented claims 12-13 and 32-35 recite that the therapeutic protein is administered in combination with a second agent selected from a steroid (dexamethasone), an anti-histamine, acetaminophen, and an anti-IL-6R antagonist (sarilumab). Patented claim 14 recites that the dexamethasone is administered 1-3 hours prior to at least one of F1D3 and F2D3.
Relevant to claims 134-135, 138-139, 189-190, and 194, patented claims 23-26 recite that the B-cell malignancy is follicular lymphoma (grade 1-3a).
Relevant to claims 149 and 151, patented claims 38-41 recite that the subject is refractory to or has relapsed after previous treatment with an anti-CD20 antibody.
Relevant to claim 155, patented claims 44-47 recite that the anti-CD20 VH and VL and the anti-CD3 VH and VL comprise identical amino acid sequences. Relevant to claims 156, 158-159, and 161-162, the respective anti-CD3 and anti-CD20 heavy and light chains comprise identical amino acid sequences to those instantly claimed.
However, the reference patent does not expressly recite all of the specific doses of the initial, first intermediate, and second intermediate doses (including fractional doses thereof) as set forth in claim 123, in particular a dose corresponding approximately to the “first intermediate dose” of 4 mg set forth in the instant claim.
The teachings of Hosseini and Topp are recited in the 35 U.S.C. § 103 rejections above.
Chu describes a fractionated dose escalation method for treating B-cell proliferative disorders using a bispecific anti-CD20/CD3 antibody intended to reduce incidence of cytokine release syndrome and other cytokine-driven toxicities (e.g., Abstract; ¶ 0084-0095). The method of Chu comprises (a) a first dosing cycle comprising a first dose (C1D1) between about 0.02 mg to about 4.0 mg, a second dose (C1D2) between about 0.05 mg to about 20.0 mg, and a third dose (C1D3) between about 0.2 mg to about 20.0 mg, wherein C1D1 and C1D2 are no greater than C1D3, and (b) a second dosing cycle comprising a single dose (C2D1) of the bispecific antibody, and wherein the C1D1, C1D2, and C1D3 are administered on or about days 1, 8, and 15 (i.e., about one week apart) (e.g., claims 1-7 and 10; ¶ 0005-0010), relevant to claim 123. In some embodiments, the bispecific antibody is an IgG1 antibody (e.g., ¶ 0013), relevant to claims 156-157.
Chu also recites that in the event of a CRS event, the subject can be treated with an anti-IL-6R antibody such as tocilizumab, as well as antihistamines, antipyretics, and/or analgesics as needed (e.g., ¶ 0218-0025).
Considered altogether, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to arrive at a dosing regimen for treating a B-cell malignancy with REGN1979 which comprises a split initial dose of 0.7 mg, a split first intermediate dose of 4 mg, a split second intermediate dose of 20 mg, a full dose administered weekly between weeks 4-12, and a maintenance dose thereafter, determined through the process of routine optimization. The skilled artisan would have been motivated to build off of the fractionated dosing regimen of the reference patent in order to minimize the adverse effects associated with cytokine release syndrome. Hosseini notes that step-fractionated dosing for an alternative anti-CD20/CD3 bispecific antibody reduces markers of CRS (e.g., IL-6 release) without sacrificing anti-tumor efficacy of the treatment regimen, and both REGN1979 and mosunetuzumab illicit peak release of IL-6 and other cytokines upon the first administration of the drug (as taught by Hosseini and Topp). Chu provides an exemplary showing of a dosing regimen that starts with lower cycle 1 doses for this intended purpose, and Topp similarly demonstrates that a dosing regimen starting with similarly low doses may be implemented for REGN1979. There would have been a reasonable expectation of success because it was well within the skill of one of ordinary skill in the art at the time of filing to monitor patients for cytokine release syndrome when administering an anti-tumor therapy and to modify the dosing schedule as necessary to reduce or mitigate observed side effects.
Furthermore, with regard to the specific dosage and interval amounts recited in the instant claims, "[w]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955), and see M.P.E.P. § 2144.05 (II)(A). Moreover, it is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804,809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989). This is because, as is made clear from the prior art, the determination of the dosage regimen of a known drug is well within the purview of one of ordinary skill in the art at the time the invention was made, and it would have been obvious to one of ordinary skill in the art at the time Applicants' invention was made to determine all operable and optimal intervals of treatment because optimal intervals is an art-recognized result-effective variable which would have been routinely determined and optimized in the pharmaceutical art. Therefore, it would be conventional and within the skill of the art to identify the optimal dosages administered and optimal intervals to achieve target levels and therapeutically effective doses. Further, it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. It is clear that both the prior art and claimed method perform the same protocol to achieve the same results. It would be conventional and within the skill of the art to determine the optimal treatment regimens. Accordingly, one can see that the courts, over a period of over 50 years, have consistently held that dosage and treatment interval optimization is obvious.
(2)
Claims 123 and 160 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-53 of U.S. Patent No. 11,590,223 (cited in IDS) in view of Hosseini (NPJ Systems Biology and Applications (2020) 6: 28; supra), Topp (Blood (2017) 130 (Suppl_1): 1495; supra), and Chu (US 2018/0134798 A1) as applied to claims 123-139, 149, 151, 155-159, 161-162, 187-190, and 194, further in view of further in view of Davis (U.S. Patent No. 9,359,437; supra).
The teachings of the reference patent, Hosseini, Topp, and Chu are recited in the non-statutory double patenting rejection above.
The reference patent does not claim that the bispecific antibody administered in the dosing regimen of the invention comprises a first heavy chain constant region comprising the amino acid sequence of instant SEQ ID NO: 18 and a second heavy chain constant region comprising the amino acid sequence of instant SEQ ID NO: 19. However, this deficiency is remedied by Davis as taught above.
Accordingly, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to incorporate into the bispecific anti-CD20/CD3 antibody administered in the dosing regimen of the patented claims the heavy chain constant regions comprising instant SEQ ID NO: 18 and 19, respectively. The skilled artisan would have been motivated to do so because Davis teaches that said heavy chain constant regions have reduced effector functions, which Davis notes is desirable for bispecific antibodies (including T cell engagers) where the binding specificities are the primary contribution to its therapeutic properties. There would have been a reasonable expectation of success because the bispecific antibody used in the method of the patented claims is a bispecific antibody that has specificity for a tumor-associated antigen (CD20) and for CD3, which activates T cells, and because the heavy chain constant regions described by Davis are expressly suited for use in a bispecific antibody.
(3)
Claims 123, 163-166, 169, 173-174, and 180-183 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-53 of U.S. Patent No. 11,590,223 (cited in IDS) in view of Hosseini (NPJ Systems Biology and Applications (2020) 6: 28; supra), Topp (Blood (2017) 130 (Suppl_1): 1495; supra), and Chu (US 2018/0134798 A1) as applied to claims 123-139, 149, 151, 155-159, 161-162, 187-190, and 194, further in view of Zugmaier (US 2013/0287774 A1; supra).
The teachings of the reference patent, Hosseini, Topp, and Chu are recited in the non-statutory double patenting rejection above.
The reference patent does not claim that the dosing regimen further comprising the step of administering a dose of steroid to the subject from 12-24 hours prior to each of the first dose fraction of the initial dose, the first dose fraction of the first intermediate dose, and the first dose fraction of the second intermediate dose. However, this deficiency is remedied by Zugmaier as taught above.
Accordingly, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to modify the dosing regimen recited in the patented claims by adding the additional step of administering a dose of steroid (e.g., 20 mg dexamethasone) to the subject 12-24 hours prior to administration of the first dose fractions at each step. The skilled artisan would have been motivated to do so because Zugmaier teaches that this early dexamethasone schedule decreases the frequency of dose-limiting toxicities (DLTs) and CRS-related events in patients being treated for a B-cell malignancy. There would have been a reasonable expectation of success because (1) Zugmaier teaches that dexamethasone suppresses cytokines such as IL-6 and IFN-γ, which Chu notes are elevated during CRS (e.g., ¶ 0128), and (2) the method of Zugmaier is carried out in combination with treatments comprising an anti-CD3 antigen-binding domain, and the bispecific antibody administered in the dosing regimen of the co-pending claims comprises an anti-CD3 binding domain.
(4)
Claims 123, 163, 167-168, 170-173, 175-179, and 184-186 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-53 of U.S. Patent No. 11,590,223 (cited in IDS) in view of Hosseini (NPJ Systems Biology and Applications (2020) 6: 28; supra), Topp (Blood (2017) 130 (Suppl_1): 1495; supra), and Chu (US 2018/0134798 A1), further in view of Zugmaier (US 2013/0287774 A1; supra) as applied to claims 123, 163-166, 169, 173-174, and 180-183, further in view of Goodman (The Oncology Nurse (TON) – APNPA (2015) 8(5); supra) and Plante (Current Oncology (2021) 28: 4118-4128; supra).
The teachings of the reference patent, Hosseini, Topp, Chu, and Zugmaier are recited in the non-statutory double patenting rejection above.
The reference patent does not claim the steps of administering a dose of antihistamine (e.g., 25 mg diphenhydramine) 30-60 minutes prior to administering a dose of the therapeutic protein or administering a dose of acetaminophen (e.g., 650 mg) 30-60 minutes prior to administering a dose of the therapeutic protein in the dosing regimen. However, this deficiency is remedied by Goodman and Plante as taught above.
Based on the further teachings of Goodman and Plante, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to further incorporate the step of administering 650 mg acetaminophen and/or 25 mg diphenhydramine about 30 minutes before each infusion of the therapeutic protein in the dosing regimen of the reference patent claims. The skilled artisan would have been motivated to do so because Goodman and Plante teach that these measures reduce the incidence of CRS/IRR in patients with hematological cancers who are being treated with an anti-CD20 antibody. There would have been a reasonable expectation of success because the therapeutic protein used in the dosing regimen of the patented claims likewise comprises an anti-CD20 antigen-binding domain and seeks to treat hematological malignancies.
(5)
Claims 123-139, 148-159, 161-162, 187-190, and 194 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 99-158 of co-pending Application No. 18/101,310 (reference application) in view of Brownstein (US 2020/0129617 A1; supra), Hosseini (NPJ Systems Biology and Applications (2020) 6: 28; supra), and Topp (Blood (2017) 130 (Suppl_1): 1495; supra).
The co-pending reference application claims a method of administering a therapeutic protein to a subject to mitigate adverse effects of CRS or IRR in the treatment of a CD20-expressing B-cell malignancy. Pertinent to claims 123-139, 189-190, and 194, co-pending claims 99-106, 108, 110-118, and 129 recite that the method comprises the steps of:
administering fractions of a primary dose (D1; from 0.5-1 mg) comprising no more than 10 mg of the therapeutic protein in week 1 of the dosing regimen, wherein a first dose fraction (F1D1) comprises 10-90% of the total primary dose and is administered to the subject on day 1 of week 1 and a second dose fraction (F2D1) comprises the remaining 10-90% of the total primary dose and is administered to the subject from 12 to 96 hours following administration of the F1D1;
administering fractions of a secondary dose (D2; 20 mg) of the therapeutic protein which is greater than the primary dose and comprises no more than one-half of a maximum weekly dose of the therapeutic protein in week 2 of the dosing regimen, wherein a first dose fraction (F1D2) comprises 10-90% of the total secondary dose, a second dose fraction (F2D2) comprises the remaining 10-90% of the total secondary dose, and the F2D2 is administered to the subject from 12 to 96 hours following administration of the F1D2;
administering fractions of a tertiary dose (D3) of the therapeutic protein comprising no less than one-half of the maximum weekly dose of the therapeutic protein in week 3 of the regimen, wherein a first dose fraction (F1D3) comprises 10-90% of the total tertiary dose, a second dose fraction (F2D3) comprises the remaining 10-90% of the total tertiary dose, and the F2D3 is administered to the subject from 12 to 96 hours following administration of the F1D3;
administering the tertiary dose as a single dose in weeks 4-12 of the dosing regimen; and
administering the maximum weekly dose (from 80 mg to 320 mg) of the therapeutic protein to the subject as a single dose in a subsequent week (i.e., any one of weeks 4-36) of the dosing regimen, once every two weeks or once every four weeks,
wherein the therapeutic protein is a bispecific antibody comprising a first antigen-binding domain that binds to CD3 and a second antigen-binding domain that binds to human CD20, each comprising identical CDRs as recited in the instant claims, and wherein the cancer is selected from follicular lymphoma among others.
Co-pending claim 120-121 recites that the therapeutic agent is administered in combination with a second agent selected from a steroid, an antihistamine, acetaminophen, or an IL-6R antagonist; or dexamethasone, administered 1-3 hours prior to at least one of F1D1, F2D1, F1D2, and F2D2; or sarilumab.
Pertinent to claims 149 and 151, co-pending claim 123 recites that the patient is refractory to or has relapsed after previous treatment and has previously been treated with an anti-CD20 antibody.
Relevant to claim 155, co-pending claims 126-128 recites that the anti-CD20 antigen-binding domain comprises a VH having the amino acid sequence of SEQ ID NO: 13 and a VL having the amino acid sequence of SEQ ID NO: 15 (which share 100% sequence identity to instant SEQ ID NOs: 4 and 6, respectively), and that the anti-CD3 antigen-binding domain comprises a VH having the amino acid sequence of SEQ ID NO: 14 and a VL having the amino acid sequence of SEQ ID NO: 15 (which share 100% sequence identity to instant SEQ ID NOs: 5 and 6, respectively). Relevant to claims 161-162, co-pending claims 130-132 recite an anti-CD20/CD3 antibody comprising structurally identical heavy and light chains.
Co-pending claims 136-148, 150-155, and 158 also recite a similar dosing regimen to that of the instantly claimed invention, comprising a fractionated primary dose, a fractionated secondary dose, a maximum weekly dose, and a maintenance dose, for a subject with follicular lymphoma.
The co-pending reference application does not expressly recite all of the specific doses of the initial, first intermediate, and second intermediate doses (including fractional doses thereof) as set forth in claim 123, in particular a dose corresponding approximately to the “first intermediate dose” of 4 mg set forth in the instant claim. However, these deficiencies are remedied by the teachings of Brownstein, Hosseini, and Topp as set forth in the 35 U.S.C. § 103 above.
Accordingly, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to arrive at a dosing regimen for treating a B-cell malignancy with REGN1979 which comprises a split initial dose of 0.7 mg, a split first intermediate dose of 4 mg, a split second intermediate dose of 20 mg, a full dose administered weekly between weeks 4-12, and a maintenance dose thereafter, determined through the process of routine optimization. The skilled artisan would have been motivated to do so because Brownstein teaches that a similar regimen mitigates the adverse effects associated with cytokine release syndrome. Furthermore, Hosseini notes that step-fractionated dosing for an alternative anti-CD20/CD3 bispecific antibody reduces markers of CRS (e.g., IL-6 release) without sacrificing anti-tumor efficacy of the treatment regimen, and both REGN1979 and mosunetuzumab illicit peak release of IL-6 and other cytokines upon the first administration of the drug (as taught by Hosseini and Topp). There would have been a reasonable expectation of success because it was well within the skill of one of ordinary skill in the art at the time of filing to monitor patients for cytokine release syndrome when administering an anti-tumor therapy and to modify the dosing schedule as necessary to reduce or mitigate observed side effects.
Furthermore, with regard to the specific dosage and interval amounts recited in the instant claims, "[w]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955), and see M.P.E.P. § 2144.05 (II)(A). Moreover, it is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804,809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989). This is because, as is made clear from the prior art, the determination of the dosage regimen of a known drug is well within the purview of one of ordinary skill in the art at the time the invention was made, and it would have been obvious to one of ordinary skill in the art at the time Applicants' invention was made to determine all operable and optimal intervals of treatment because optimal intervals is an art-recognized result-effective variable which would have been routinely determined and optimized in the pharmaceutical art. Therefore, it would be conventional and within the skill of the art to identify the optimal dosages administered and optimal intervals to achieve target levels and therapeutically effective doses. Further, it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. It is clear that both the prior art and claimed method perform the same protocol to achieve the same results. It would be conventional and within the skill of the art to determine the optimal treatment regimens. Accordingly, one can see that the courts, over a period of over 50 years, have consistently held that dosage and treatment interval optimization is obvious.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
(6)
Claims 123 and 160 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 99-158 of co-pending Application No. 18/101,310 (reference application) in view of Brownstein (US 2020/0129617 A1; supra), Hosseini (NPJ Systems Biology and Applications (2020) 6: 28; supra), and Topp (Blood (2017) 130 (Suppl_1): 1495; supra) as applied claims 123-139, 148-159, 161-162, 187-190, and 194 above, further in view of Davis (U.S. Patent No. 9,359,437; supra).
The teachings of the co-pending reference application, Brownstein, Hosseini, and Topp are recited in the provisional non-statutory double patenting rejection above.
The co-pending claims do not recite that the bispecific antibody administered in the dosing regimen of the invention comprises a first heavy chain constant region comprising the amino acid sequence of instant SEQ ID NO: 18 and a second heavy chain constant region comprising the amino acid sequence of instant SEQ ID NO: 19. However, this deficiency is remedied by Davis.
Accordingly, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to incorporate into the bispecific anti-CD20/CD3 antibody administered in the dosing regimen of the co-pending claims the heavy chain constant regions comprising instant SEQ ID NO: 18 and 19, respectively. The skilled artisan would have been motivated to do so because Davis teaches that said heavy chain constant regions have reduced effector functions, which Davis notes is desirable for bispecific antibodies (including T cell engagers) where the binding specificities are the primary contribution to its therapeutic properties. There would have been a reasonable expectation of success because the bispecific antibody used in the method of the co-pending claims is a bispecific antibody that has specificity for a tumor-associated antigen (CD20) and for CD3, which activates T cells, and because the heavy chain constant regions described by Davis are expressly suited for use in a bispecific antibody.
(7)
Claims 123, 163-166, 169, 173-174, and 180-183 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 99-158 of co-pending Application No. 18/101,310 (reference application) in view of Brownstein (US 2020/0129617 A1; supra), Hosseini (NPJ Systems Biology and Applications (2020) 6: 28; supra), and Topp (Blood (2017) 130 (Suppl_1): 1495; supra) as applied claims 123-139, 148-159, 161-162, 187-190, and 194 above, further in view of Zugmaier (US 2013/0287774 A1; supra).
The teachings of the co-pending reference application, Brownstein, Hosseini, and Topp are recited in the provisional non-statutory double patenting rejection above.
The co-pending claims do not recite that the dosing regimen further comprising the step of administering a dose of steroid to the subject from 12-24 hours prior to each of the first dose fraction of the initial dose, the first dose fraction of the first intermediate dose, and the first dose fraction of the second intermediate dose. However, this deficiency is remedied by Zugmaier.
Accordingly, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to modify the dosing regimen recited in the co-pending claims by adding the additional step of administering a dose of steroid (e.g., 20 mg dexamethasone) to the subject 12-24 hours prior to administration of the first dose fractions at each step. The skilled artisan would have been motivated to do so because Zugmaier teaches that this early dexamethasone schedule decreases the frequency of dose-limiting toxicities (DLTs) and CRS-related events in patients being treated for a B-cell malignancy. There would have been a reasonable expectation of success because (1) Zugmaier teaches that dexamethasone suppresses cytokines such as IL-6 and IFN-γ, which Brownstein notes are elevated during CRS, and (2) the method of Zugmaier is carried out in combination with treatments comprising an anti-CD3 antigen-binding domain, and the bispecific antibody administered in the dosing regimen of the co-pending claims comprises an anti-CD3 binding domain.
(8)
Claims 123, 163, 167-168, 170-173, 175-179, and 184-186 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 99-158 of co-pending Application No. 18/101,310 (reference application) in view of Brownstein (US 2020/0129617 A1; supra), Hosseini (NPJ Systems Biology and Applications (2020) 6: 28; supra), Topp (Blood (2017) 130 (Suppl_1): 1495; supra) and further in view of Zugmaier (US 2013/0287774 A1; supra) as applied to claims 123, 163-166, 169, 173-174, and 180-183 above, further in view of Goodman (The Oncology Nurse (TON) – APNPA (2015) 8(5)) and Plante (Current Oncology (2021) 28: 4118-4128).
The teachings of the co-pending reference application, Brownstein, Hosseini, Topp, and Zugmaier are recited in the provisional non-statutory double patenting rejection above.
The co-pending claims do not expressly teach the steps of administering a dose of antihistamine (e.g., 25 mg diphenhydramine) 30-60 minutes prior to administering a dose of the therapeutic protein or administering a dose of acetaminophen (e.g., 650 mg) 30-60 minutes prior to administering a dose of the therapeutic protein in the dosing regimen. However, this deficiency is remedied by Goodman and Plante.
Based on the further teachings of Goodman and Plante, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to further incorporate the step of administering 650 mg acetaminophen and/or 25 mg diphenhydramine about 30 minutes before each infusion of the therapeutic protein in the dosing regimen of the co-pending claims. The skilled artisan would have been motivated to do so because Goodman and Plante teach that these measures reduce the incidence of CRS/IRR in patients with hematological cancers who are being treated with an anti-CD20 antibody. There would have been a reasonable expectation of success because the therapeutic protein used in the dosing regimen of the co-pending claims likewise comprises an anti-CD20 antigen-binding domain and seeks to treat hematological malignancies.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Elizabeth A Shupe whose telephone number is (703) 756-1420. The examiner can normally be reached Monday to Friday, 9:30am - 6:00pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Wu can be reached at (571) 272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ELIZABETH A SHUPE/Examiner, Art Unit 1643
/Brad Duffy/Primary Examiner, Art Unit 1643
1 Claims 164-166 recite conditional language (“if the first dose fraction … and the second dose fraction … are not administered to the subject on consecutive days, then …”). As set forth above, and consistent with the fact pattern presented in Ex parte Schulhauser, the broadest reasonable interpretation of the claim includes an embodiment in which the first and second dose fractions are administered on consecutive days and thus the administration of the steroid prior to the second dose fractions is not required to meet the limitations of the claim. Brownstein sets forth above that the second dose fractions can be administered 12-96 hours after the first dose fractions. Within the scope of this limitation are embodiments in which the second dose fractions are performed on the following day (e.g., 18 hours, or 24 hours, or 30 hours).
2 “Tylenol” and “Benadryl” are brand/trade names associated with acetaminophen and diphenhydramine, respectively.
Prosecution Insights