DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Claims 3-5 and 23 have been cancelled; claims 1-2, 6-14, 17-22, and 35 have been amended; and, claims 48-52 have been newly added, as requested in the amendment filed on 05/01/2026. Following the amendment, claims 1-2, 6-22, and 24-52 are pending in the instant application.
Claims 1-2, 6-22, and 24-52 are under examination in the instant office action.
Priority - Updated
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Claims 1-2, 6-22, and 24-52 have an effective filing date of October 2, 2020 corresponding to PRO 63/086,658
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/01/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Specification - Objection Withdrawn
The specification was objected to for including improperly demarcated trade names and/or marks used in commerce. Applicant has submitted an amended specification such that the trade names and/or marks used in commerce are properly represented. As such, the objection to the specification is withdrawn.
Claim Rejections - 35 USC § 112 - Withdrawn
Claims 35 and 40-42 were 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.
Applicant has amended claim 35 such that the claim now refers to specific antagonistic antibodies instead of the broad recitation of various inhibitors. Furthermore, it is noted that claim 1 has been amended to incorporate sequence limitations regarding the bispecific anti-CD20/CD3 antibody and the anti-PD-1 antibody wherein the sequences corresponding to HCDRs 1-3, LCDRs 1-3, HCVR, and LCVR sequences for each of (i) the anti-CD0 antigen-binding arm, (ii) the anti-CD3 antigen-binding arm, and (ii) the anti-PD-1 antibody are all recited. As such, subsequently dependent claims 40-42 are now considered to be adequately described wherein they further limit the recited structure of the bispecific antibody of claim 1 which sufficiently describes complimentary HCVR and LCVR sequences required for the formation of functional antigen-binding domains. In view of the above-listed claim amendments, the rejection of claims 35 and 40-42 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 is withdrawn.
Claims 1 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, regarding scope of enablement.
Applicant has amended independent claim 1 such that the claim is now drawn to a method of treating or inhibiting the growth of a tumor comprising “selecting a subject with a CD20-expressing cancer”. As such, independent claim 1, and subsequently dependent claims 6-22 and 24-47 are deemed to be enabled. Claims 3-5 and 23 have been cancelled, rendering their rejection moot. Thus, the rejection of claims 1 and 3-47 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, regarding scope of enablement, are withdrawn.
Claims were rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite.
Claims 3-5 and 23 have been cancelled, rendering their rejection moot.
With regard to claim 1, Applicant argues that at Paragraph 106 of the specification, “bispecific antibody” is defined as “an immunoglobulin protein” comprising a first antigen-binding domain and a second antigen-binding domain; thus a “bispecific antibody” refers to a single molecule with at least two different binding moieties. Applicant’s argument is deemed persuasive.
With regard to claims 6-9 and 15-18, Applicant has amended claim 7 to remove the term “about” and further argues that the specification discloses at Paragraph 154 that the term “about” refers to a range of values that fall within up to 25% of the stated reference values and thus does not render the claims indefinite. Applicant’s arguments are deemed persuasive.
With regard to claims 26-28, Applicant argues that at Paragraph 083 of the specification, “prior therapy” is defined as being administered prior to the combination of bispecific antibody and the anti-PD-1 antibody; thus the recited prior therapy occurs before steps (a)-(b) of claim 1. Applicant’s argument is deemed persuasive.
In view of the amendments and arguments above, the rejection of claims 1-47under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn.
Claim 23 was rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 23 has been cancelled, rendering its rejection moot. As such, the rejection of claim 23 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, for being of improper dependent form is withdrawn.
Claim Rejections - 35 USC § 102 - Withdrawn
Claims 1-3, 5, 22, 24-39, and 44-47 were rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by US 2017/0174779 A1 (previously cited on PTO-892; herein after referred to as "Varghese").
Applicant has amended independent claims 1 and 2 such that the claims now require “administering to the subject an antibody or antigen-binding fragment thereof that specifically binds programmed death 1 (PD-1) at least 5 weeks after administering the first dose of the bispecific antibody or antigen-binding fragment thereof”. It is noted that Varghese does not explicitly teach an embodiment wherein the anti-PD-1 antibody is administered at least 5 weeks after administering the first dose of the bispecific anti-CD20/CD3 antibody and as such does not anticipate claims 1-2, 22, 24-39, and 44-47. Thus, the rejection of claims 1-3, 5, 22, 24-39, and 44-47 under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Varghese is withdrawn.
Claim Rejections - 35 USC § 103 - Withdrawn
Claims 1-35 and 44-47 were rejected under 35 U.S.C. 103 as being unpatentable over US 2017/0174779 A1 (previously cited on PTO-892; herein after referred to as "Varghese") in view of non-patent literature by Hosseini et. al. (npj Systems Biology and Applications, August 2020, 6(28); previously cited on PTO-892; herein after referred to as "Hosseini").
Claims 36-43 were rejected under 35 U.S.C. 103 as being unpatentable over US 2017/0174779 A1 (previously cited on PTO-892; herein after referred to as "Varghese") and non-patent literature by Hosseini et. al. (npj Systems Biology and Applications, August 2020, 6(28); previously cited on PTO-892; herein after referred to as "Hosseini"), as applied to claims 1-35 and 44-47 above, and in further view of US 2015/0266966 A1 (previously cited on PTO-892; herein after referred to as "Smith").
With regard to the above-listed claim rejections under 35 U.S.C. 103, it is noted that Applicant has amended independent claims 1 and 2 such that the claims now require “administering to the subject an antibody or antigen-binding fragment thereof that specifically binds programmed death 1 (PD-1) at least 5 weeks after administering the first dose of the bispecific antibody or antigen-binding fragment thereof”. It is noted that Varghese does not explicitly teach/suggest an embodiment wherein the anti-PD-1 antibody is administered at least 5 weeks after administering the first dose of the bispecific anti-CD20/CD3, and neither of Hosseini or Smith remedy this deficiency as they do not suggest a second therapeutic or provide motivation to administer a second agent at least 5 weeks after a bispecific anti-CD20/CD3 antibody. Thus, the rejection of claims 1-35 and 44-47 under 35 U.S.C. 103 in view of Varghese and Hosseini and the rejection of claims 36-43 under 35 U.S.C. 103 in view of Varghese, Hosseini, and Smith are withdrawn.
Double Patenting - Withdrawn
Claims 1-47 were rejected on the ground of nonstatutory double patenting as being unpatentable over the pertinent claims of the below-listed U.S. Patent Nos. in view of US 2017/0174779 A1 (previously cited on PTO-892; herein after referred to as "Varghese") and non-patent literature by Hosseini et. al. (npj Systems Biology and Applications, August 2020, 6(28); previously cited on PTO-892; herein after referred to as "Hosseini"), and/or US 2015/0266966 A1 (previously cited on PTO-892; herein after referred to as "Smith").
US Patent No.
Brief Description of the Invention
Pertinent Claims
11590223
Method of Administering a Bispecific Anti-CD20/CD3 Antibody to a Subject in a Dosing Regimen to Mitigate CRS
1-53
12054557
Method of Treating or Inhibiting the Growth of a Tumor Comprising Administering an Anti-CD20/CD3 Bispecific Antibody and Anti-PD-1 Antibody
1-33
12274747
Method for Treating Cancer and Inhibiting CRS in a Subject Comprising Conjointly Administering a Multispecific Antigen Binding Molecule with an Anti-CD3 Arm and Anti-Tumor Antigen Arm
1-2, 5-10, 12-13, 16-24, 27-33
Claims 1-47 were provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the pertinent claims of the below-listed copending Application Nos. in view of US 2017/0174779 A1 (previously cited on PTO-892; herein after referred to as "Varghese") and non-patent literature by Hosseini et. al. (npj Systems Biology and Applications, August 2020, 6(28); previously cited on PTO-892; herein after referred to as "Hosseini"), and/or US 2015/0266966 A1 (previously cited on PTO-892; herein after referred to as "Smith").
Copending Application No.
Brief Description of the Invention
Pertinent Claims
17355532
Method for Treating B-Cell Cancer in a Subject Comprising Administering a Bispecific Anti-CD20/CD3 Antibody
63-72
18101310
Method of Administering a Bispecific Anti-CD20/CD3 Antibody to a Subject to Mitigate Adverse Effects of CRS
99-151
18114057
Dosing Regimen for Anti-CD20/CD3 Bispecific Antibody to Treat a B-Cell Malignancy
123-195
19077873
Method of Treating Cancer and Inhibiting CRS in a Subject Comprising Conjointly Administering a Bispecific Anti-CD20/CD3 Binding Molecule
1, 9, 11-12, 26-27, 33, 39, 41, 42, 54, 55, 59-60, 66, 68, 72-74, 110-116
With regard to the above-listed claim rejections under nonstatutory double patenting, it is noted that Applicant has amended independent claims 1 and 2 such that the claims now require “administering to the subject an antibody or antigen-binding fragment thereof that specifically binds programmed death 1 (PD-1) at least 5 weeks after administering the first dose of the bispecific antibody or antigen-binding fragment thereof”. It is noted that none of the cited reference patents, cited reference applications, nor Varghese explicitly teach/suggest an embodiment wherein the anti-PD-1 antibody is administered at least 5 weeks after administering the first dose of the bispecific anti-CD20/CD3, and neither of Hosseini or Smith remedy this deficiency as they do not suggest a second therapeutic or provide motivation to administer a second agent at least 5 weeks after a bispecific anti-CD20/CD3 antibody. Thus, the rejection of claims 1-47 under nonstatutory double patenting in view of the cited reference patents or the cited reference applications each in view of Varghese, Hosseini, and Smith are withdrawn.
Claim Rejections - 35 USC § 112 - Maintained
Claim 2 stands as rejected, and new claims 48-52 which depend from claim 2 are newly rejected, under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, regarding scope of enablement.
While it is acknowledged that claim 2 is an independent claim and not dependent from claim 1 as mistakenly indicated in the previous Office Action (11/04/2025), it is specifically noted that, much like independent claim 1, independent claim 2 is drawn to a method of ameliorating CRS in a subject with a tumor, comprising selecting a subject with cancer and generally administering a bispecific anti-CD20/CD3 antibody after which an anti-PD-1 antibody is administered. As such, the independent claim 2, and subsequently dependent new claims 48-52, generally read on the amelioration of CRS for any and all cancers, the full scope of which is not enabled by the method as instantly claimed.
As indicated by Baxevanis et. al. (previously made of record and cited on PTO-892), the art does not recognize a single antibody that is an effective therapy against all tumors and the function of the therapeutic antibody must correlate with an effect on its target conducive to tumor growth inhibition or tumor lysis, resulting in patient benefit. Furthermore, all working Examples provided by Applicant (Pages 48-55 of the specification) utilize CD20+ tumor cells (e.g., WSU-DLCL2 cells, which is a human B-cell lymphoma cell line) or utilize models/simulations based on B-NHL (all of which are CD20-expressing cancers) to evaluate therapeutic efficacy regarding cancer/tumor treatment and CRS.
As such, it is maintained that in view of the lack of the predictability of the art to which the invention pertains as evidenced by the art above, the lack of guidance and direction provided by Applicant, and the absence of working examples, undue experimentation would be required to use the method of claim 2 in the amelioration of CRS in patients having any and all cancers with a reasonable expectation of success, absent a specific and detailed description in Applicant’s specification of how to effectively practice this and absent working examples providing evidence which is reasonably predictive that the claimed method is functional, commensurate in scope with the claimed invention.
Claim Rejections - 35 USC § 103 - New as Necessitated by Amendment
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2, 6-22, and 24-52 are rejected under 35 U.S.C. 103 as being unpatentable over US 2017/0174779 A1 (previously cited on PTO-892; herein after referred to as "Varghese"), US 2015/0266966 A1 (previously cited on PTO-892; herein after referred to as "Smith"), non-patent literature by Hosseini et. al. (npj Systems Biology and Applications, August 2020, 6(28); previously cited on PTO-892; herein after referred to as "Hosseini"), and non-patent literature by Ceschi et. al. (Frontiers in Pharmacology, May 2020, 11(557), 1-7; herein after referred to as "Ceschi").
Varghese teaches methods for treating, reducing the severity, or inhibiting the growth of cancer (e.g., a B-cell cancer such as Hodgkin's lymphoma or acute lymphoblastic leukemia) wherein the methods of the invention comprise administering to a subject in need thereof a therapeutically effective amount of an antibody or antigen-binding fragment thereof that specifically binds to programmed death 1 (PD-1) receptor in combination with a therapeutically effective amount of a bispecific antibody that specifically binds to CD20 and CD3 (Abstract). The expression “a subject in need thereof” means a human or non-human mammal that exhibits one or more symptoms or indications of cancer, and/or who has been diagnosed with cancer, including a B-cell cancer, and who needs treatment for the same; the expression also includes patients with a B-cell cancer that is resistant to or refractory to or is inadequately controlled by prior therapy (e.g., treatment with a conventional anti-cancer agent), including subjects who have previously been treated with a CD20 inhibitor (e.g., rituximab, and anti-CD20 antibody) (Paragraph 0035), and therefore “a subject in need thereof” includes a patient that has cancer wherein said cancer may be refractory/inadequately responsive to a prior therapy such as an anti-CD20 antibody. The expression “in combination with” means that the anti-CD20/anti-CD3 bispecific antibody is administered before, after, or concurrent with the anti-PD-1 antibody; the term “in combination with” also includes sequential or concomitant administration of anti-PD-1 antibody and a bispecific anti-CD20/anti-CD3 antibody (Paragraph 0073; emphasis added). When administered “after” the bispecific anti-CD20/anti-CD3 antibody, the anti-PD-1 antibody may be administered about 10 minutes, about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours, about 72 hours, or more than 72 hours after the administration of the bispecific anti-CD20/anti-CD3 antibody (Id.). Varghese teaches methods which comprise administering an anti-PD-1 antibody in combination with a bispecific anti-CD20/CD3 antibody to a subject wherein the antibodies are contained within separate or combined (single) pharmaceutical composition; methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes (Paragraphs 0078-0079). The phrase "therapeutically effective amount" means an amount of antibody (anti-PD-1 antibody or bispecific anti-CD20/CD3 antibody) that results in one or more of: (a) a reduction in the severity or duration of a symptom of a B-cell cancer; (b) inhibition of tumor growth, or an increase in tumor necrosis, tumor shrinkage and/or tumor disappearance; (c) delay in tumor growth; (d) inhibit or retard or stop tumor metastasis; (e) prevention of recurrence of tumor growth; (f) increase in survival of a subject with a B-cell cancer; and/or (g) a reduction in the use or need for conventional anti-cancer therapy (e.g., reduced or eliminated use of chemotherapeutic or cytotoxic agents) as compared to an untreated subject or a subject administered with either antibody as monotherapy (Paragraph 0093). More specifically, Varghese teaches increased inhibition of tumor growth by 10-80% compared to an untreated subject or subject administered with either antibody as a monotherapy and/or a delay in tumor growth by 3+ days, 1+ months, and/or 3+ years compared to an untreated subject or subject administered with either antibody as a monotherapy (Paragraph 0047). In certain embodiments, each dose of the anti-CD20/anti-CD3 antibody is administered in more than one fractions, e.g., in 2-5 fractions ("split dosing") within the given dosing period; the anti-CD20/anti-CD3 bispecific antibody may be administered in split doses to reduce or eliminate the cytokine "spikes" induced in response to administration of the antibody wherein cytokine spikes refer to the clinical symptoms of the cytokine release syndrome ("cytokine storm") and infusion related reactions, seen in patients administered anti-CD20 antibodies (Paragraph 0039). In certain embodiments, a dose of the bispecific antibody is split into 2 or more fractions, wherein each fraction comprises an amount of the antibody equal to the other fractions and in other embodiments, a dose of the bispecific antibody is administered split into 2 or more fractions, wherein the fractions comprise unequal amounts of the antibody, e.g., more than or less than the first fraction (Id.). a therapeutically effective amount of the bispecific anti-CD20/CD3 antibody can be from about 10 micrograms (mcg) to about 8000 mcg (Paragraph 0095) and the amount may also be expressed in terms of milligrams of antibody per kilogram of subject body weight wherein bispecific anti-CD20/CD3 antibody used in the methods of the invention may be administered to a subject at a dose of about 0.0001 to about 100 mg/kg of subject body weight and, more specifically, the bispecific anti-CD20/anti-CD3 antibody may be administered at a dose of about 0.1 mg/kg to about 10 mg/kg of a patient's body weight (Paragraph 0096). A therapeutically effective amount of an anti-PD-1 antibody can be from about 0.05 mg to about 600 mg (Paragraph 0094) and the amount may also be expressed in terms of milligrams of antibody per kilogram of subject body weight wherein anti-PD-1 antibody used in the methods of the invention may be administered to a subject at a dose of about 0.0001 to about 100 mg/kg of subject body weight and, more specifically, 0.1 mg/kg to about 20 mg/kg of a patient's body weight (Paragraph 0096). Varghese teaches that methods of the invention comprise: (i) administering to a subject an anti-PD-1 antibody at a dosing frequency of about four times a week, twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every eight weeks, once every twelve weeks, or less frequently so long as a therapeutic response is achieved and (ii) administering to a subject a bispecific anti-CD20/CD3 antibody at a dosing frequency of about four times a week, twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every eight weeks, once every twelve weeks, or less frequently so long as a therapeutic response is achieved (Paragraph 0084). In certain embodiments, the methods of the invention comprise administering 0-50 therapeutic doses each of an anti-PD-1 antibody and a bispecific antibody against CD20 and CD3, wherein each dose is administered 0.5-12 weeks after the immediately preceding dose, wherein in certain embodiments each dose of the anti-PD-1 antibody is administered once a week, once in 2 weeks or once in 4 weeks and each dose of the bispecific antibody is administered once a week, once in 2 weeks or once in 4 weeks; in one embodiment, each dose of the anti-PD-1 antibody is administered once in 2 weeks and each dose of the bispecific antibody is administered once a week (Paragraph 0015). Varghese teaches an exemplary antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10; this exemplary antibody is the fully human anti-PD-1 antibody known as REGN2810 (Paragraph 0058). It is specifically noted that Varghese SEQ ID NOs: 9 and 10 are 100% matches to instant SEQ ID NOs: 9 and 10, respectively. As such, Varghese SEQ ID NO: 9 comprises 100% matches to instant SEQ ID NOs: 3-8 (corresponding to heavy chain CDR1-3 and light chain CDR1-3) and 1-2 (corresponding to the heavy chain variable and light chain variable regions). It is specifically noted that REGN2810 is known in the art as cemiplimab. Varghese further teaches an exemplary bispecific anti-CD20/anti-CD3 antibody ("bsAbl" which is also known as "Antibody 1" as disclosed in US 2015/0266966, i.e., “Smith”), a fully human bispecific monoclonal antibody against CD20 and CD3 wherein the antibody comprises an anti-CD20 binding arm comprising a first heavy chain variable region (A-HCVR) comprising the amino acid sequence of SEQ ID NO: 11 and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 12; and an anti-CD3 binding arm comprising a second heavy chain variable region (B-HCVR) comprising the amino acid sequence of SEQ ID NO: 13 and a LCVR comprising the amino acid sequence of SEQ ID NO: 12 (Paragraphs 0071 and 0099). It is specifically noted that Varghese SEQ ID NOs: 11-13 are 100% matches to instant SEQ ID NOs: 11-13, respectively, and comprise 100% matches to instant SEQ ID NOs: 14-19 (heavy chain CDR1-3 and light chain CDR1-3 of anti-CD20 arm) and SEQ ID NOs: 17-22 (light chain CDR1-3 and heavy chain CDR1-3 of anti-CD3 arm). The Smith reference is solely relied upon to provide the full sequences corresponding to exemplary “bsAb1” or “Antibody 1” of Varghese, wherein it is noted that Smith further discloses the full heavy and light chain sequences of “Antibody 1” (i.e., REGN1979) in the sequence listing. More specifically, Smith SEQ ID NO: 35, 37, and 40 are identified as the shared light chain of the of REGN1979, the heavy chain of the anti-CD20 arm of REGN1979, and the heavy chain of the anti-CD3 arm of REGN1979, respectively. It is specifically noted that Smith SEQ ID NOs: 35, 37, and 40 are 100% matches to instant SEQ ID NOs: 24, 23, and 25, respectively, and it is further noted that REGN1979 is known in the art as odronextamab. Varghese further teaches that methods of the invention can further comprise administration of a third therapeutic agent selected from the group including, for example, radiation, surgery, a cancer vaccine, a PD-Ll inhibitor (e.g., an anti-PD-Ll antibody), a LAG-3 inhibitor, a CTLA-4 inhibitor (e.g., ipilimumab ), a TIM3 inhibitor, a BTLA inhibitor, a TIGIT inhibitor, a CD47 inhibitor, etc. (Paragraph 0075). Thus, Varghese teaches/suggests methods of treating cancer comprising administering, to a patient having cancer wherein said cancer may be a B-cell cancer that is refractory/inadequately responsive to a prior therapy, a therapeutically effective amount of a bispecific anti-CD20/CD3 antibody (i.e., REGN1979, odronextamab) and an anti-PD-1 antibody (i.e., REGN2810, cemiplimab), wherein said anti-PD-1 antibody may be administered after the bispecific antibody, wherein the bispecific antibody is administered in split doses to reduce or eliminate cytokine spikes, and wherein said treatment may further comprise administration of a third therapeutic agent such that the treatment results in one or more of: (a) a reduction in the severity or duration of a symptom of a B-cell cancer; (b) inhibition of tumor growth, or an increase in tumor necrosis, tumor shrinkage and/or tumor disappearance; (c) delay in tumor growth; (d) inhibit or retard or stop tumor metastasis; (e) prevention of recurrence of tumor growth; (f) increase in survival of a subject with a B-cell cancer; and/or (g) a reduction in the use or need for conventional anti-cancer therapy (e.g., reduced or eliminated use of chemotherapeutic or cytotoxic agents) as compared to an untreated subject or a subject administered with either antibody as monotherapy.
However, it is noted that neither Varghese nor Smith explicitly teach or suggest administering the anti-PD-1 antibody at least five weeks after administering the first dose of the bispecific anti-CD20/CD3 antibody. This deficiency is remedied by the combined teachings of Hosseini and Ceschi.
Hosseini teaches that mosunetuzumab, a T-cell dependent bispecific antibody that binds CD3 and CD20 to drive T-cell mediated B-cell killing, is currently being tested in non-Hodgkin lymphoma, but potent immune stimulation with T-cell directed therapies poses the risk of cytokine release syndrome, potentially limiting dose and utility; a novel mechanistic model of immune and antitumor responses to the T-cell bispecifics (mosunetuzumab and blinatumomab), including the dynamics of B- and T-lymphocytes in circulation, lymphoid tissues, and tumor wherein simulations delineated mechanisms contributing to observed cell and cytokine (IL6) dynamics and predicted that initial step-fractionated dosing limits systemic T-cell activation and cytokine release without compromising tumor response and these results supported a change to a step-fractionated treatment schedule of mosunetuzumab in the ongoing Phase I clinical trial, enabling safer administration of higher doses (Abstract). In a Phase 1 clinical trial, the authors have tested a range of mosunetuzumab doses from 0.05 to 2.8 mg for the Cycle 1 Day 1 dose in patients with r/r NHL; overall, we observed that cycle 1 double-step fractionated dosing of mosunetuzumab appears to mitigate CRS-related toxicity in r/r NHL patients (Page 6, Column 2, Paragraph 4). Model predictions for IL6 levels suggest that: (i) 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; (ii) 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; (iii) 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 (Page 6, Last Paragraph of Column 1 through First Full Paragraph of Column 2; Figure 5, reproduced below). The doses/schedules of Figure 5 are: (1) a, e, and i: 20mg on Cycle 1 Day 1 (C1D1); (2) b, f, and j: 6.7 mg on C1D1, C1D8, C1D15; (3) c, g, and k: 1.6/10/10 mg on C1D1, C1D8, and C1D15; (4) d, h, and l: 1.6/20 mg on C1D1, and C1D8; and in all regimens 20 mg is administered on Day 1 of subsequent cycles.
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Greyscale
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 (Page 6, Column 2, Second Full Paragraph). Simulations accurately predicted the levels and ranges of peak IL6 levels measured in more than 95 patients in our Phase 1 clinical trial, with only one exception in cohort 1.6 mg for a patient whose IL6 levels exceeded the range predicted by the model; however, this patient is also an outlier with respect to the clinical data, with IL6 levels about 30-fold higher than the next highest measurement (Page 7, Column 1, Paragraph 1; Figure 6). Thus, the increased safety with the altered clinical strategy and the emerging cytokine data support the accuracy and value of the model predictions wherein this toxicity-mitigation dosing strategy has enabled administration of higher, more efficacious doses without reaching maximum tolerated dose (Id.). Hosseini teaches that for bispecific anti-CD20/CD3 antibody mosunetuzumab, dosing strategies, e.g., step-fractionated dosing, of anti-CD20/CD3 antibodies can serve as a method for mitigating CRS in patients and further indicates that cytokine release profiles (IL-6 specifically) for various dosing regimen generally demonstrate increased cytokine and/or cytokine spikes through approximately days 21-28.
Ceschi teaches that immune checkpoint inhibitors (ICIs) have proven effective in the treatment of numerous cancers; however, they have been associated with immune-related adverse events (irAEs), among which cytokine release syndrome (CRS) has been reported in a few case reports (Abstract). Table 1 summarizes baseline characteristics of ICI-related CRS safety reports, wherein ICI-related CRS reporting increased over time, with 27 cases (47%) in 2019 (no cases of ICI-related CRS reported in 2020 as of January 12th); melanoma (n=17, 29%) and hematologic malignancies (n=16, 28%) were the most common underlying cancers and regardless of cancer type, ICI-related CRS safety reports were more numerous for anti-PD-1/PD-L1 antibodies (43, 74%) (Page 3, Column 1, First Paragraph). It is noted that of the anti-PD-1 monotherapy safety reports pulled, cemiplimab only demonstrated one instance of CRS (i.e., 2% of cases) compared to nivolumab and pembrolizumab (21 cases/36% and 12 cases/21%, respectively). In CRS, T cells, B cells, natural killer cells, macrophages and endothelial cells, release a variety of cytokines, among which interleukin-6 (IL 6) plays a central role (Page 3, Column 2, Discussion, Second Paragraph). ICI-related CRS developed with a median of 4 weeks since ICI initiation and ICI-related CRS either recovered or was recovering at the time of reporting in most cases, with only two fatal outcomes (Column 2 of Page 4 through Column 1 of Page 5). Thus, Ceschi teaches that ICI therapies as monotherapies are capable of inducing CRS, wherein CRS develops within a median of 4 weeks after initiation of therapy.
In the test of whether it is “obvious to try” there must be:
(1) a finding in the art at the time of filing of the invention that there had been a recognized problem or need in the art;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
In the instant case (i) Varghese, in view of the sequences taught by Smith, discloses the therapeutic combination of an anti-CD20/CD3 bispecific antibody (e.g., odronextamab) and an anti-PD-1 antibody (e.g., cemiplimab) and teaches that CRS is a common occurrence with anti-CD20 therapies wherein adjusting dosing/schedules may mitigate the risk of CRS; (ii) bispecific anti-CD20/CD3 antibody mosunetuzumab, dosing strategies, e.g., step-fractionated dosing, of anti-CD20/CD3 antibodies can serve as a method for mitigating CRS in patients and further indicates that cytokine release profiles (IL-6 specifically) for various dosing regimen generally demonstrate increased cytokine and/or cytokine spikes through approximately days 21-28; and (iii) Ceschi teaches that ICI therapies as monotherapies are also capable of inducing CRS, wherein CRS develops within a median of 4 weeks after initiation of therapy.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to optimize the dosing/schedule of the anti-CD20/CD3 bispecific antibody and anti-PD-1 antibody as taught by Varghese, wherein the anti-CD20/CD3 antibody is odronextamab and the anti-PD-1 antibody is cemiplimab as suggested by the combination of Varghese and Smith, such that the anti-PD-1 antibody is administered at a sufficient period after the administration of the bispecific antibody such that there is reduced risk for overlapped cytokine release from each therapeutic. One would have been motivated to optimize the dosing/schedule of the anti-CD20/CD3 bispecific antibody and anti-PD-1 antibody to maintain efficacy while preventing known adverse events, including CRS as suggested by Varghese, Hosseini, and Ceschi. One of ordinary skill in the art would have a reasonable expectation of success of both treating a tumor and ameliorating CRS in patients having CD20-expressing cancers because both Varghese and Hosseini disclose that CRS is a common adverse event when anti-CD20 therapies (and more specifically bispecific anti-CD20/CD3 therapies) are administered, Hosseini more specifically indicates cytokine release periods for IL-6 at various dosing schedules effective to reduce CRS, Ceschi teaches that ICI therapies (including various anti-PD-1 therapies) are also capable of inducing CRS within a median of 4 weeks, and Varghese suggests that doses/dosing schedules of each agent of the combination therapy comprising the anti-CD20/CD3 bispecific antibody odronextamab and anti-PD-1 antibody cemiplimab are variable and may be modified/optimized such that there is: (a) a reduction in the severity or duration of a symptom of a B-cell cancer; (b) inhibition of tumor growth, or an increase in tumor necrosis, tumor shrinkage and/or tumor disappearance; (c) delay in tumor growth; (d) inhibit or retard or stop tumor metastasis; (e) prevention of recurrence of tumor growth; (f) increase in survival of a subject with a B-cell cancer; and/or (g) a reduction in the use or need for conventional anti-cancer therapy (e.g., reduced or eliminated use of chemotherapeutic or cytotoxic agents) as compared to an untreated subject or a subject administered with either antibody as monotherapy.
MPEP 2144.05 states: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[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)”. In the instant case, given the known function of each antibody in cancer treatment, given their demonstrated utility together in cancer treatment, given the disclosure of Varghese for arriving at therapeutic doses and dose timing wherein each of the bispecific anti-CD20/CD3 antibody and anti-PD-1 antibody may be administered at dosing frequencies of about four times a week, twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every eight weeks, once every twelve weeks, or less frequently so long as a therapeutic response is achieved, it is well within the level of the ordinary skilled artisan to adjust the dosages and timing of administration for optimal therapeutic efficacy and safety, and to arrive at the doses and timing of administration instantly claimed, wherein the anti-PD-1 antibody may be administered 5 weeks after the administration of the bispecific anti-CD20/CD3 antibody (odronextamab) at either a flat dose or preferably as a fractionated dose, which would reasonably be expected to provide therapeutic treatment with reduced CRS.
Response to Arguments - 35 USC § 103
Applicant’s arguments, see 20-24 of Remarks, filed 05/01/2026, with respect to the rejection(s) of claim(s) 1-47 under 35 U.S.C. 103 have been fully considered in view of the instant claim amendments and are persuasive. Therefore, the rejection(s) has/have been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of US 2017/0174779 A1 (previously cited on PTO-892; herein after referred to as "Varghese"), US 2015/0266966 A1 (previously cited on PTO-892; herein after referred to as "Smith"), non-patent literature by Hosseini et. al. (npj Systems Biology and Applications, August 2020, 6(28); previously cited on PTO-892; herein after referred to as "Hosseini"), and non-patent literature by Ceschi et. al. (Frontiers in Pharmacology, May 2020, 11(557), 1-7; herein after referred to as "Ceschi").
It is specifically noted that applicant has amended independent claims 1-2 such that the claims now recite the limitation “administering to the subject an antibody or antigen-binding fragment thereof that specifically binds programmed death 1 (PD-1) at least 5 weeks after administering the first dose of the bispecific antibody or antigen-binding fragment thereof”. It is noted that the combination of Varghese, Hosseini, and/or Smith did not provide sufficient motivation alone regarding the administration of an anti-PD-1 antibody at least five weeks after administering the first dose of the bispecific anti-CD20/CD3 antibody. However, this deficiency is addressed by Ceschi. As outlined in the 103 section above, it is specifically noted that (i) Varghese, in view of the sequences taught by Smith, discloses the therapeutic combination of an anti-CD20/CD3 bispecific antibody (e.g., odronextamab) and an anti-PD-1 antibody (e.g., cemiplimab) and teaches that CRS is a common occurrence with anti-CD20 therapies wherein adjusting dosing/schedules may mitigate the risk of CRS; (ii) bispecific anti-CD20/CD3 antibody mosunetuzumab, dosing strategies, e.g., step-fractionated dosing, of anti-CD20/CD3 antibodies can serve as a method for mitigating CRS in patients and further indicates that cytokine release profiles (IL-6 specifically) for various dosing regimen generally demonstrate increased cytokine and/or cytokine spikes through approximately days 21-28; and (iii) Ceschi teaches that ICI therapies as monotherapies are also capable of inducing CRS, wherein CRS develops within a median of 4 weeks after initiation of therapy.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to optimize the dosing/schedule of the anti-CD20/CD3 bispecific antibody and anti-PD-1 antibody as taught by Varghese, wherein the anti-CD20/CD3 antibody is odronextamab and the anti-PD-1 antibody is cemiplimab as suggested by the combination of Varghese and Smith, such that the anti-PD-1 antibody is administered at a sufficient period after the administration of the bispecific antibody such that there is reduced risk for overlapped cytokine release from each therapeutic. One would have been motivated to optimize the dosing/schedule of the anti-CD20/CD3 bispecific antibody and anti-PD-1 antibody to maintain efficacy while preventing known adverse events, including CRS as suggested by Varghese, Hosseini, and Ceschi. One of ordinary skill in the art would have a reasonable expectation of success of both treating a tumor and ameliorating CRS in patients having CD20-expressing cancers because both Varghese and Hosseini disclose that CRS is a common adverse event when anti-CD20 therapies (and more specifically bispecific anti-CD20/CD3 therapies) are administered, Hosseini more specifically indicates cytokine release periods for IL-6 at various dosing schedules effective to reduce CRS, Ceschi teaches that ICI therapies (including various anti-PD-1 therapies) are also capable of inducing CRS within a median of 4 weeks, and Varghese suggests that doses/dosing schedules of each agent of the combination therapy comprising the anti-CD20/CD3 bispecific antibody odronextamab and anti-PD-1 antibody cemiplimab are variable and may be modified/optimized such that there is: (a) a reduction in the severity or duration of a symptom of a B-cell cancer; (b) inhibition of tumor growth, or an increase in tumor necrosis, tumor shrinkage and/or tumor disappearance; (c) delay in tumor growth; (d) inhibit or retard or stop tumor metastasis; (e) prevention of recurrence of tumor growth; (f) increase in survival of a subject with a B-cell cancer; and/or (g) a reduction in the use or need for conventional anti-cancer therapy (e.g., reduced or eliminated use of chemotherapeutic or cytotoxic agents) as compared to an untreated subject or a subject administered with either antibody as monotherapy.
MPEP 2144.05 states: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[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)”. In the instant case, given the known function of each antibody in cancer treatment, given their demonstrated utility together in cancer treatment, given the disclosure of Varghese for arriving at therapeutic doses and dose timing wherein each of the bispecific anti-CD20/CD3 antibody and anti-PD-1 antibody may be administered at dosing frequencies of about four times a week, twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every eight weeks, once every twelve weeks, or less frequently so long as a therapeutic response is achieved, it is well within the level of the ordinary skilled artisan to adjust the dosages and timing of administration for optimal therapeutic efficacy and safety, and to arrive at the doses and timing of administration instantly claimed, wherein the anti-PD-1 antibody may be administered 5 weeks after the administration of the bispecific anti-CD20/CD3 antibody (odronextamab) at either a flat dose or preferably as a fractionated dose, which would reasonably be expected to provide therapeutic treatment with reduced CRS.
More specifically with regard to the argument of an unexpected reduction in cytokine production that would not have been predictable, it is specifically noted that:
The data being argued is not fully commensurate in scope with the instant claims.
The fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
Obviousness does not require absolute predictability, only a reasonable expectation of success, i.e., a reasonable expectation of obtaining similar properties. See, e.g., In re O’Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir. 1988).
MPEP 716.02b: The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992) (Mere conclusions in appellants’ brief that the claimed polymer had an unexpectedly increased impact strength "are not entitled to the weight of conclusions accompanying the evidence, either in the specification or in a declaration."); Ex parte C, 27 USPQ2d 1492 (Bd. Pat. App. & Inter. 1992) (Applicant alleged unexpected results with regard to the claimed soybean plant, however there was no basis for judging the practical significance of data with regard to maturity date, flowering date, flower color, or height of the plant.). See also In re Nolan, 553 F.2d 1261, 1267, 193 USPQ 641, 645 (CCPA 1977) and In re Eli Lilly, 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) as discussed in MPEP § 716.02(c).
With regard to (1), it is specifically noted that the data argued as demonstrating unexpected effects is drawn to the administration of odronextamab and cemiplimab following a single, specific dosing schedule at specific doses. Specifically, it is noted that the data argued with respect to instant Figures 10-11 require escalating, split/fractionated dosing of odronextamab at 1, 20, and 160 mg QW and cemiplimab dosing of 3 mg/kg Q2W, wherein the initial dose of cemiplimab is administered at various starting times (i.e., 1-5 weeks after the initial dose of odronextamab). However, the instant claims encompass dosing schedules/dosages beyond the specific conditions argued in Figures 10-11. For example, the claims encompass embodiments wherein one or more doses of odronextamab may be administered, the dosing schedule ranging from once a day to every four weeks, doses that may or may not be split/fractionated doses, split doses that may be escalating or equal, and the one or more doses ranging from (i) 0.1 mg/kg to 15 mg/kg or (ii) 1 mg to 800 mg. Similarly, the instant claims encompass embodiments wherein cemiplimab may be administered once a day to once every day to once every six weeks, cemiplimab may be administered in one or more doses, each of the one or more doses ranging from (i) 0.1 mg/kg to 20 mg/kg or (ii) 1 mg to 1500 mg. Thus, the argument of unexpected results for a specific dosing schedule as used in Figures 10-11 is not commensurate in scope with the instant claims which encompass significantly more possible embodiments.
With regard to (2)-(4), it is specifically noted that Ceschi is specifically relied upon to demonstrate that ICI therapies (including cemiplimab) are capable of inducing CRS on their own, which would suggest to one of ordinary skill in the art that when used in combination with other agents known to induce CRS (e.g., anti-CD20 therapies) dosing schedules should be optimized in order to reduce the risk of CRS while maintaining efficacy. The motivation to combine the now cited prior art references and optimize dosing schedules/dosages is addressed above, and an explanation regarding a reasonable expectation of success is also addressed. Furthermore, it is noted that the data argues as showing unexpected results does not include any statistical analysis to support such a conclusion, and absent such statistical analysis it is unclear that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance.
Double Patenting - New as Necessitated by Amendment
Claims 1-2, 6-22, and 24-52 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 63-72 of copending Application No. 17/355,532 (herein after referred to as “532”) in view of US 2017/0174779 A1 (previously cited on PTO-892; herein after referred to as "Varghese"), US 2015/0266966 A1 (previously cited on PTO-892; herein after referred to as "Smith"), non-patent literature by Hosseini et. al. (npj Systems Biology and Applications, August 2020, 6(28); previously cited on PTO-892; herein after referred to as "Hosseini"), and non-patent literature by Ceschi et. al. (Frontiers in Pharmacology, May 2020, 11(557), 1-7; herein after referred to as "Ceschi").
Claims 1-2, 6-22, and 24-52 are rendered obvious by the combined teachings of the prior art above as discussed in the 103 section, the 103 being incorporated here. The addition of the patented claims above over related subject matter only further supports this obviousness.
Claim 63 of 532 is drawn to a method for treating a B-cell cancer in a subject, the method comprising administering to the subject a bispecific antigen-binding molecule comprising a first antigen-binding domain that specifically binds human CD3, and a second antigen-binding domain that specifically binds human CD20, wherein the first antigen-binding domain comprises HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 domains, respectively, comprising the amino acid sequences of SEQ ID NOs: 116-118-120-124-126-128. Claim 64 further limits the method of claim 63 wherein the bispecific antigen-binding molecule (a) induces proliferation of human and cynomolgus peripheral blood mononuclear cells (PBMCs) in vitro, (b) induces IFN-gamma release and CD25 up-regulation in human whole blood, (c) induces T-cell mediated cytotoxicity of human B-cells, (d) induces T-cell mediated cytotoxicity of human B-cells that are resistant to anti-CD20-mediated cytotoxicity, and/or (e) causes a reduction in the number of B cells in a subject below detectable levels by about day 1 after a single administration of the bispecific antigen-binding molecule to the subject at a dose of about 0.01 mg/kg. Claim 65 further limits the method of claim 63 wherein the B-cell cancer is selected from the group consisting of. follicular lymphoma, B cell chronic lymphocytic leukemia, B cell lymphoblastic lymphoma, Hodgkin lymphoma, Non-Hodgkin lymphoma, diffuse large B cell lymphoma, marginal zone lymphoma, mantle cell lymphoma, hairy cell leukemia, and Burkitt lymphoma, and claim 66 further limits claim 65 wherein the B-cell cancer is follicular lymphoma, or diffuse large B cell lymphoma. Claims 67-69 further limit the method of claim 63 wherein, respectively: (i) the subject is afflicted with a tumor that is resistant to, or incompletely responsive to anti-CD20 monospecific therapy alone, (ii) the subject is afflicted with a tumor that is resistant to, or incompletely responsive to rituximab monotherapy, and (iii) the subject has received an anti-CD20 monospecific antibody therapy at least 1 day to 1 year prior to the administration of the bispecific antigen-binding molecule. Claims 70-72 further limit the method of claim 63 wherein, respectively: (i) the first antigen-binding domain comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 114, (ii) the first antigen-binding domain comprises a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 122, and (iii) the first antigen-binding domain comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 114, and a LCVR comprising the amino acid sequence of SEQ ID NO: 122. It is specifically noted that 532 SEQ ID NO: 114 is an exact match for instant SEQ ID NOs: 13, and 532 SEQ ID NO: 122 is an exact match for residues 1-107 of instant SEQ ID NO: 12 (532 SEQ ID NO: 122 does not comprise the C-terminal arginine residue of instant SEQ ID NO: 12). Additionally, 532 SEQ ID NOs: 114 and 122 comprise exact matches for instant SEQ ID NOs: 20-21-22-17-18-19 (corresponding to HCDRs 1-3 and LCDRs 1-3, respectively).
However, it is noted that 532 does not explicitly claim a method of (i) treating or inhibiting the growth of a tumor and/or (ii) ameliorating cytokine release syndrome comprising administering a bispecific anti-CD20/CD3 antibody (i.e., odronextamab) in combination with an anti-PD-1 antibody (i.e., cemiplimab) wherein the anti-PD-1 antibody is administered at least five weeks after administering the first dose of the bispecific anti-CD20/CD3 antibody. These deficiencies are remedied by Varghese, Smith, Hosseini, and Ceschi, whose teachings are detailed in the 103 section, the 103 being incorporated here.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the treatment method claimed by 532 such as to optimize the dosing/schedule of the anti-CD20/CD3 bispecific antibody and further comprise administering an anti-PD-1 antibody as taught by Varghese, wherein the anti-CD20/CD3 antibody is odronextamab and the anti-PD-1 antibody is cemiplimab as suggested by the combination of Varghese and Smith, such that the anti-PD-1 antibody is administered at a sufficient period after the administration of the bispecific antibody such that there is reduced risk for overlapped cytokine release from each therapeutic. One would have been motivated to optimize the dosing/schedule of the anti-CD20/CD3 bispecific antibody and anti-PD-1 antibody to maintain efficacy while preventing known adverse events, including CRS as suggested by Varghese, Hosseini, and Ceschi. One of ordinary skill in the art would have a reasonable expectation of success of both treating a tumor and ameliorating CRS in patients having CD20-expressing cancers because both Varghese and Hosseini disclose that CRS is a common adverse event when anti-CD20 therapies (and more specifically bispecific anti-CD20/CD3 therapies) are administered, Hosseini more specifically indicates cytokine release periods for IL-6 at various dosing schedules effective to reduce CRS, Ceschi teaches that ICI therapies (including various anti-PD-1 therapies) are also capable of inducing CRS within a median of 4 weeks, and Varghese suggests that doses/dosing schedules of each agent of the combination therapy comprising the anti-CD20/CD3 bispecific antibody odronextamab and anti-PD-1 antibody cemiplimab are variable and may be modified/optimized such that there is: (a) a reduction in the severity or duration of a symptom of a B-cell cancer; (b) inhibition of tumor growth, or an increase in tumor necrosis, tumor shrinkage and/or tumor disappearance; (c) delay in tumor growth; (d) inhibit or retard or stop tumor metastasis; (e) prevention of recurrence of tumor growth; (f) increase in survival of a subject with a B-cell cancer; and/or (g) a reduction in the use or need for conventional anti-cancer therapy (e.g., reduced or eliminated use of chemotherapeutic or cytotoxic agents) as compared to an untreated subject or a subject administered with either antibody as monotherapy.
MPEP 2144.05 states: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[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)”. In the instant case, given the known function of each antibody in cancer treatment, given their demonstrated utility together in cancer treatment, given the disclosure of Varghese for arriving at therapeutic doses and dose timing wherein each of the bispecific anti-CD20/CD3 antibody and anti-PD-1 antibody may be administered at dosing frequencies of about four times a week, twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every eight weeks, once every twelve weeks, or less frequently so long as a therapeutic response is achieved, it is well within the level of the ordinary skilled artisan to adjust the dosages and timing of administration for optimal therapeutic efficacy and safety, and to arrive at the doses and timing of administration instantly claimed, wherein the anti-PD-1 antibody may be administered 5 weeks after the administration of the bispecific anti-CD20/CD3 antibody (odronextamab) at either a flat dose or preferably as a fractionated dose, which would reasonably be expected to provide therapeutic treatment with reduced CRS.
Similarly, claims 1-2, 6-22, and 24-52 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the pertinent claims of the below-listed copending Application Nos. in view of US 2017/0174779 A1 (previously cited on PTO-892; herein after referred to as "Varghese"), US 2015/0266966 A1 (previously cited on PTO-892; herein after referred to as "Smith"), non-patent literature by Hosseini et. al. (npj Systems Biology and Applications, August 2020, 6(28); previously cited on PTO-892; herein after referred to as "Hosseini"), and non-patent literature by Ceschi et. al. (Frontiers in Pharmacology, May 2020, 11(557), 1-7; herein after referred to as "Ceschi").
Copending Application No.
Brief Description of the Invention
Pertinent Claims
18101310
Method of Administering a Bispecific Anti-CD20/CD3 Antibody to a Subject to Mitigate Adverse Effects of CRS
99-151
18114057
Dosing Regimen for Anti-CD20/CD3 Bispecific Antibody to Treat a B-Cell Malignancy
123-195
19077873
Method of Treating Cancer and Inhibiting CRS in a Subject Comprising Conjointly Administering a Bispecific Anti-CD20/CD3 Binding Molecule
1, 9, 11-12, 26-27, 33, 39, 41, 42, 54, 55, 59-60, 66, 68, 72-74, 110-116
It is noted that all of the above copending reference applications are generally drawn to methods of treating cancer and/or mitigating CRS comprising administering a multispecific antibody, wherein said multispecific antibody may be an anti-CD20/CD3 bispecific antibody. However it is noted that the patents do not necessarily disclose that the bispecific antibody is odronextamab, co-administering an anti-PD-1 antibody wherein the anti-PD-1 antibody is cemiplimab, or the instantly claimed dosing schedule and patient limitations. These deficiencies are addressed by the cited references, as provided by the teachings specified in the 103 section.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the treatment methods/dosing regimen claimed by the copending reference applications such as to optimize the dosing/schedule of the anti-CD20/CD3 bispecific antibody and further comprise administering an anti-PD-1 antibody as taught by Varghese, wherein the anti-CD20/CD3 antibody is odronextamab and the anti-PD-1 antibody is cemiplimab as suggested by the combination of Varghese and Smith, such that the anti-PD-1 antibody is administered at a sufficient period after the administration of the bispecific antibody such that there is reduced risk for overlapped cytokine release from each therapeutic. One would have been motivated to optimize the dosing/schedule of the anti-CD20/CD3 bispecific antibody and anti-PD-1 antibody to maintain efficacy while preventing known adverse events, including CRS as suggested by Varghese, Hosseini, and Ceschi. One of ordinary skill in the art would have a reasonable expectation of success of both treating a tumor and ameliorating CRS in patients having CD20-expressing cancers because both Varghese and Hosseini disclose that CRS is a common adverse event when anti-CD20 therapies (and more specifically bispecific anti-CD20/CD3 therapies) are administered, Hosseini more specifically indicates cytokine release periods for IL-6 at various dosing schedules effective to reduce CRS, Ceschi teaches that ICI therapies (including various anti-PD-1 therapies) are also capable of inducing CRS within a median of 4 weeks, and Varghese suggests that doses/dosing schedules of each agent of the combination therapy comprising the anti-CD20/CD3 bispecific antibody odronextamab and anti-PD-1 antibody cemiplimab are variable and may be modified/optimized such that there is: (a) a reduction in the severity or duration of a symptom of a B-cell cancer; (b) inhibition of tumor growth, or an increase in tumor necrosis, tumor shrinkage and/or tumor disappearance; (c) delay in tumor growth; (d) inhibit or retard or stop tumor metastasis; (e) prevention of recurrence of tumor growth; (f) increase in survival of a subject with a B-cell cancer; and/or (g) a reduction in the use or need for conventional anti-cancer therapy (e.g., reduced or eliminated use of chemotherapeutic or cytotoxic agents) as compared to an untreated subject or a subject administered with either antibody as monotherapy.
MPEP 2144.05 states: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[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)”. In the instant case, given the known function of each antibody in cancer treatment, given their demonstrated utility together in cancer treatment, given the disclosure of Varghese for arriving at therapeutic doses and dose timing wherein each of the bispecific anti-CD20/CD3 antibody and anti-PD-1 antibody may be administered at dosing frequencies of about four times a week, twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every eight weeks, once every twelve weeks, or less frequently so long as a therapeutic response is achieved, it is well within the level of the ordinary skilled artisan to adjust the dosages and timing of administration for optimal therapeutic efficacy and safety, and to arrive at the doses and timing of administration instantly claimed, wherein the anti-PD-1 antibody may be administered 5 weeks after the administration of the bispecific anti-CD20/CD3 antibody (odronextamab) at either a flat dose or preferably as a fractionated dose, which would reasonably be expected to provide therapeutic treatment with reduced CRS.
Claims 1-2, 6-22, and 24-52 are rejected on the ground of nonstatutory double patenting as being unpatentable over the pertinent claims of the below-listed U.S. Patent Nos. in view of US 2017/0174779 A1 (previously cited on PTO-892; herein after referred to as "Varghese"), US 2015/0266966 A1 (previously cited on PTO-892; herein after referred to as "Smith"), non-patent literature by Hosseini et. al. (npj Systems Biology and Applications, August 2020, 6(28); previously cited on PTO-892; herein after referred to as "Hosseini"), and non-patent literature by Ceschi et. al. (Frontiers in Pharmacology, May 2020, 11(557), 1-7; herein after referred to as "Ceschi").
US Patent No.
Brief Description of the Invention
Pertinent Claims
11590223
Method of Administering a Bispecific Anti-CD20/CD3 Antibody to a Subject in a Dosing Regimen to Mitigate CRS
1-53
12054557
Method of Treating or Inhibiting the Growth of a Tumor Comprising Administering an Anti-CD20/CD3 Bispecific Antibody and Anti-PD-1 Antibody
1-33
12274747
Method for Treating Cancer and Inhibiting CRS in a Subject Comprising Conjointly Administering a Multispecific Antigen Binding Molecule with an Anti-CD3 Arm and Anti-Tumor Antigen Arm
1-2, 5-10, 12-13, 16-24, 27-33
Claims 1-2, 6-22, and 24-52 are rendered obvious by the combined teachings of the prior art above as discussed in the 103 section, the 103 being incorporated here. The addition of the patented claims above over related subject matter only further supports this obviousness.
It is noted that all of the above patents are generally drawn to methods of treating cancer and/or mitigating CRS comprising administering a multispecific antibody, wherein said multispecific antibody may be an anti-CD20/CD3 bispecific antibody. However it is noted that the patents do not necessarily disclose that the bispecific antibody is odronextamab, co-administering an anti-PD-1 antibody wherein the anti-PD-1 antibody is cemiplimab, or the instantly claimed dosing schedule and patient limitations. These deficiencies are addressed by the cited references, as provided by the teachings specified in the 103 section.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the treatment methods/dosing regimen claimed by the reference patents such as to optimize the dosing/schedule of the anti-CD20/CD3 bispecific antibody and further comprise administering an anti-PD-1 antibody as taught by Varghese, wherein the anti-CD20/CD3 antibody is odronextamab and the anti-PD-1 antibody is cemiplimab as suggested by the combination of Varghese and Smith, such that the anti-PD-1 antibody is administered at a sufficient period after the administration of the bispecific antibody such that there is reduced risk for overlapped cytokine release from each therapeutic. One would have been motivated to optimize the dosing/schedule of the anti-CD20/CD3 bispecific antibody and anti-PD-1 antibody to maintain efficacy while preventing known adverse events, including CRS as suggested by Varghese, Hosseini, and Ceschi. One of ordinary skill in the art would have a reasonable expectation of success of both treating a tumor and ameliorating CRS in patients having CD20-expressing cancers because both Varghese and Hosseini disclose that CRS is a common adverse event when anti-CD20 therapies (and more specifically bispecific anti-CD20/CD3 therapies) are administered, Hosseini more specifically indicates cytokine release periods for IL-6 at various dosing schedules effective to reduce CRS, Ceschi teaches that ICI therapies (including various anti-PD-1 therapies) are also capable of inducing CRS within a median of 4 weeks, and Varghese suggests that doses/dosing schedules of each agent of the combination therapy comprising the anti-CD20/CD3 bispecific antibody odronextamab and anti-PD-1 antibody cemiplimab are variable and may be modified/optimized such that there is: (a) a reduction in the severity or duration of a symptom of a B-cell cancer; (b) inhibition of tumor growth, or an increase in tumor necrosis, tumor shrinkage and/or tumor disappearance; (c) delay in tumor growth; (d) inhibit or retard or stop tumor metastasis; (e) prevention of recurrence of tumor growth; (f) increase in survival of a subject with a B-cell cancer; and/or (g) a reduction in the use or need for conventional anti-cancer therapy (e.g., reduced or eliminated use of chemotherapeutic or cytotoxic agents) as compared to an untreated subject or a subject administered with either antibody as monotherapy.
MPEP 2144.05 states: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[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)”. In the instant case, given the known function of each antibody in cancer treatment, given their demonstrated utility together in cancer treatment, given the disclosure of Varghese for arriving at therapeutic doses and dose timing wherein each of the bispecific anti-CD20/CD3 antibody and anti-PD-1 antibody may be administered at dosing frequencies of about four times a week, twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every eight weeks, once every twelve weeks, or less frequently so long as a therapeutic response is achieved, it is well within the level of the ordinary skilled artisan to adjust the dosages and timing of administration for optimal therapeutic efficacy and safety, and to arrive at the doses and timing of administration instantly claimed, wherein the anti-PD-1 antibody may be administered 5 weeks after the administration of the bispecific anti-CD20/CD3 antibody (odronextamab) at either a flat dose or preferably as a fractionated dose, which would reasonably be expected to provide therapeutic treatment with reduced CRS.
Response to Arguments - Double Patenting
Applicant’s arguments, see Pages 24-27 of Remarks, filed 05/01/2026, with respect to the rejection(s) of claim(s) 1-47 under nonstatutory double patenting have been fully considered in view of the instant claim amendments and are persuasive. Therefore, the rejection(s) has/have been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of US 2017/0174779 A1 (previously cited on PTO-892; herein after referred to as "Varghese"), US 2015/0266966 A1 (previously cited on PTO-892; herein after referred to as "Smith"), non-patent literature by Hosseini et. al. (npj Systems Biology and Applications, August 2020, 6(28); previously cited on PTO-892; herein after referred to as "Hosseini"), and non-patent literature by Ceschi et. al. (Frontiers in Pharmacology, May 2020, 11(557), 1-7; herein after referred to as "Ceschi").
It is specifically noted that applicant has amended independent claims 1-2 such that the claims now recite the limitation “administering to the subject an antibody or antigen-binding fragment thereof that specifically binds programmed death 1 (PD-1) at least 5 weeks after administering the first dose of the bispecific antibody or antigen-binding fragment thereof”. It is noted that the pertinent claims of the cited reference patents and the cited reference applications in view of Varghese, Hosseini, and/or Smith did not provide sufficient motivation alone regarding the administration of an anti-PD-1 antibody at least five weeks after administering the first dose of the bispecific anti-CD20/CD3 antibody. However, this deficiency is addressed by Ceschi.
As outlined above, it is specifically noted that the instant claims are rendered obvious by the combined teachings of the now cited prior art above as discussed in the 103 section. The addition of the patented claims or copending claims each in view of related subject matter only further supports this obviousness. It is specifically noted that (i) Varghese, in view of the sequences taught by Smith, discloses the therapeutic combination of an anti-CD20/CD3 bispecific antibody (e.g., odronextamab) and an anti-PD-1 antibody (e.g., cemiplimab) and teaches that CRS is a common occurrence with anti-CD20 therapies wherein adjusting dosing/schedules may mitigate the risk of CRS; (ii) bispecific anti-CD20/CD3 antibody mosunetuzumab, dosing strategies, e.g., step-fractionated dosing, of anti-CD20/CD3 antibodies can serve as a method for mitigating CRS in patients and further indicates that cytokine release profiles (IL-6 specifically) for various dosing regimen generally demonstrate increased cytokine and/or cytokine spikes through approximately days 21-28; and (iii) Ceschi teaches that ICI therapies as monotherapies are also capable of inducing CRS, wherein CRS develops within a median of 4 weeks after initiation of therapy.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to optimize the dosing/schedule of the anti-CD20/CD3 bispecific antibody and anti-PD-1 antibody as taught by Varghese and claimed by the reference patents or as claimed by the reference applications, wherein the anti-CD20/CD3 antibody is odronextamab and the anti-PD-1 antibody is cemiplimab as suggested by the combination of Varghese and Smith, such that the anti-PD-1 antibody is administered at a sufficient period after the administration of the bispecific antibody such that there is reduced risk for overlapped cytokine release from each therapeutic. One would have been motivated to optimize the dosing/schedule of the anti-CD20/CD3 bispecific antibody and anti-PD-1 antibody to maintain efficacy while preventing known adverse events, including CRS as suggested by Varghese, Hosseini, and Ceschi. One of ordinary skill in the art would have a reasonable expectation of success of both treating a tumor and ameliorating CRS in patients having CD20-expressing cancers because both Varghese and Hosseini disclose that CRS is a common adverse event when anti-CD20 therapies (and more specifically bispecific anti-CD20/CD3 therapies) are administered, Hosseini more specifically indicates cytokine release periods for IL-6 at various dosing schedules effective to reduce CRS, Ceschi teaches that ICI therapies (including various anti-PD-1 therapies) are also capable of inducing CRS within a median of 4 weeks, and Varghese suggests that doses/dosing schedules of each agent of the combination therapy comprising the anti-CD20/CD3 bispecific antibody odronextamab and anti-PD-1 antibody cemiplimab are variable and may be modified/optimized such that there is: (a) a reduction in the severity or duration of a symptom of a B-cell cancer; (b) inhibition of tumor growth, or an increase in tumor necrosis, tumor shrinkage and/or tumor disappearance; (c) delay in tumor growth; (d) inhibit or retard or stop tumor metastasis; (e) prevention of recurrence of tumor growth; (f) increase in survival of a subject with a B-cell cancer; and/or (g) a reduction in the use or need for conventional anti-cancer therapy (e.g., reduced or eliminated use of chemotherapeutic or cytotoxic agents) as compared to an untreated subject or a subject administered with either antibody as monotherapy.
MPEP 2144.05 states: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[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)”. In the instant case, given the known function of each antibody in cancer treatment, given their demonstrated utility together in cancer treatment, given the disclosure of Varghese for arriving at therapeutic doses and dose timing wherein each of the bispecific anti-CD20/CD3 antibody and anti-PD-1 antibody may be administered at dosing frequencies of about four times a week, twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every eight weeks, once every twelve weeks, or less frequently so long as a therapeutic response is achieved, it is well within the level of the ordinary skilled artisan to adjust the dosages and timing of administration for optimal therapeutic efficacy and safety, and to arrive at the doses and timing of administration instantly claimed, wherein the anti-PD-1 antibody may be administered 5 weeks after the administration of the bispecific anti-CD20/CD3 antibody (odronextamab) at either a flat dose or preferably as a fractionated dose, which would reasonably be expected to provide therapeutic treatment with reduced CRS.
More specifically with regard to the argument of an unexpected reduction in cytokine production that would not have been predictable, it is specifically noted that:
The data being argued is not fully commensurate in scope with the instant claims.
The fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
Obviousness does not require absolute predictability, only a reasonable expectation of success, i.e., a reasonable expectation of obtaining similar properties. See, e.g., In re O’Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir. 1988).
MPEP 716.02b: The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992) (Mere conclusions in appellants’ brief that the claimed polymer had an unexpectedly increased impact strength "are not entitled to the weight of conclusions accompanying the evidence, either in the specification or in a declaration."); Ex parte C, 27 USPQ2d 1492 (Bd. Pat. App. & Inter. 1992) (Applicant alleged unexpected results with regard to the claimed soybean plant, however there was no basis for judging the practical significance of data with regard to maturity date, flowering date, flower color, or height of the plant.). See also In re Nolan, 553 F.2d 1261, 1267, 193 USPQ 641, 645 (CCPA 1977) and In re Eli Lilly, 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) as discussed in MPEP § 716.02(c).
With regard to (1), it is specifically noted that the data argued as demonstrating unexpected effects is drawn to the administration of odronextamab and cemiplimab following a single, specific dosing schedule at specific doses. Specifically, it is noted that the data argued with respect to instant Figures 10-11 require escalating, split/fractionated dosing of odronextamab at 1, 20, and 160 mg QW and cemiplimab dosing of 3 mg/kg Q2W, wherein the initial dose of cemiplimab is administered at various starting times (i.e., 1-5 weeks after the initial dose of odronextamab). However, the instant claims encompass dosing schedules/dosages beyond the specific conditions argued in Figures 10-11. For example, the claims encompass embodiments wherein one or more doses of odronextamab may be administered, the dosing schedule ranging from once a day to every four weeks, doses that may or may not be split/fractionated doses, split doses that may be escalating or equal, and the one or more doses ranging from (i) 0.1 mg/kg to 15 mg/kg or (ii) 1 mg to 800 mg. Similarly, the instant claims encompass embodiments wherein cemiplimab may be administered once a day to once every day to once every six weeks, cemiplimab may be administered in one or more doses, each of the one or more doses ranging from (i) 0.1 mg/kg to 20 mg/kg or (ii) 1 mg to 1500 mg. Thus, the argument of unexpected results for a specific dosing schedule as used in Figures 10-11 is not commensurate in scope with the instant claims which encompass significantly more possible embodiments.
With regard to (2)-(4), it is specifically noted that Ceschi is specifically relied upon to demonstrate that ICI therapies (including cemiplimab) are capable of inducing CRS on their own, which would suggest to one of ordinary skill in the art that when used in combination with other agents known to induce CRS (e.g., anti-CD20 therapies) dosing schedules should be optimized in order to reduce the risk of CRS while maintaining efficacy. The motivation to combine the now cited prior art references and optimize dosing schedules/dosages is addressed above, and an explanation regarding a reasonable expectation of success is also addressed. Furthermore, it is noted that the data argues as showing unexpected results does not include any statistical analysis to support such a conclusion, and absent such statistical analysis it is unclear that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance.
Conclusion
Claims 1-2, 6-22, and 24-52 are pending. Claims 1-2, 6-22, and 24-52 are rejected. No claims are allowed.
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. Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALYSSA RAE STONEBRAKER whose telephone number is (571)270-0863. The examiner can normally be reached Monday-Thursday 7:00 am - 5:00 pm.
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/ALYSSA RAE STONEBRAKER/Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
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