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, 5-6, 9-10, 12-13, 15-16, 19-22, 24-26, 29-35, 38-41, 45, 48-50, 55-57, 59-61, 65-66, 68-72, 74-79, 83-85, 88-90, 93, 96-102, 104, 106, 108-119, and 121-126 have been cancelled and claims 4, 7-8, 11, 14, 17-18, 23, 27, 36, 46, 58, 62, 64, 67, 80, 86-87, 91-92, 94, 103, 105, 107, and 120 have been amended, as requested in the preliminary amendment filed on March 28, 2023. Following the amendment, claims 1-2, 4, 7-8, 11, 14, 17-18, 23, 27-28, 36-37, 42-44, 46-47, 51-54, 58, 62-64, 67, 73, 80-82, 86-87, 91-92, 94-95, 103, 105, 107, and 120 are pending in the instant application.
Claims 1-2, 4, 7-8, 11, 14, 17-18, 23, 27-28, 36-37, 42-44, 46-47, 51-54, 58, 62-64, 67, 73, 80-82, 86-87, 91-92, 94-95, 103, 105, 107, and 120 are under examination in the instant office action.
Priority
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, 4, 7-8, 11, 14, 17-18, 23, 27-28, 36-37, 42-44, 46-47, 51-54, 58, 103, 105, 107, and 120 have an effective filing date of March 26, 2020 corresponding to PRO 63/000,229. Claims 62-64, 67, 73, 80-82, 86-87, 91-92, and 94-95 have an effective filing date of March 25, 2021 corresponding to PCT/US2021/024127 because earlier-filed application PRO 63/000,229 does not provide support for anti-BCMA antibodies being administered in combination with immunomodulatory agents, anti-CD38 antibodies, or gamma secretase inhibitors.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 01/05/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claim 86 is objected to because of the following informalities: line 3 of the claim recites "once per day on Days 1-21" but should read "once per day on days 1-21" as is utilized throughout the rest of the claims. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-2, 4, 7-8, 11, 14, 17-18, 23, 27-28, 36-37, 42-44, 46-47, 51-54, 58, 62-64, 67, 73, 80-82, 86-87, 91-92, 94-95, 103, 105, and 107 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.
The term “about” in claims 1, 11, 14, 17-18, 28, 64, 67, 73, 80, and 87 is a relative term which renders the claim indefinite. The term “about” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. As such, dosages and administration schedules recited in the above-identified claims are considered to be indefinite due to the recitation of "about". Claims 2, 4, 7-8, 23, 27, 36-37, 42-44, 46-47, 51-54, 58, 62-63, 81-82, 87, 91-92, 94-95, 103, 105, and 107 are included in this rejection as they depend from or incorporate one of the above-identified claims reciting the relative term “about”.
It is noted that claim 7 is further regarded as being indefinite due to the recitation of “a heavy chain variable domain comprising an amino acid sequence of SEQ ID NO: 4” and “a light chain variable domain comprising an amino acid sequence of SEQ ID NO: 8”. The recitations of “an amino acid sequence” are considered indefinite because it is unclear as to if the heavy/light chain variable domains must comprise the entirety of the identified SEQ ID NOs, or if the scope is intended to include fragments of the identified SEQ ID NOs. For the purposes of examination, claim 7 is being interpreted such that the heavy/light chain variable domains must comprise the entirety of the identified SEQ ID NOs. The claim is being interpreted as follows: “a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 4” and “a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 8”.
It is noted that claim 92 is further regarded as being indefinite because the claim recites the limitation "the induction doses", "the induction ", "the ", and "the ". There is insufficient antecedent basis for these limitations in the claim.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 103 is 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 103 recites "wherein the subject has been previously diagnosed as having multiple myeloma, or relapsed or refractory multiple myeloma" (emphasis added). Thus, under BRI the claim may be interpreted as “wherein the subject has been previously diagnosed as having multiple myeloma”. This does not further limit claim 1 from which claim 103 depends, as claim 1 indicates that the subject has multiple myeloma, and as such must have been previously (before the claimed method of treatment) been diagnosed with multiple myeloma. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
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 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.
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.
Claim(s) 1-2, 4, 7-8, 11, 14, 17-18, 23, 103, and 120 is/are rejected under 35 U.S.C. 103 as being unpatentable over US 2017/0233484 A1 (herein after referred to as "Sussman").
With regard to claim 1, Sussman teaches monoclonal antibodies that specifically bind to BCMA wherein the antibodies are useful for treatment and diagnoses of various cancers and immunological disorders (Paragraph 0067). The anti-BCMA antibodies of the invention can be used to treat cancer, wherein cancers treatable with said antibodies include, for example, multiple myeloma and said antibodies can be administered alone in an effective regime meaning a dosage, route of administration and frequency of administration that delays the onset, reduces the severity, inhibits further deterioration, and/or ameliorates at least one sign or symptom of cancer (Paragraphs 0162-0165). Exemplary dosages for a monoclonal antibody of the invention are 0.1 mg/kg to 50 mg/kg of the patient's body weight, wherein in some methods the patient is administered the antibody every two, three or four weeks; the dosage depends on the frequency of administration, condition of the patient and response to prior treatment, if any, and whether the disorder is acute or chronic, among other factors (Paragraphs 0166-0169). The average weight of an adult human is approximately 62 kg, and thus Sussman discloses antibody dosages (for an average adult) of approximately 6.2 mg to 3,100 mg. Additionally, as evidenced by the reference, it is noted that working dosages and/or dosing schedules for anti-BCMA antibodies of the invention are recognized as therapeutic variables which achieve a recognized result and as set forth in MPEP 2144.05: “A particular parameter must first be recognized as a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation.” In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977). It is a common objective in the art to optimize result effective variables, so as achieve optimal effect and maximal benefit. See In re Boesch, 617 F.2d 272, 276, 205 USPQ 215, 219 (CCPA 1980) (“[D]iscovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.” (citations omitted)). Therefore, any optimization of anti-BCMA antibody dosages and/or dosing schedules for therapeutic applications (i.e., methods of treatment) would be seen as routine optimization.
Sussman is considered to be analogous to the present invention as Sussman is the same field of anti-BCMA antibodies and cancer therapy comprising such antibodies. Thus, it would have been obvious to one of ordinary skill in the art from the disclosure of Sussmann that anti-BCMA antibodies of the invention could be utilized for treating multiple myeloma wherein said antibodies are administered in at least one dose of 0.1 mg/kg to 50 mg/kg of the patient's body weight, which generally falls into the instantly recited dosage range of claim 1 when considering the average weight of an adult human; said dosage could also be optimized as would be recognized by one of ordinary skill in the art.
With regard to claim 2, Sussman further teaches that a preferred form of modification of glycosylation of antibodies of the invention is reduced core fucosylation and Sussman further indicates that Methods of making non-fucosylated antibodies by incubating antibody-producing cells with a fucose analogue are described in the art wherein any of the presented methods can be used to generate a cell line that would be able to produce a nonfucosylated antibody, e.g., a humanized, chimeric or veneered SG16.17 antibody (Paragraphs 0122-0130). Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the reference.
With regard to claims 4 and 7-8, Sussman further discloses exemplary humanized antibodies hSG16.17 that bind BCMA in Table 6; one such exemplary antibody comprises the heavy chain variable domain vH3 and the light chain variable domain vK2, corresponding to hSG16.17 #9 (Page 21, Table 6; emphasis added). It is specifically noted that vH6 and vK2 correspond to Sussman SEQ ID NOs: 13 and 19, respectively, which comprise Kabat CDRs corresponding to Sussman SEQ ID NOs: 60-62 and 90-92, respectively (Paragraph 0084). Sussmann SEQ ID NOs: 13, 19, 60-62, and 90-92 are 100% matches to instant SEQ ID NOs: 4, 8, 1-3, and 5-7, respectively. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the reference.
With regard to claims 11, 14, 17-18, and 23, Sussman teaches that the anti-BCMA antibodies of the invention can be used to treat cancer, wherein cancers treatable with said antibodies include, for example, multiple myeloma and said antibodies can be administered alone in an effective regime meaning a dosage, route of administration and frequency of administration that delays the onset, reduces the severity, inhibits further deterioration, and/or ameliorates at least one sign or symptom of cancer (Paragraphs 0162-0165). Exemplary dosages for a monoclonal antibody of the invention are 0.1 mg/kg to 50 mg/kg of the patient's body weight, wherein in some methods the patient is administered the antibody every two, three or four weeks; the dosage depends on the frequency of administration, condition of the patient and response to prior treatment, if any, and whether the disorder is acute or chronic, among other factors (Paragraphs 0166-0169). The average weight of an adult human is approximately 62 kg, and thus Sussman discloses antibody dosages (for an average adult) of approximately 6.2 mg to 3,100 mg. Additionally, as evidenced by the reference, it is noted that working dosages and/or dosing schedules for anti-BCMA antibodies of the invention are recognized as therapeutic variables which achieve a recognized result and as set forth in MPEP 2144.05. Therefore, any optimization of anti-BCMA antibody dosages and/or dosing schedules for therapeutic applications (i.e., methods of treatment) would be seen as routine optimization. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the reference.
With regard to claim 103, Sussman teaches that the anti-BCMA antibodies of the invention can be used to treat cancer, wherein cancers treatable with said antibodies include, for example, multiple myeloma and said antibodies can be administered alone in an effective regime meaning a dosage, route of administration and frequency of administration that delays the onset, reduces the severity, inhibits further deterioration, and/or ameliorates at least one sign or symptom of cancer (Paragraphs 0162-0165). Sussman further teaches that treatment with anti-BCMA antibodies, optionally in combination with any of the other agents or regimes
described above, alone, or as an antibody drug conjugate, can increase the median progression-free survival or overall survival time of patients with cancer, especially when relapsed or refractory (Paragraph 0172). Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the reference.
With regard to claim 120, Sussman discloses exemplary humanized antibodies hSG16.17 that bind BCMA in Table 6; one such exemplary antibody comprises the heavy chain variable domain vH3 and the light chain variable domain vK2, corresponding to hSG16.17 #9 (Page 21, Table 6). It is specifically noted that vH6 and vK2 correspond to Sussman SEQ ID NOs: 13 and 19, respectively, which comprise Kabat CDRs corresponding to Sussman SEQ ID NOs: 60-62 and 90-92, respectively (Paragraph 0084). Sussmann SEQ ID NOs: 13, 19, 60-62, and 90-92 are 100% matches to instant SEQ ID NOs: 4, 8, 1-3, and 5-7, respectively. Sussman also teaches pharmaceutical compositions for parenteral administration are preferably sterile and substantially isotonic and manufactured under GMP conditions; pharmaceutical compositions can be provided in unit dosage form (i.e., the dosage for a single administration) (Paragraph 0170; emphasis added). Pharmaceutical compositions can be formulated using one or more physiologically acceptable carriers, diluents, excipients or auxiliaries (Id.). The antibodies can also be sold as research reagents for laboratory research in detecting cells bearing BCMA and their response to various stimuli; in such uses, monoclonal antibodies can be labeled with fluorescent molecules, spin-labeled molecules, enzymes or radioisotypes, and can be provided in the form of kit with all the necessary reagents to perform the assay for BCMA (Paragraph 0174; emphasis added). Sussman further discloses that any feature, step, element, embodiment, or aspect of the invention can be used in combination with any other unless specifically indicated otherwise (Paragraph 0175); thus it would have been obvious to one of ordinary skill in the art that unit dosage forms of the antibodies of the invention could further be provided in a kit for therapeutic methods. MPEP 2111.05 recites that to be given patentable weight, printed matter and associated product must be in a functional relationship. A functional relationship can be found where the printed matter performs some function with respect to the product to which it is associated. See Lowry, 32 F.3d at 1584, 32 USPQ2d at 1035 (citing Gulack, 703 F.2d at 1386, 217 USPQ at 404). Where the printed matter and product do not depend upon each other, no functional relationship exists. For example, in a kit containing a set of chemicals and a printed set of instructions for using the chemicals, the instructions are not related to that particular set of chemicals. In re Ngai, 367 F.3d at 1339, 70 USPQ2d at 1864. Thus, the recitation of instruction is not given patentable weight and the recitation of the antibody and a pharmaceutically acceptable carrier as listed in instant claim 120 is sufficient to meet the limitation(s) of the claim. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the reference.
Claim(s) 27-28, 36-37, and 42-44 is/are rejected under 35 U.S.C. 103 as being unpatentable over US 2017/0233484 A1 (herein after referred to as "Sussman"), as applied to claims 1-2, 4, 7-8, 11, 14, 17-18, 23, 103, and 120 above, and in further view of US 2016/0297885 A1 (herein after referred to as “Kuo”).
With regard to claims 27-28, 36-37, and 42-44, it is noted that the claims are all generally drawn to various treatment regimens, wherein the doses, dosing frequency, and dosing phases are further specified.
Sussman teaches monoclonal antibodies that specifically bind to BCMA wherein the antibodies are useful for treatment and diagnoses of various cancers and immunological disorders (Paragraph 0067). The anti-BCMA antibodies of the invention can be used to treat cancer, wherein cancers treatable with said antibodies include, for example, multiple myeloma and said antibodies can be administered alone in an effective regime meaning a dosage, route of administration and frequency of administration that delays the onset, reduces the severity, inhibits further deterioration, and/or ameliorates at least one sign or symptom of cancer (Paragraphs 0162-0165). Exemplary dosages for a monoclonal antibody of the invention are 0.1 mg/kg to 50 mg/kg of the patient's body weight, wherein in some methods the patient is administered the antibody every two, three or four weeks; the dosage depends on the frequency of administration, condition of the patient and response to prior treatment, if any, and whether the disorder is acute or chronic, among other factors (Paragraphs 0166-0169). The average weight of an adult human is approximately 62 kg, and thus Sussman discloses antibody dosages (for an average adult) of approximately 6.2 mg to 3,100 mg. However, it is noted that Sussman does not explicitly teach/suggest initial/induction doses and subsequent/maintenance doses representing different phases/cycles of treatment.
Kuo teaches antibodies, e.g., full length antibodies or antigen binding fragments thereof, that specifically bind to BCMA (B-Cell Maturation Antigen) and/or CD3 (Cluster of Differentiation 3), compositions comprising the BCMA antibodies, and methods of using the BCMA antibodies for treating conditions associated with cells expressing BCMA (e.g., cancer or autoimmune disease) (Abstract). Methods of treating a condition associated with malignant cells expressing a tumor antigen (e.g., BCMA) in a subject comprising administering to a subject in need thereof an effective amount of the pharmaceutical compositions of the invention wherein, in some embodiments, the condition is cancer and the cancer can be, for example, multiple myeloma (Paragraph 0028). An "effective dosage" or "effective amount" of drug, compound, or pharmaceutical composition is an amount sufficient to effect any one or more beneficial or desired results; an effective dosage can be administered in one or more administrations and an effective dosage of drug, compound, or pharmaceutical composition is an amount sufficient to accomplish therapeutic treatment either directly or indirectly wherein, as is understood in the clinical context, an effective dosage of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition (Paragraph 0083). The antibodies (e.g., BCMA or CD3-BCMA bispecific) can be administered using any suitable method and, generally, for administration of an antibody an initial candidate dosage may be about 2 mg/kg, a typical daily dosage may range from about any of 3 μg/kg to 30 μg/kg to 300 μg/kg to 3 mg/kg, to 30 mg/kg, to 100 mg/kg or more, depending on various factors (Paragraph 0318), e.g., condition to be treated, use of additional therapies, route of administration, etc. (Paragraphs 0300-0318). For repeated administrations over several days or longer, depending on the condition, the treatment is sustained until a desired suppression of symptoms occurs or until sufficient therapeutic levels are achieved wherein exemplary dosing regimen may comprise: (i) administering an initial dose of about 2 mg/kg, followed by a weekly
maintenance dose of about 1 mg/kg of the antibody or followed by a maintenance dose of about 1 mg/kg every other week; or (ii) administering increasing doses (e.g., initial dose of 1 mg/kg and gradual increase to one or more higher doses every week or longer time period) (Paragraph 0318; emphasis added). Other dosage regimens may also be useful, depending on the pattern of pharmacokinetic decay that the practitioner wishes to achieve; in some embodiments, dosing from one to four times a week is contemplated while in other embodiments, dosing once a month or once every other month or every three months is contemplated (Id.). Additionally, Kuo indicates that the progress of therapy is easily monitored by conventional techniques and assays wherein the dosing regimen (including the antibody (e.g., BCMA or CD3-BCMA bispecific) or the BCMA antibody conjugate used) can vary over time (Id.).
Thus, as evidenced by the references, it is noted that working dosages and/or dosing schedules for anti-BCMA antibodies of the invention are recognized as therapeutic variables which achieve a recognized result and as set forth in MPEP 2144.05: “A particular parameter must first be recognized as a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation.” In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977). It is a common objective in the art to optimize result effective variables, so as achieve optimal effect and maximal benefit. See In re Boesch, 617 F.2d 272, 276, 205 USPQ 215, 219 (CCPA 1980) (“[D]iscovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.” (citations omitted)). Therefore, any optimization of anti-BCMA antibody dosages and/or dosing schedules for therapeutic applications (i.e., methods of treatment) would be seen as routine optimization. One of ordinary skill in this art has a high level of skill and so can readily identify certain parameters.
"[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation." Application of Aller, 220 F.2d 454, 456, 105 USPQ 233, 235-236 (C.C.P.A. 1955). "No invention is involved in discovering optimum ranges of a process by routine experimentation." Id. at 458, 105 USPQ at 236-237. The "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." Application of Boesch, 617 F.2d 272, 276, 205 USPQ 215, 218-219 (C.C.P.A. 1980). Thus, it is clear that all doses, intervals of dosing, sequence of administrations, and number of doses of each composition are result effective variables and can be determined by one of ordinary skill in this art with only routine experimentation. Thus, all said values and parameters in the instant claims are obvious.
Claim(s) 46-47, 51-54, 58, 62-64, 67, 73, 80-82, 86-87, 91-92, 105, and 107 is/are rejected under 35 U.S.C. 103 as being unpatentable over US 2017/0233484 A1 (herein after referred to as "Sussman") and of US 2016/0297885 A1 (herein after referred to as “Kuo”), as applied to claims 1-2, 4, 7-8, 11, 14, 17-18, 23, 27-28, 36-37, 42-44, 103, and 120 above, and in further view of non-patent literature by Chari et. al. (Blood, 2017, 130(8), 974-981; herein after referred to as “Chari”).
With regard to claims 46-47, 51-54, and 58, it is noted that the claims are all generally drawn to various treatment regimens, wherein an additional agent of dexamethasone is administered in addition to an anti-BCMA antibody. With regard to claims 62-64, 67, and 73, it is noted that the claims are all generally drawn to various treatment regimens, wherein an additional agent of an anti-CD38 antibody (e.g., daratumumab) is administered in addition to an anti-BCMA antibody. With regard to claims 80-82 and 86-87, it is noted that the claims are all generally drawn to various treatment regimens, wherein an additional agent of an immunomodulatory agent (e.g., pomalidomide) is administered in addition to an anti-BCMA antibody. With regard to claims 91-92, it is noted that the claims are all generally drawn to various treatment regimens, wherein two additional agents of dexamethasone and pomalidomide are administered in addition to an anti-BCMA antibody. With regard to claims 105 and 107, the claims are drawn to the subject having received prior lines of therapy for multiple myeloma or cannot tolerate other lines of multiple myeloma therapy.
Sussman suggests that treatment with antibodies of the invention can be
combined with chemotherapy, radiation, stem cell treatment, and/or surgery other treatments effective against the disorder being treated (e.g., cancer such as multiple myeloma) (Paragraph 0171). Kuo also suggests that the methods of the invention further comprise a step of treating a subject with an additional form of therapy, which may be an additional anti-cancer therapy including, but not limited to, chemotherapy, radiation, surgery, hormone therapy, and/or additional immunotherapy (Paragraph 0311). More specifically, Kuo teaches the additional form of therapy comprises administering one or more therapeutic agent in addition to the antibodies of the invention, wherein the one or more therapeutic agent can be an immunomodulatory agent (e.g., lenalidomide) and/or an anti-inflammatory agent (e.g., dexamethasone); in some embodiments comprising administering at least one additional therapeutic agent, the patient is relapsing or is refractory to previous multiple myeloma therapy (Paragraph 0312). Thus, Sussman and Kuo both suggest the use of additional therapeutic agents, however neither reference teaches anti-CD38 antibodies/therapy, dosages/dosing schedules for any additional therapeutic agent, nor does either reference disclose that patients received prior lines of therapy as instantly claimed.
Chari teaches that daratumumab plus pomalidomide and dexamethasone (pom-dex) was evaluated in patients with relapsed/refractory multiple myeloma with ≥2 prior lines of therapy who were refractory to their last treatment; patients received daratumumab 16 mg/kg at the recommended dosing schedule, pomalidomide 4 mg daily for 21 days of each 28-day cycle, and dexamethasone 40 mg weekly (Abstract). Pomalidomide plus dexamethasone (pom-dex) has been shown to confer a PFS benefit in patients with relapsed and refractory MM compared with pomalidomide alone; subgroup analyses demonstrated a benefit to OS and PFS in lenalidomide-refractory patients treated with pomalidomide plus low-dose dexamethasone vs high-dose dexamethasone (Page 975, Column 1, Paragraph 2). Single-agent pomalidomide has been shown to upregulate CD38 expression on MM cell lines, and pretreatment of patient-derived effector cells with an IMiD (lenalidomide) has been shown to synergistically enhance daratumumab-mediated antibody-dependent cell-mediated cytotoxicity and pom-dex has demonstrated immune modulation, via activation of T cells, that correlated with clinical response, which could potentially complement the immunomodulatory effects demonstrated by daratumumab; for all of these reasons, pomalidomide paired with daratumumab is a rational choice for a combination regimen (Id.) Patients included in the study had received ≥2 prior lines of antimyeloma therapy, including at least 2 consecutive cycles of prior treatment that included lenalidomide (i.e., immunomodulatory agent) and bortezomib (i.e., proteasome inhibitor) wherein patients were eligible if they progressed on a regimen that combined lenalidomide and bortezomib or consecutive regimens that contained lenalidomide and bortezomib separately (Page 975, Column 1, Eligibility Criteria). Cycles were 28 days in duration, and patients received daratumumab 16 mg/kg IV weekly in cycles 1 and 2 and then every 2 weeks in cycles 3 to 6 and every
4 weeks thereafter (Page 975, Column 2, Study Design). Patients received pomalidomide 4 mg per day orally on days 1 to 21; dexamethasone 40 mg (20 mg per week in patients .75 years of age) was administered weekly and before and after the daratumumab infusions on days
when daratumumab was given to further reduce the risk for IRRs (Id.). Compared with studies of single-agent daratumumab or pom-dex alone, no additional safety signals were observed when daratumumab was combined with pom-dex, except for higher rates of neutropenia wherein there was no apparent increase in the rate of infections despite increased neutropenia; daratumumab plus pom-dex induced rapid, deep, and durable responses in a heavily treated patient population (Page 980).
Sussman, Kuo, and Chari are considered to be analogous to the present invention as they are in the same field of anti-BCMA antibodies and/or therapeutic approaches to multiple myeloma. Thus, it would have been obvious to one of ordinary skill in the art to modify the methods rendered obvious by Sussman and Kuo to arrive at the therapeutic regimen of the above-identified claims because Sussman and Kuo suggest the use of additional therapeutic agents in treating multiple myeloma and Chari specifically teaches an anti-CD38 antibody/pomalidomide/dexamethasone combination for the treatment of relapsed/refractory multiple myeloma; combining prior art elements according to known methods would be expected to yield predictable results with a reasonable expectation of success. “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted). Furthermore, as established previously, one of ordinary skill in this art has a high level of skill and so can readily identify certain parameters. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation." Application of Aller, 220 F.2d 454, 456, 105 USPQ 233, 235-236 (C.C.P.A. 1955). "No invention is involved in discovering optimum ranges of a process by routine experimentation." Id. at 458, 105 USPQ at 236-237. The "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." Application of Boesch, 617 F.2d 272, 276, 205 USPQ 215, 218-219 (C.C.P.A. 1980). Thus, it is clear that all doses, intervals of dosing, sequence of administrations, and number of doses of each composition of the above-identified claims are result effective variables and can be determined by one of ordinary skill in this art with only routine experimentation. Thus, all said values and parameters in the instant claims are obvious.
Claim(s) 94-95 is/are rejected under 35 U.S.C. 103 as being unpatentable over US 2017/0233484 A1 (herein after referred to as "Sussman") and of US 2016/0297885 A1 (herein after referred to as “Kuo”), as applied to claims 1-2, 4, 7-8, 11, 14, 17-18, 23, 27-28, 36-37, 42-44, 103, and 120 above, and in further view of non-patent literature by Eastman et. al. (Blood, 2019, 134(Supplement 1), 1-2; herein after referred to as “Eastman”).
With regard to claims 94-95, it is noted that the claims are all generally drawn to various treatment regimens, wherein an additional agent of a gamma secretase inhibitor is administered in addition to an anti-BCMA antibody. While Sussman and Kuo both suggest administering additional therapeutic agents in combination with anti-BCMA antibodies, neither reference explicitly teaches or suggests administering a gamma secretase inhibitor.
Eastman teaches that BCMA is directly shed from the plasma membrane by gamma secretase, a type-I sheddase; in order to further enhance belantamab mafodotin (a humanised monoclonal anti-BCMA antibody, which is afucosylated and conjugated to the microtubule-disrupting agent monomethyl auristatin-F) activity, the authors sought to increase cell surface levels of BCMA by blocking shedding of BCMA with a gamma-secretase inhibitor (GSI) (Page 1, Paragraphs 1-2). The authors determined the effect on the activity of belantamab mafodotin by combining belantamab mafodotin with PF-03084014, a highly-selective GSI; in order to understand combination effects against immunoconjugate activity, a 3-day proliferation assay on a panel of multiple myeloma and lymphoma cell lines with varying levels of BCMA expression was conducted and the assay showed a 50 to 3,000-fold EC50 shift in cell lines sensitive to
belantamab mafodotin across multiple lymphoma cell types (Page 1, Paragraph 2). In a 24-hour ADCC Jurkat reporter assay, an EC50 shift across multiple BCMA-expressing cell lines was observed; even cell lines with very low BCMA expression, such as Raji, showed a synergistic increase in ADCC activity in combination with PF-03084014 (Page 2, Paragraph 1). Cell lines that were non-responsive in the cell proliferation assay, showed activity in the ADCC assay, indicating low-expressing BCMA cell lines remain sensitive to belantamab mafodotin, alone and in combination with PF-03084014; synergistic effect from this preclinical work provided rationale to support clinical evaluation of belantamab mafodotin in combination with PF-03084014 in a planned clinical trial (DREAMM-5) (Page 2, Paragraphs 1-2).
Sussman, Kuo, and Eastman are considered to be analogous to the present invention as they are in the same field of BCMA targeting therapeutics and/or therapeutics for multiple myeloma. Therefore, it would have been obvious to one of ordinary skill in the art to modify the methods rendered obvious by Sussman and Kuo such that the method further comprised administering gamma secretase inhibitor PF-03084014 because PF-03084014 was demonstrated to have synergistic effects with BCMA-targeting ADC belantamab mafodotin, as taught by Eastman; combining prior art elements according to known methods would be expected to yield predictable results with a reasonable expectation of success. “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted).
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.
Claims 1-2, 4, 7-8, 11, 14, 17-18, 23, 27-28, 36-37, 42-44, 46-47, 51-54, 58, 62-64, 67, 73, 80-82, 86-87, 91-92, 94-95, 103, 105, 107, and 120 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4, 6-7, 9-10, 11-12, 15, 18, 20-24, 26-29, 31-34, 36-37, 39-41, 43-46, 48-54, 56-62, 64-67, and 69-72 of U.S. Patent No. 11,767,365 (herein after referred to as “first reference patent”) in view of US 2017/0233484 A1 (herein after referred to as "Sussman"), US 2016/0297885 A1 (herein after referred to as “Kuo”), non-patent literature by Chari et. al. (Blood, 2017, 130(8), 974-981; herein after referred to as “Chari”), and/or non-patent literature by Eastman et. al. (Blood, 2019, 134(Supplement 1), 1-2; herein after referred to as “Eastman”).
Claims 1-2, 4, 7-8, 11, 14, 17-18, 23, 27-28, 36-37, 42-44, 46-47, 51-54, 58, 62-64, 67, 73, 80-82, 86-87, 91-92, 94-95, 103, 105, 107, and 120 are rendered obvious by the combined teachings of the prior art above as discussed in the 103 section, the 103s being incorporated here. The addition of the patented claims of the first reference patent over related subject matter only further supports this obviousness.
The above-identified claims of the first reference patent are drawn to methods of treating a subject with a cancer that expresses BCMA comprising administering an effective amount of an antibody or antigen binding fragment thereof that binds to human BCMA, wherein the antibody or antigen binding fragment thereof comprises (i) a mature heavy chain variable region and a mature light chain variable region, wherein the mature heavy chain variable region comprises complementarity determining regions (CDRs) comprising the amino acid sequences of SEQ ID NOs: 60, 61 and 62, and the mature light chain variable region comprises CDRs comprising the amino acid sequences of SEQ ID NOs: 90, 91 and 92 or (ii) a mature heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 13, and a mature light chain variable region comprising the amino acid sequence of SEQ ID NO: 19 (see, for example, independent claims 1, 15, 26, 36, 43, 48, 56, 64, and 69). It is noted that the sequences of the first reference patent are identical to those of instant claims 4 and 7. The dependent claims further specify additional limitations, wherein the antibodies may be of the IgG1 isotype, the antibodies are non-fucosylated, the antibodies are humanized, the cancer is a hematological cancer such as multiple myeloma (see, for example, claims 4, 6, 9, and 10-12 which depend from independent claim 1). However, it is noted that the first reference patent does not explicitly teach doses, administration schedules, combination therapies, or kits. These deficiencies are addressed by the cited references, as provided by the teachings specified in the 103 section.
The first reference patent, Sussman, Kuo, Chari, and Eastman are all considered to be analogous to the present invention as they are in the same field of BCMA targeting therapeutics and/or therapeutics for multiple myeloma. Therefore, it would have been obvious to one of ordinary skill in the art to modify the methods of the first reference patent such that the methods are optimized with respect to doses and administration schedules (as suggested by Sussman and Kuo), comprise the administration of additional therapeutic agents (as suggested by Sussman and Kuo) wherein such additional therapeutic agents can include dexamethasone, anti-CD38 antibody daratumumab, and/or pomalidomide (as suggested by Kuo and Chari) or the additional therapeutic agent can include gamma secretase inhibitor PF-03084014 (as suggested by Eastman) because combining prior art elements according to known methods would be expected to yield predictable results with a reasonable expectation of success. Additionally, “[i]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted).
Claims 1-2, 4, 7-8, 11, 14, 17-18, 23, 27-28, 36-37, 42-44, 46-47, 51-54, 58, 62-64, 67, 73, 80-82, 86-87, 91-92, 94-95, 103, 105, 107, and 120 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 5, 8-9, 11-12, 20, 22, 24, 27-29, 36-42, and 44-66 of U.S. Patent No. 11,078, 291 (herein after referred to as “second reference patent”) in view of US 2017/0233484 A1 (herein after referred to as "Sussman"), US 2016/0297885 A1 (herein after referred to as “Kuo”), non-patent literature by Chari et. al. (Blood, 2017, 130(8), 974-981; herein after referred to as “Chari”), and/or non-patent literature by Eastman et. al. (Blood, 2019, 134(Supplement 1), 1-2; herein after referred to as “Eastman”).
Claims 1-2, 4, 7-8, 11, 14, 17-18, 23, 27-28, 36-37, 42-44, 46-47, 51-54, 58, 62-64, 67, 73, 80-82, 86-87, 91-92, 94-95, 103, 105, 107, and 120 are rendered obvious by the combined teachings of the prior art above as discussed in the 103 section, the 103s being incorporated here. The addition of the patented claims of the second reference patent over related subject matter only further supports this obviousness.
The above-identified claims of the second reference patent are drawn to an isolated antibody or antigen binding fragment thereof that binds to human BCMA, wherein the antibody or antigen binding fragment thereof comprises (i) a mature heavy chain variable region and a mature light chain variable region, wherein the mature heavy chain variable region comprises complementarity determining regions (CDRs) comprising the amino acid sequences of SEQ ID NOs: 60, 61 and 62, and the mature light chain variable region comprises CDRs comprising the amino acid sequences of SEQ ID NOs: 90, 91 and 92 or (ii) a mature heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 13, and a mature light chain variable region comprising the amino acid sequence of SEQ ID NO: 19 (see, for example, independent claims 1, 20, 36, 37, 39, 41, and 45). It is noted that the sequences of the second reference patent are identical to those of instant claims 4 and 7. The second reference patent further discloses compositions comprising said isolated antibodies, including pharmaceutical compositions (see, for example, claims 38, 40, 44, 47-49, 53, 57-59, 62, 65, and 66). The dependent claims further specify additional limitations, wherein the antibodies may be of the IgG1 isotype, the antibodies are non-fucosylated, and/or the antibodies are humanized (see, for example, claims 5, 8, 11 which depend from independent claim 1). However, it is noted that the second reference patent does not explicitly teach methods of treating multiple myeloma, doses, administration schedules, combination therapies, or kits. These deficiencies are addressed by the cited references, as provided by the teachings specified in the 103 section.
The second reference patent, Sussman, Kuo, Chari, and Eastman are all considered to be analogous to the present invention as they are in the same field of BCMA targeting therapeutics and/or therapeutics for multiple myeloma. Therefore, it would have been obvious to one of ordinary skill in the art to modify the products/compositions (comprising anti-BCMA antibodies) of the second reference patent such that the antibodies are utilized to treat multiple myeloma wherein the methods are optimized with respect to doses and administration schedules (as suggested by Sussman and Kuo), comprise the administration of additional therapeutic agents (as suggested by Sussman and Kuo) wherein such additional therapeutic agents can include dexamethasone, anti-CD38 antibody daratumumab, and/or pomalidomide (as suggested by Kuo and Chari) or the additional therapeutic agent can include gamma secretase inhibitor PF-03084014 (as suggested by Eastman) because combining prior art elements according to known methods would be expected to yield predictable results with a reasonable expectation of success. Additionally, “[i]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpo