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 .
Claims 1-121 have been cancelled. Claims 122-157 have been newly added.
Drawings
The Petition to Accept Color Drawings submitted 4/4/2023 was granted 10/12/2023
Claim Objections
Claims 128 and 134 are objected to because of the following informalities: The acronym “MM” should be spelled out to recite “multiple myeloma (MM)” in these independent claims. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 122-157 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for methods of treatment as discussed below, does not reasonably provide enablement for all methods encompassed by the claims. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Independent claims 122, 128, and 134 are directed to a method of treating multiple myeloma. No specific therapeutic effect is required by any of the claims.
Dependent claim 152 recites treating a cytokine release syndrome (CRS) event.
Dependent claim 153 recites managing the CRS event.
The specification defines “treatment” as a clinical intervention in an attempt to alter the natural course of the individual being treated, and can be performed either for prophylaxis or during the course of clinical pathology. Desirable effects of treatment include, but are not limited to, preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, preventing metastasis, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis.
The claims require that the subject has a multiple myeloma so the prevention aspects of the definition of “treatment” are precluded by the claims. However, the claims are considered to include cure. In view of the fact that page 1, line 21, of the specification indicates that multiple myeloma is incurable, these aspects of the claims are not enabled.
Claim 152 requires that the subject has a cytokine release syndrome (CRS) event so the prevention aspects the definition of “treatment” are precluded by the claim. However, the claim is considered to include cure or complete reversal of CRS. While inhibition of cytokine toxicities are disclosed, complete reversal or cure of the toxicities has not been shown. In particular, see results in Tables 31 and 34. Note that these results do not reflect all dosing regimens encompassed by the claims. See also Table 2 where CRS events may result in termination of the bispecific antibody treatment because the symptoms cannot be managed. See also symptoms of CRS in Table 5A. Note that CRS is disclosed as being associated with elevations in a wide array of cytokines, including marked elevations in IFN-y, IL-6, and tumor necrosis factor-alpha (TNF-a) levels. See page 104, line 31, through page 105, line 4. The specification does not disclose managing all of these cytokines.
The specification discloses administering a particular bispecific antibody, cevostamab
(also referred to as BFCR4350A or RO7187797) which is an Fc-engineered, humanized, full-length non-glycosylated IgG1 kappa T-cell-dependent bispecific antibody (TDB) that binds FcRH5 and CD3 and comprises an anti-FcRH5 arm comprising the heavy chain polypeptide sequence of SEQ ID NO: 35 and the light chain polypeptide sequence of SEQ ID NO: 36 and an anti-CD3 arm comprising the heavy chain polypeptide sequence of SEQ ID NO: 37 and the light chain polypeptide sequence of SEQ ID NO: 38. Cevostamab comprises a threonine to tryptophan amino acid substitution at position 366 on the heavy chain of the anti-FcRH5 arm (T366W) using EU numbering of Fc region amino acid residues and three amino acid substitutions (tyrosine to valine at position 407, threonine to serine at position 366, and leucine to alanine at position 368) on the heavy chain of the anti-CD3 arm (Y407V, T366S, and L368A) using EU numbering of Fc region amino acid residues to drive heterodimerization of the two arms (half-antibodies). Cevostamab also comprises an amino acid substitution (asparagine to glycine) at position 297 on each heavy chain (N297G) using EU numbering of Fc region amino acid residues, which results in a non-glycosylated antibody that has minimal binding to Fc (Fcγ) receptors and, consequently, prevents Fc-effector function. See at least specification page 15.
The specification discloses particular dosage regimens within the scope of the claims for cevostamab. However, the results presented for these dosage regimens are not commensurate in scope with the regimens encompassed by the claims. The results from one regimen cannot be used to predict the results from a different regimen having a different antibody, different dosages, numbers of doses, numbers of cycles, and/or different timing for the cycles and doses.
Figure 1 discloses a single-step dose-escalation Arm A and multistep dose-escalations in Arm B. In Figure 3 and Figures 4A-B, the designations C1D1, C1D8, C1D15 appear to mean dose 1/day 1; dose 1/day 8; dose 1/day 15 with escalating doses. This differs from C1D1 in claims 122, 128, and 134 which appears to mean first dosing cycle /dose 1.
For Arm B (i.e. the method of the instant claims), two step-up doses are given on a weekly basis on Days 1 and 8 followed by administration of the target dose on Day 15. The target dose is administered 7 days after the last step-up dose. The starting dose of cevostamab was 1.2 mg, 3.6 mg, and 60 mg on C1D1, C1D8, and C1D15, respectively, administered intravenously (FIG. 4B). Doses of 0.3 or 0.6 mg, 3.6 mg, and 90 mg on C1D1, C1D8, and C1D15, respectively, administered intravenously, were also tested (FIG. 4B). See page 116, line 36, through page 117, line 4.
The Cycle 2, Day 1 (C2D1) dose (see at least instant claims 129-130) must be given a minimum of 14 days after the target dose is given in Cycle 1 for Arm A and a minimum of 7 days after the target dose is given in Cycle 1 for Arm B. Thereafter, cevostamab is administered on Day 1 of a 21-day cycle. See page 117, lines 5-8.
Table 12 discloses results of the 61 efficacy-evaluable patients in Arms B and D where 25 patients (41%) had objective responses. Arm B had 10 of 30 patients (33.3%) with objective responses. At least for example, 8 (26.7%) had a partial response and (5) 16.7% had progressive disease (PD) (i.e. at least for example, did not have remission as included by the definition of treatment). Note that Table 12 reflects five different dosage escalations for Arm B. The table legend indicates that non-response includes minimal response (MR), stable disease (SD), progressive disease (PD), clinical relapse, or missing/non-evaluable (i.e. 18/30 subjects for Arm B). Thus, approximately 60% of subjects in Arm B were non-responders. See Table 4 for definitions of responses according to International Myeloma Working Group (IMWG) uniform response criteria (2016).
That is, even for the particular dosing regimens exemplified, the results do not support all aspects of “treatment” as defined by the specification. In addition, the results in the specification cannot be extrapolated to predict results for other dosing regimens within the scope of the claims.
In particular for claims 140-141 while being enabling for the antibody having the anti-FcRH5 antibody VH/VL of SEQ ID NOS: 7 and 8, respectively, and the anti-CD3 antibody VH/VL of SEQ ID NOS: 15 and 16 respectively, these claims do not reasonably provide enablement for all antibodies encompassed by these claims.
Claim 140 depends upon claim 122. Claim 141 depends upon claim 140. Claim 122 is not directed to any particular bispecific antibody that binds to FcRH5 and CD3. As written, claim 140 includes the recited anti-FcRH5 VH of SEQ ID NO: 7 without the corresponding VL of SEQ ID NO: 8; the VL of SEQ ID NO: 8 without the corresponding VH of SEQ ID NO: 7;
the recited anti-CD3 VH of SEQ ID NO: 15 without the corresponding VL of SEQ ID NO: 16; and the VL of SEQ ID NO: 16 without the corresponding VH of SEQ ID NO: 15. Antigen binding requires both the VH and VL of the antibody. The specification does not disclose nor enable pairing the VH of SEQ ID NO: 7 with a VL other than SEQ ID NO: 8 and getting antigen binding (and vice versa). The specification does not disclose nor enable pairing the VH of SEQ ID NO: 15 with a VL other than SEQ ID NO: 16 and getting antigen binding (and vice versa). Note that the sequence identity of “at least 95%” permits variation in the CDRs of the recited VH and VL where any changes to the CDRs have unpredictable effects on antigen binding. The claim language does not require retention of the CDRs. Finally, claims 140-141 recite “comprising an amino acid sequence.” The recitation of “an “ is considered to include subsequences and not the complete sequences of SEQ ID NOS: 7-8 and/or 15-16. Antibodies having unspecified subsequences would not have been expected to result in antigen binding.
The scope of the claims is not enabled.
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 124-127, 143-145, 150-151, and 153-157 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 123 depends upon claim 122. Claim 123 recites alternative embodiments in parts (a) and (b) (i.e. “and/or”). Claim 124 depends upon claim 123. Claim 124 has alternative parts (a)-(e) (i.e. “and/or”). Claims 125-127, 150-151, and 155-157 ultimately depend upon claim 124 and have alternative parts (i.e. “and/or” and “or”). The claims are confusing in the multiplicity of alternative choices in each claim, particularly as the alternatives may be unrelated to each other (e.g length of first dosing cycle, type of multiple myeloma, particular dosage) within the claim and within the chain of dependent claims. The claims are confusing with respect to the metes and bounds of the methods being claimed.
Claim 143, part (b), is directed in part to antibody fragments. This claim does not appear to be properly dependent upon claim 122 as claim 122 is not directed to antibody fragments. Claim 144, part (c) is confusing for the same reason.
Claim 145, part (a), is confusing as claim 122 is implicitly directed to a full length bispecific antibody.
Claim 150 administering an “effective amount” of various therapeutic agents. However, the claim does not make clear what therapeutic effect must be achieved by any of these therapeutic agents. The metes and bounds of the claims cannot be determined.
Claim 153, part (a), recites “to manage the CRS event.” It is unclear what “managing” requires. There is no specific definition in the specification. The metes and bounds of the claim cannot be determined.
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 122-125, 128-131, and 139-154 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 102-123 of copending Application No. 19/016,060 (4/30/2025 claim set, common applicant Genentech; common inventor Cooper). Although the claims at issue are not identical, they are not patentably distinct from each other.
The claims in co-pending application 19/016,060 (4/30/2025 claim set) are directed to treating a subject having a relapsed or refractory multiple myeloma (see instant claim 124, part (e) and instant claim 130, part (d)) by administering a bispecific antibody that bind the FcRH5 and CD3 with C1D1, C1D2, and C1D3. Co-pending claim 102 recites the C1D1 and C1D2 dosages in instant claim 122 and co-pending claims 103-104 teach the C1D3 dosages in instant claim 122-123 and instant claims 129, part (c). The CDRs of co-pending claim 102 correspond to instant claim 139. Co-pending claim 102 recites a first 21-day dosing cycle as in instant claim 124, part (c). See also instant claim 130, part (b). Co-pending claim 105 recites additional dosing cycles as in instant claim 125, part (I)(c) and instant claim 131, part (I)(c). Co-pending claims 107-108 recites the sequence in instant claims 140-142. Co-pending claims 109-123 disclose the limitations of instant claims 143-151. Co-pending claim 118 corresponds to instant claim 152-154.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The instant application is senior to the co-pending application.
The art of record and not relied upon is considered pertinent to applicant's disclosure.
Cohen et al. (of record, submitted 7/17/2025, Journal of Clinical Oncology, published on line 25 May 2020) discusses the GO39775 (NCT 03275103) clinical trial but does not provide the dosage limitations of independent claims 1, 128, and 134. This clinical trial is disclosed in the instant application. See at least Figures 1-3 and 4A-B. The Cohen et al. document submitted 8/9/2023 having essentially the same citation as the Cohen et al. document submitted 7/17/2025 is illegible and has not been considered. These two documents are not identical.
The NCT03275103 clinical trial documents (version 33 dated 11 September 2020 and version 34 dated 13 October 2020, both of record) do not provide the dosage limitations of independent claims 1, 128, and 134.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARIANNE P ALLEN whose telephone number is (571)272-0712. The examiner can normally be reached 7:00-3:30 EST Monday-Friday.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama can be reached at 571-272-2911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/Marianne P Allen/Primary Examiner, Art Unit 1647
mpa