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 Status
Claims 8-9, 11-18, and 24-32 are under consideration in this office action.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on December 29, 2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS is being considered by the examiner.
Maintained Rejections
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 8-9, 11-18, and 24-32 are rejected under 35 U.S.C. 103 as being unpatentable over US 20180037651, published January 25, 2018 (“Attar”; see PTO-892 from 11/14/2022) in view of US clinical trial NCT03399799, first posted January 16, 2018 and updated September 9, 2019 (“clinical trial ‘799”; see PTO-892 from 11/14/2022) and Chen et al, published online July 26, 2019 (“Chen et al”; see PTO-892 from 3/27/2024).
Claims 8 and 9 are directed to a method for treating relapsed or refractory multiple myeloma in a human comprising subcutaneous administration to a subject a GPRC5DXCD3 bispecific antibody comprising HCDR1-3 of SEQ ID NOs: 4-6 and LCDR1-3 of SEQ ID NOs: 7-9 for GPRC5D and HCDR1-3 of SEQ ID NO: 14-16 and LCDR1-3 of SEQ ID NOs: 17-19 for CD3.
Attar teaches a method of treating GPRC5D-expressing cancer, such as multiple myeloma in humans, comprising administering a GPRC5DxCD3 bispecific antibody for a time sufficient to treat the cancer [0035-0036]. The bispecific antibody of Attar is comprised of anti-GPRC5D antibody of HCDR1-3 of SEQ ID NOs: 4, 8, and 12 and LCDR1-3 of SEQ ID NOs: 15, 18, and 21, which are identical to instant SEQ ID NOs: 4-6 for HCDR1-3 and SEQ ID NOs: 7-9 for HCDR1-3, as in claims 8-9 and 24. Further VH/VL pair of the anti-GPRC5D arm of the bispecific antibody is comprised of SEQ ID NOs: 55/58, which is the same as instant SEQ ID NOs: 10/11, as in claim 11. The light chain and heavy chain of the anti-GPRC5D arm have the amino acid sequence of SEQ ID NO: 12 and 13, respectively, as in claims 14 and 27; the heavy and light chains of the antibody of Attar have the same six CDRs of the instant antibody and, thus the antibodies are patentably indistinct. The CD3 arm of the bispecific antibody of Attar is comprised of VH/VL pair of SEQ ID NO: 25/26 and HC/LC pair of SEQ ID NO: 99/100, which are comprised of the six CDRs of instant SEQ ID NOs: 14-19, as in claim 14. Further, the HC/LC pair of Attar is the same as instant HC/LC pair SEQ ID NO: 22/23, as in claim 27.
Attar teaches that the efficient dosages and the dosage regimens for the multispecific antibodies and fragments depend on the disease or condition to be treated and may be determined by one skilled in the art [0203]. An exemplary range for a therapeutically effective amount of a compound of the present invention is about 1-1000 mg/kg, for instance about 1, about 10, about 100, or about 1000 mg/kg [203]. Administration may be parenteral, such as subcutaneous administration [204], as in claims 8 and 9. The dosage of the bispecific antibody of Attar is within the range of the dosage of instant claims 8-9 and 32 (10 mg/kg, 60 mg/kg, 400 mg/kg, 800 mg/kg) [0205]. The wide range of Attar encompasses different parenteral modes of administration, including intravenous, intramuscular, subcutaneous, and intraperitoneal routes [0190], and the amount to be administered will vary depending on the parenteral mode, which can be determined empirically. The doses of the instant claims overlap with the range taught by Attar, and therefore, Attar teaches the GPRC5DxCD3 bispecific antibody dosage
The GPRC5DxCD3 bispecific antibody of Attar may be administered by maintenance therapy, e.g., once a week for up to six months or more [0206], as in instant claim 8. As such, Attar recognizes that dosing interval is a result-effective variable.
The dosing interval for maintenance therapy of claim 9 is limited to biweekly administration; and, although biweekly administration is not taught by Attar, dosing interval is recognized as a result-effective variable, and, absent evidence to the contrary, identification of this dosing interval could be readily determined by routine optimization via methods known in the art.
Claims 12-13 and 25-26 are directed to GPRC5DxCD3 bispecific antibody wherein the heavy chains comprise mutations of specific amino acid residues. Attar teaches that the effector function of the antibody can be reduced or eliminated by modification of the Fc segment on IgG. In some embodiments, Attar teaches a GPRC5DxCD3 bispecific antibody wherein the CD3-binding arm has an IgG4 isotype containing S228P, L234A, L235A, F405L, and R409K substitutions in the Fc region [0169] as in instant claims 12-13 and 25-26. In some embodiments, the GPRC5D-binding arm is IgG4 isotype containing S228P, L234A, and L235A substitution in the Fc region [0167] as in instant claims 12-13 and 25-26. As Attar teaches, for many applications of therapeutic antibodies, Fc-receptor-mediated effector functions are not part of the mechanism of action; rather modifying effector function is associated with changed in the affinity for the Fc receptors [0014-0015]. Thus, Attar teaches typical and modified residues at positions 228, 234, 235, 405, and 409 of instant claims 12-13 and 25-26.
Although Attar teaches that the dosing of GPRC5xCD3 antibody could start doses at levels lower than that required in order to achieve the desired therapeutic effect and gradually increased until the desired effect is achieved [0204], Attar does not teach a method comprised of priming doses.
Chen et al teaches that T-cell engaging bispecific antibodies bind CD3 on T cells and a tumor-associated antigen on tumor cells to direct T cell cytotoxicity against tumor cells (see abstract); the bispecific antibody of the instant claims is a T-cell engaging bispecific antibody. A common adverse event for these types of bispecific antibodies is cytokine release syndrome, which may limit the ability to achieve sufficient drug exposure for efficacy (pg 600, column 2, ln 7-10). A priming dose strategy has been shown to mitigate cytokine release syndrome and help achieve efficacious doses with T-cell engaging bispecific antibodies (pg 601, column 1, ln 1-8). Given that Attar is drawn to a GPRC5xCD3 antibody and method for treating multiple myeloma, and further given that Chen et al teaches that T-cell engaging bispecific antibodies are associated with cytotoxic adverse events, one of ordinary skill in the art would have been motivated to use a lower priming dose in patients initiating the GPRC5DxCD3 bispecific antibody treatment for multiple myeloma.
The use of priming and maintenance dosage protocols for T-cell engaging bispecific antibodies is standard within the art, as taught by Chen et al. Furthermore, adjusting a dosage strategy is considered routine optimization. The dose protocols recited in the claims offer no obvious distinction from dosage protocols as exemplified by the prior art. The Court has stated that generally such differences amount to mere optimization and will not support patentability unless there is evidence indicating the claimed feature 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).
Attar does not explicitly teach a method for treating relapsed or refractory multiple myeloma nor does it teach outcome measures and intended results.
NCT03399799 discloses a method for treating an adult with relapsed or refractory multiple myeloma comprising administering antibody JNJ-64407564 (Study description, ln 3-4), as in claims 8 and 9. While this reference does not explicitly describe the specificity of JNJ-64407564, it is known in the art to be a bispecific antibody directed to GPRC5D and CD3; JNJ-64407564 is also called talquetamab, as evidenced by US clinical trial NCT04634552 (see Arms and Interventions; see PTO-892 from 6/6/23), as required in instant claim 28.
Secondary outcome measures of clinical trial ‘799 are very good partial response, complete response, and stringent complete response according to IMWG criteria, as required in claims 7 and 8. Additional secondary outcome measured include GPRC5DxCD3 bispecific antibody serum concentrations, overall response rate, and clinical benefit rate (defined as proportion of participants who have a minimal response rate) (Outcome Measures, secondary outcome measures), as in the metrics of treatment efficacy of claims 16, 18, and 29-31. One of ordinary skill in the art would use these metrics with the expectation that improvement in the parameters taught by clinical trial ‘799 would reflect improvement in patients with multiple myeloma treated with the antibody and method of Attar in view of Chen et al.
While the references are silent on the intended results in instant claims 8-9, 16-18 and 29-31, such as achievement of complete response that is characterized by negative MRD status and achievement of a specific Cmax or AUC0-14d at steady state, Attar in view of Chen et al and NCT ‘799 teach the required antibody and method for treating disease. Therefore, the GPRC5DxCD3 bispecific antibody will produce the same results as the instantly claimed method since one is practicing the same active steps and administering the same antibody to the same patient population. MPEP 2145(II) states: “The fact that appellant 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.” Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985)” (“The recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention.”).
It would have been obvious to a person of ordinary skill in the art to modify the teachings of Attar, Chen et al, and clinical trial ‘799 to arrive at the presently claimed GPRC5DxCD3 bispecific antibody priming and maintenance doses and method for treating relapsed or refractory multiple myeloma; especially since the prior art has already recognized that dose and dose interval modification is part of routine optimization. Indeed, clinical trial ‘799 is directed to determining optimal Phase 2 dosage (Study Description, Brief Summary).
Overall, given the teachings of the combination of references, one of ordinary skill in the art would have reasonably expected to have identified the doses in the range of Attar in view of the teachings of clinical trial ‘799. When taken together, the references teach a therapeutic dosing protocol. The bispecific antibody and method of the instant claims fully overlaps with those taught by the combined teachings of Attar, Chen et al, and clinical trial ‘799.
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 8-9, 11-18, and 24-32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 4 of U.S. Patent No. 10,562,968 in view of PG Pub US 20180037651 (“Attar”), Chen et al, and clinical trial ‘799. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims and the patented claims are both drawn to the same GPRC5DxCD3 bispecific antibody comprised of the same sequences. The anti-GPRC5D antibody of HCDR1-3 of SEQ ID NOs: 4, 8, and 12 and LCDR1-3 of SEQ ID NOs: 15, 18, and 21 of patent ‘968 are identical to the anti-GPRC5D antibody of HCDR1-3 of instant SEQ ID NOs: 5-6 and LCDR1-3 of SEQ ID NOs: 11-13.
The instant claims are directed to a method of using a GPRC5DXCD3 bispecific antibody in the treatment of relapsed or refractory multiple myeloma, the method comprising priming doses of 10 and 60 mg/kg followed by maintenance doses of 400 or 800 mg/kg administered weekly or biweekly. The patent ‘968 claims teach the antibody, Attar teaches the bispecific antibody and dose range and interval, clinical trial ‘799 teaches the method for treating relapsed or refractory multiple myeloma, and Chen et al teaches the motivation to use a priming dose for T-cell engaging bispecific antibodies (detailed discussion of the teachings of these references, alone and in combination, are provided above under the rejection of the instant claims under 35 U.S.C. 103). Given that the combined references teach the claimed method, the instant claims are not patentable over patent ‘968.
Claims 8-9, 11-18, and 24-32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 16-17 of copending Application No. 18/639,233 in view of PG Pub US 20180037651 (“Attar”), Chen et al, and clinical trial ‘799. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims and the patented claims are both drawn to the same bispecific antibody comprised of the same sequences. The anti-GPRC5DXCD3 bispecific antibody of HCDR1-3 of SEQ ID NOs: 24-26 and LCDR1-3 of SEQ ID NOs: 27-29 for the GPRC5D binding domain and HCDR1-3 of SEQ ID NOs: 14-16 and LCDR1-3 of SEQ ID NOs: 17-19 for the CD3 binding domain of application ‘233 claim 16 are identical to the GPRC5D binding domain of HCDR1-3 of instant SEQ ID NOs: 5-6 and LCDR1-3 of SEQ ID NOs: 11-13 and CD3 binding domain of HCDR1-3 of instant SEQ ID NOs: 14-16 and LCDR1-3 of SEQ ID NOs: 17-19.
The instant claims are directed to a method of using a GPRC5DXCD3 bispecific antibody in the treatment of relapsed or refractory multiple myeloma, the method comprising priming doses of 10 and 60 mg/kg followed by maintenance doses of 400 or 800 mg/kg administered weekly or biweekly. ‘233 claims teach the bispecific antibody, Attar teaches the dose range and interval, clinical trial ‘799 teaches the method for treating relapsed or refractory multiple myeloma, and Chen et al teaches the motivation to use a priming dose for T-cell engaging bispecific antibodies (detailed discussion of the teachings of these references, alone and in combination, are provided below under the rejection of the instant claims under 35 U.S.C. 103). Given that the combined references teach the claimed method, the instant claims are not patentable over application ‘233.
This is a provisional nonstatutory double patenting rejection.
Claims 8-9, 11-18, and 24-32 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 9-10, and 14-16 of copending Application No. 18/052172. Although the claims at issue are not identical, they are not patentably distinct from each other because they are directed to the same GPRC5DXCD3 bispecific antibody for the treatment of relapsed or refractory multiple myeloma. The dosages and dosing intervals recited in the copending claims overlap with those of the instant claims. Given that a similar method of treatment is described in the copending claims, without specific evidence that the indicated dose amounts and dose schedules are critical to the method, the identification of these properties will not render the subject matter patentable.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 8-9, 11-18, and 24-32 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6, 8, 13, and 18-21 of copending Application No. 18/528157 in view of PG Pub US 20180037651 (“Attar), Chen et al, and clinical trial ‘799. Although the claims at issue are not identical, they are not patentably distinct from each other because they are directed to the same anti-GPRC5D antibody and a GPRC5DxCD3 bispecific antibody for the treatment of multiple myeloma. The anti-GPRC5D antibody of HCDR1-3 of SEQ ID NOs: 4, 8, and 12 and LCDR1-3 of SEQ ID NOs: 15, 18, and 21 of application ‘157 are identical to the anti-GPRC5D antibody of HCDR1-3 of instant SEQ ID NOs: 5-6 and LCDR1-3 of SEQ ID NOs: 11-13.
The instant claims are directed to a method of using the GPRC5DXCD3 bispecific in the treatment of relapsed or refractory multiple myeloma, the method comprising priming doses of 10 and 60 mg/kg followed by maintenance doses of 400 or 800 mg/kg administered weekly or biweekly. The patent ‘968 claims teach the antibody, whereas Attar teaches the GPRC5DxCD3 bispecific antibody and dose range and interval, clinical trial ‘799 teaches the method for treating relapsed or refractory multiple myeloma, and Chen et al teaches the motivation to use a priming dose for T-cell engaging bispecific antibodies (detailed discussion of the teachings of these references, alone and in combination, are provided above under the rejection of the instant claims under 35 U.S.C. 103). Given that the combined references teach the claimed method, the instant claims are not patentable over application ‘157.
Response to Arguments
Applicant's arguments filed December 29, 2025 have been fully considered but they are not persuasive.
I. Rejection under 35 U.S.C. 103
Applicant asserts that Attar in view of Chen and NCT03399799 does not teach or suggest selection of the claimed dosing regimen because the cited references do not disclose several elements of the claimed dosing regimen; these include at least 2 priming doses, the amount of the doses, treatment dose amount, treatment dose frequency, and method of administration (remarks, pg 6-7). Applicant references recent Federal Circuit opinion Janssen Pharmaceuticals, Inc. v. Teva Pharmaceuticals USA, Inc., 141 F.4th 1367, 1378 (C.A. Fed (N.J.), 2025) (“Janssen v. Teva”). In this decision, the Court found that a combination of doses (i.e. a loading dose/maintenance dose protocol) was not obvious over cited art that taught a drug dose range that encompasses the claimed doses (remarks, pg 9). The court found that the crucial choice made by Janssen in Janssen v. Teva was the choice to start with a particular high first loading dose and then follow it with a second, lower loading dose. After review of Janssen v. Teva, the examiner finds that the specific facts and procedural posture of that case do not apply to the instant claims. The main disparity is that the two agents under consideration in Janssen v. Teva, paliperidone and haloperidol, were not found to be equivalents (structurally or functionally), and thus the motivation to use a loading/maintenance dose of haloperidol in a dosing regimen for paliperidone was not obvious. Further, in Janssen v. Teva there was no prior art to support that paliperidone would be an effective treatment for schizophrenia; there was only a Janssen Phase III clinical trial for testing the hypothesis that a regimen of three equal-amount doses of paliperidose would be more effective than placebo (Janssen v. Teva, pg 9). In contrast, here, the agents are two bispecific T-cell engagers antibodies (one in Attar and one in Chen), and one of ordinary skill in the art would appreciate that these bispecific antibodies are similar both functionally (e.g., activates T cells) and structurally (e.g., bispecific antibodies). Based on the combined teachings of Attar and Chen, one would have a reasonable expectation of applying the claimed priming/maintenance dosing protocol of Attar and Chen et al for the treatment of multiple myeloma. In addition, Attar teaches that all GPRC5CXCD3 bispecific antibodies completely inhibited multiple myeloma cell tumor growth ([0051], Figure 12). Because Attar teaches the antibody and maintenance dose and Chen teaches the motivation to use priming/maintenance dose protocol of a different bispecific T cell engager, choosing a priming dose is obvious and not critical for nonobviousness. With regards to the treatment of relapsed or refractory multiple myeloma, it is the Office’s position that this species within the multiple myeloma genus, can be at once envisaged from the prior art because the species within this genus (e.g., refractory and relapsed multiple myeloma) are sufficiently limited and well delineated; see MPEP 2131.02(III) and In re Petering (wherein the courts determined that a reference describing a generic formula encompassing about 20 compounds was found to anticipate each of the 20 species without specifically naming them). One looking for a treatment of a subset of multiple myeloma patients that are not responsive to standard of care would look to new therapies, such as the claimed bispecific antibody. It would be obvious to one of ordinary skill in the art to use an agent with known benefit in multiple myeloma in those subjects who do not respond well to conventional first-line therapies. Indeed, clinical trial ‘799 is directed to a method of treating relapsed/refractory multiple myeloma with the same claimed bispecific antibody. Although, as iterated by applicant, clinical trial ‘799 is a posting that provides a proposal to try to administer an investigation agent for the treatment of disease (remarks, pg 19), it is this express contemplation for the treatment of relapsed or refractory multiple myeloma that makes the claimed method obvious.
Applicant argues that formulating an antibody is inherently unpredictable and that the claimed dosing regimen could not have been predicted a priori (remarks, pg 9-10). Applicant then points to Chen et al, who states that “the determination of the optimal priming dose regimen remains a major challenge, due to the large number of possible permutations of dose levels and priming steps.” (Chen, pg 605, remarks, pg 10). It is important to note the sentence that follows: “Quantitative modeling is a valuable tool that can help increase the efficiency by integrating existing knowledge to make predictions for decision making” (Chen, pg 605). Although Chen acknowledges the difficultly in determining optimal dosing, Chen actually teaches a method to predictably and efficiently determine an optimal dosing regimen for T cell engaging bispecific antibodies using a quantitative cytokine modelling (Chen, abstract). This model takes into account the priming effect where cytokine release is attenuated following repeated doses (Chen pg 606). Indeed, Chen states that with the proposed modeling framework, cytokine data from an initial clinical study can be utilized to establish the model, which can prospectively simulate cytokine profiled under various dosing regimens (Chen pg, 607).
Applicant submits Shastri (Exhibit B) to support arguments related to unpredictability of dose selection in the field of T-cell engaging antibodies (pg 10). After reviewing Shastri, it is apparent that there are multiple methods available to those of ordinary skill in the art to identify first-in-human starting doses, including MABEL, PK/PD-based methods, and combinations thereof (Shastri, pg 36-38). Therefore, the unpredictability in determining the claimed doses is not beyond the skill of the ordinary artisan. Further, applicant admits that the claimed dosing regimen was the product of extensive modeling and analyses of pre-clinical and clinical data and that there is no reason to believe that it could have been arrived at by blindly selecting a dosing schedule from Attar and Chen (remarks, pg 12). The examiner agrees that the dosing regimen could not have been arrived at blindly, which is the center of the obviousness rejection. The doses within the broad range of Attar do not exhibit results that are not dissimilar in kind, and the doses identified by applicant are not unexpectedly good. The determination of the exact doses in view of the patient’s conditions is well within the skill of those skilled artisans. Further, it is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272, 276, 205 USPQ 215,219 (CCPA 1980). It is the examiner’s position that the result-effective variables of dose amount and interval were determined by routine optimization by methods that were already known in the art.
Routine optimization is comprised of methods that are well-understood and conventional activities previously known to the industry. When considering whether the determination of the optimum or workable ranges of a variable (e.g., dose) might be characterized as routine experimentation, the particular parameter must first be recognized as a result-effective variable (see MPEP 2144.05(I)-(II). KSR International Co. v. Teleflex held that “obvious to try” was a valid rational for an obviousness finding when the invention is directed to a result-effective variable. In this case, an artisan prior to the effective filing date of the invention would have a reason to vary the dose of the anti-GPRC5xCD3 bispecific antibody of Attar, because Attar recognizes dose as a result-effective variable and suggests the dose range 5-1000 mg [0194]. When provided with all of the starting conditions, including the therapeutic of Attar and the target population of Attar and trial ‘799, discovering the optimum or workable ranges for those components when performing the prior art method of treatment by routine experimentation does not make the instant claims patentable. Absolute predictability is not a necessary prerequisite to a case of obviousness. Rather, a degree of predictability that one of ordinary skill would have found to be reasonable is sufficient. “Good science and useful contributions do not necessarily result in patentability.” PharmaStem Therapeutics, Inc. v. Viacell, Inc., 491 F.3d 1342 (Fed. Cir. 2007).
If the inventive concept is determined by the application of a well-known problem-solving strategy, which is the work of a skilled artisan, the invention is obvious over the prior art teaching and is not patentable. What is claimed is merely the optimization of variables within the claims that flow from the “normal desire of scientists or artisans to improve upon what is already generally known.” In re Peterson, 315 F.3d 1325, 1330 (Fed.Cir.2003). In the instant case, the steps performed in pharmacokinetic, pharmacodynamic, and efficacy studies to determine the optimal doses are via methods already well-described in the art.
Regarding applicant’s argument that Chen et al falls short in providing the requisite motivation to arrive at the specifically claimed priming doses, it is important to noted that Chen et al is used as a secondary reference to provide the reasons to use a priming dose protocol and methods of determining a dose. In this case, Chen teaches use of a priming dose prior to higher maintenance doses for T-cell-engaging bispecific antibodies in order to minimize CRS toxicities; this is the motivation to use of a priming dose with the claimed T-cell-engaging bispecific antibody. Since dose and dosing interval are result-effective variables and since Attar teaches the dose, one of ordinary skill in the art would be able to determine the claimed doses via routine optimization.
See MPEP 2144.05.III.A, which states that applicants can rebut a prima facie case of obviousness by showing the criticality of the range. "The law is replete with cases in which the difference between the claimed invention and the prior art is some range or other variable within the claims. . . . In such a situation, the applicant must show that the particular range is critical, generally by showing that the claimed range achieves unexpected results relative to the prior art range." In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Thus, the burden is on the applicant to demonstrate that the specific doses of 10, 60, 400, and 800 mg/kg show unexpected results over the previously recited dose of 1-1000 mg/kg from Attar. Types of unexpected results include greater than expected results, superiority of a property shared with the prior art, presence of an unexpected property, or absence of an expected property (see MPEP 716.02(a)I.
Alternatively, applicants may rebut a prima facie case of obviousness based on optimization of a variable disclosed in a range in the prior art by showing that the claimed variable was not recognized in the prior art to be a result-effective variable. E.I. Dupont de Nemours & Company v. Synvina C.V., 904 F.3d 996, 1008, 128 USPQ2d 1193, 1202 (Fed. Cir. 2018). If the prior art does recognize that the variable affects the relevant property or result, then the variable is result-effective. Applicants must articulate why the variable at issue would not have been recognized in the prior art as result-effective.
Applicant points out that clinical trial ‘799 does not provide data regarding the efficacy or safety of the GPRC5DxCD3 bispecific antibody in the treatment of multiple myeloma (remarks, pg 17); however, it is not necessary for this secondary reference to do so, as Attar teaches the successful treatment of a mouse model of multiple myeloma [0051].
II. Double Patenting
Arguments related to the double patenting rejection over patent 10,562,968 in view of Attar, Chen et al, and clinical trial ‘799 have been considered but are not persuasive. Applicant is directed to arguments above regarding the 103 rejections related to Attar in view of Chen et al and clinical trial ‘799.
Regarding the provisional nonstatutory double patenting rejections, applicant’s arguments are not persuasive. It is only upon identification of allowable subject that the rejections of later filed Application Nos. 18/052,172 and 18/528,157 will be withdrawn. Until then, these rejections are maintained.
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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Jennifer Benavides
Examiner
Art Unit 1675
/JENNIFER A BENAVIDES/Examiner, Art Unit 1675
/AURORA M FONTAINHAS/Primary Examiner, Art Unit 1675