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 .
Status of Application, Amendments and/or Claims
1. Claims 1-30 are pending and under examination in the present office action.
Information Disclosure Statement
2. The information disclosure statement (IDS) filed October 1, 2025 has been considered and the references therein are of record.
Claim Objections
3. Claim 28 is objected to because of the following informalities: claim 28 repeats the term “esophageal cancer” twice within the listing of cancer types. 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.
4. Claim 28 is 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.
Regarding claim 28, the "for example” phrase in line 5, “(e.g. hormone refractory prostate adenocarcinoma)”, renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention or else definitively limit the term “prostate cancer”. See MPEP § 2173.05(d).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
5. Claim(s) 1-4, 6, 14 and 20-30 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sharma et al. (US 9,220,776 B2) as evidenced by Wang et al. (Oncoimmunology, 2021, 10(1):1896643) (both listed on 10/01/2025 IDS).
Sharma et al. disclose stable formulations comprising an antibody directed against human programmed death receptor PD-1 (i.e., an anti-human PD-1 antibody) or antigen binding fragments thereof and methods for treating various cancers using these stable formulation of anti-human PD-1 antibodies (see col. 3, lines 24-30). Sharma teaches that the PD-1 blocking antibody is h409A11 (see col. 4 lines 49-50). As evidenced by Wang et al., the h409A11 humanized anti-PD-1 antibody is alternatively called pembrolizumab or MK3475 (see figure legend for Figure 2D at p. 7). See also col. 4 lines 56-59 of Sharma describing a method of treating cancer in a mammalian subject in need thereof, comprising administering an effective amount of any of the disclosed antibody formulations, and col. 6 lines 47-49 teaching that desirable subjects include human patients with cancer. Thus, Sharma discloses antibody formulations comprising the anti-human PD-1 antibody pembrolizumab and their use in the treatment of cancer in a human patient, as in claims 1 and 24.
In particular, a liquid formulation is taught to include: (a) 25-100 mg/mL antibody, or antigen binding fragment thereof (i.e., about 5 mg/mL to about 200 mg/mL antibody or antigen binding fragment thereof; claims 1a and 24a; about 25 mg/ml to about 100 mg/ml; claim 21); (b) about 10 mM histidine buffer (about 5 mM to about 20 mM buffer; claims 1b and 24b); (c) about 70 mg/ml sucrose, which is 7% w/v sucrose (about 6% to about 8% w/v sucrose; claims 1ci, 6 and 24 ci); (d) about 0.2 mg/mL polysorbate 80, which is 0.02% of a non-ionic surfactant (about 0.01% to about 0.10% non-ionic surfactant; claims 1d, 14 and 24d); and (e) at pH 5.0 to 6.0 (the formulation has a pH between 5.0 and 6.0; claim 2). See column 4, lines 1-7 and 15-16 of Sharma. An exemplary liquid antibody formulation comprising 10 mM histidine buffer, pH 5.5, 7% sucrose, 0.02% polysorbate 80, and 25 mg/ml h409A11 (i.e., pembrolizumab) is provided, for instance, at col. 20 lines 16-18.
Thus, the patent’s teachings are directly on point to elements a, c and d of present claims 1 and 24, the concentration of buffer in claims 1b and 24b, the pH of claim 2, the stabilizer of claim 6, the surfactant of claim 14, and the liquid formulation of claim 20.
Reconstituted liquid formulations may comprise antibody at a concentration of about 25 mg/ml (or about 10, 15, 20, 25, 30, 40, 50, 60, 75, 80, 90 or 100 mg/ml), or higher concentrations such as 150 mg/ml or 200 mg/ml (col. 19 lines 1-4), which teach and suggest antibody concentration limitations of present claims 21 (about 25 mg/ml to about 100 mg/ml), claims 22 and 25 (about 25 mg/ml), and claim 23 and 26 (about 165 mg/ml to about 170 mg/ml).
Regarding claim 28 reciting different forms of cancer to be treated according to the presently claimed methods, Sharma discloses that the anti-human PD-1 antibody formulations are used in therapeutic methods for the treatment of: melanoma, myeloma, renal cancer, prostate cancer (e.g., hormone refractory prostate adenocarcinoma), bladder cancer, pancreatic cancer, breast cancer, colon cancer, lung cancer, squamous cell carcinoma of the head and neck, liver cancer, ovarian cancer, cervical cancer, thyroid cancer, glioblastoma, glioma, leukemia, lymphoma, and other neoplastic malignancies such as melanoma, colorectal, liver, kidney, stomach, esophageal, breast, pancreas, and ovarian cancer (col. 6 lines 51-67; col. 7 lines 7-20). Additional cancers that are disclosed as being beneficially treated include nasopharyngeal cancer, cervical, vulval, anal, penile and oral cancers (col. 7 lines 30-38).
And regarding claim 27, Sharma teaches that the antibody formulations can be given by subcutaneous administration (col. 3, lines 16-19; col. 15 lines 51-53; and col. 20 lines 53-55).
Finally, at col. 13, lines 1-14, Sharma discloses that the term “buffer” encompasses those agents which maintain the solution pH in an acceptable range prior to lyophilization. Examples of buffers will control the pH within the range of about 5.0 to about 6.0 are taught to include succinate, gluconate, histidine, citrate and other organic acid buffers. Sharma indicates that histidine, acetate and citrate buffers in the range of 5.0-6.0 were explored for suitability in the antibody formulation, wherein histidine and acetate were noted to perform better than the citrate system.
Thus, while not preferred embodiments, the disclosure of acetate and citrate as suitable buffers nonetheless meets the limitations of present claims 1b, 3-4 and 24b. A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Laboratories, 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989). See also Upsher-Smith Labs. v. Pamlab, LLC, 412 F.3d 1319, 1323, 75 USPQ2d 1213, 1215 (Fed. Cir. 2005).
Accordingly, it would have been obvious to one of ordinary skill in the art at the time of filing to have substituted acetate or citrate buffer for histidine buffer in the exemplary formulation and thereby arrive at the presently claimed invention. Sharma teaches that each of these buffers (citrate, acetate and histidine) is capable of maintaining the desired pH of the antibody formulation in the range of 5.0-6.0, and thus recognizes the functional equivalency of the buffering agents. Again, while histidine is indicated as a preferred embodiment, this in no way negates or teaches away from the use of either acetate or citrate as a buffer in a liquid antibody formulation as claimed. Thus, the substitution of histidine with either acetate or citrate as a buffering agent would have been obvious and predictable. This is because the artisan has good reason to pursue the known options within his or her technical grasp to obtain predictable results. Such would amount to the simple substitution of equivalent elements (i.e., one buffer for another) to achieve a predictable outcome.
6. Claim(s) 1-6, 14 and 20-30 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sharma et al. (US 9,220,776 B2) as evidenced by Wang et al. (Oncoimmunology, 2021, 10(1):1896643) as applied to claims 1-4, 6, 14 and 20-30 above, and in view of Wang et al. (Mol. Pharmaceutics, 2015, 12, 4478-4487; hereinafter “Wang 2015”) and Barry et al. (US 2009/0060906 A1) (all references listed on 10/01/2025 IDS).
The reasons why the teachings of Sharma et al. render obvious the invention of claims 1-4, 6, 14 and 20-30 is discussed above. As indicated above, Sharma teaches that the antibody formulation may additionally include amino acids such as arginine (col. 13 lines 24-25 of Sharma).
However, the reference does not teach that the formulation further comprises from about 1% to about 3% w/v L-arginine, or a pharmaceutically acceptable salt thereof, as in claim 5.
Wang 2015 teaches that antibody formulations comprising high concentrations of antibody can benefit from the addition of amino acid excipients or the salt forms to reduced viscosity and improve stability (see abstract). In particular, Wang teaches that the excipient arginine hydrochloride (ArgHCl) can lower the viscosity of antibody formulations (see Fig. 2) without causing detectable antibody aggregation, conformational changes, or decreased storage stability (see Conclusion at p. 4485).
Consistent with the teachings of Wang 2015, Barry et al. teach stable antibody formulations that include about 0.01% to about 5% arginine, with specific embodiments containing, for example, 1.0%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5% or 5% arginine (see [0005] and [0080]). In particular, an exemplary formulation can contain 100 mg/mL antibody, 10 mM histidine, 5% sucrose, 0.01% Tween 80 (polysorbate 80), 2% arginine and has a pH of 6.0 (see [0064]). Such teachings are directly on point to limitations regarding L-Arg in claim 3.
As such, it would have been obvious to one of ordinary skill in the art to have included L-arginine, as taught by Wang 2015 and Barry et al. as part of an anti-PD-1 antibody formulation so as to arrive at the presently claimed invention. The artisan would have been motivated to have included L-Arg so as to reduce viscosity of the composition and thereby reduce the risk of antibody aggregation. Given the well-established knowledge related to the inclusion of arginine in antibody formulations, the artisan would have had a reasonable expectation that including either L-Arg in the formulation would predictably improve the resultant antibody formation.
7. Claim(s) 1-4, 6-7, 9-15 and 17-30 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sharma et al. (US 9,220,776 B2) as evidenced by Wang et al. (Oncoimmunology, 2021, 10(1):1896643) as applied to claims 1-4, 6, 14 and 20-30 above, and in view of Li et al. (WO 2017/054646 A11; Pub April 6, 2017 with priority to earlier filing date) and Luisi et al. (US 2006/0210557 A1) (all references listed on 10/01/2025 IDS).
The reasons why the teachings of Sharma et al. render obvious the invention of claims 1-4, 6, 14 and 20-30 is discussed above. Additionally, Sharma indicates that greater stability of antibody formulations is desirable, particularly for long-term storage (col. 12 lines 65-66). Sharma indicates that agents that provide stability (i.e., stabilizers) to antibody formulations include bulking agents such as mannitol, glycine and sucrose (col. 12 lines 59-62); cryoprotectants (including sugars such as sucrose, glucose, trehalose and lactose; surfactants such as polysorbates; amino acids such as glycine, arginine and serine; col. 13 lines 17-25); and lyoprotectants such as polyols or sugars such as sucrose and trehalose (col. 13 lines 32-41).
Therefore, Sharma teaches and suggests an antibody formulation comprising pembrolizumab, a buffer (i.e., acetate or citrate), a stabilizer or “bulking agent” (i.e., sucrose, trehalose, mannitol or glycine; see col. 12 lines 59-66), and a non-ionic surfactant (i.e., polysorbate 80). However, Sharma does not teach the presently recited agents and their concentrations/percentages of trehalose (about 6-8% w/v), mannitol, sorbitol, L-arginine or L-proline (about 3-5% w/v), or glycine (about 1.8-2.2% w/v), as in claims 1, 7, 9-13 and 24, or that the surfactant may be polysorbate 20 (claim 15). And although Sharma teaches that the antibody formulation may also comprise amino acids such as glycine, arginine or serine, Sharma does not teach that the composition may further comprise about 1 mM to about 20 mM of an anti-oxidant (claim 14), wherein the anti-oxidant is L-methionine (claim 15) or L-methionine HCl (claim 16).
Li et al. teach stable pharmaceutical formulations comprising an anti-PD-1 antibody, a buffer, at least one stabilizer, and a surfactant ([0005]-[0006]). Li defines the term stabilizer to include lyoprotectants, which include saccharides, polyols and amino acids ([0060]). In particular, lyoprotectants can be selected from saccharides such as sucrose and trehalose ([0017], [0058], [0060]), aminosaccharides, polyols such as mannitol and sorbitol, and amino acids such as arginine and glycine, and mixtures thereof ([0060]). In addition to saccharides, amino acids and polyols, stabilizers are also taught to include surfactants, anti-oxidants, preservatives, cyclodextrins, salts and chelators ([0049]). Preferred stabilizers are suggested to include sucrose, trehalose and sorbitol ([0049] and [0017]). Li further discloses that the term “amino acid” includes, among others, arginine, glycine, methionine and proline ([0059]), and can be used in an amount of about 5 mM to about 500 mM, particularly about 5 to about 200 mM, and more particularly in about 100 mM to about 150 mM ([0049]).
Note that 3-5% w/v L-arginine is equivalent to about 172 mM to 287 mM, 3-5% w/v L-proline is equivalent to about 261 mM to 434 mM, and 1.8-2.2% w/v glycine is equivalent to about 240 mM to 293 mM. Thus, the range of 5 mM to 500 mM taught by Li encompasses all of the presently recited ranges for L-arginine, L-proline and glycine.
Further, Li teaches that the stabilizer can be present in the formulation in an amount from 30 mg/ml to 100 mg/ml (i.e., 3% w/v to 10% w/v), preferably from 60 mg/ml to 90 mg/ml (i.e., 6% w/v to 9% w/v/) ([0049]) or more preferably 85 to 95 mg/ml ([0017]) (i.e., 8.5% w/v to 9.5% w/v). Examples of formulations having 60 mg/ml (6% w/v) trehalose are given, for instance, at [0026]-[0028]. Taken together, such teachings provide for a stabilizer that may be: 6-8% w/v trehalose (claims 1ci, 7 and 24ci), 3-5% w/v mannitol, sorbitol, L-arginine or L-proline (claims 1cii, 9-12 and 24cii), or 1.8-2.2% w/v glycine (claims 1ciii, 13 and 24ciii).
Regarding claims 14-15, Li teaches that the surfactant can be polysorbate 20 (PS20), polysorbate 80 (PS80), or poloxamer (Pluronic) (0055], [0018] and [0026]-[0028]).
Finally, Li teaches that the addition of an antioxidant to an anti-PD-1 antibody formulation can prevent oxidation of the active pharmaceutical agent. Suitable antioxidants can include, among others, methionine ([0057]).
Consistent with the teachings of Li et al., Luisi et al. teach stabilized liquid formulations for maintaining the stability of polypeptides, including therapeutic antibodies, wherein the formulations include an antioxidant in a sufficient amount as to inhibit by-product formation, such as the formation of high molecular weight polypeptide aggregates, low molecular weight polypeptide degradation fragments, and mixtures thereof (see abstract). A stabilized formulation comprising a therapeutically active antibody is taught to include a tonicity agent, such as about 2% w/v to about 6% w/v mannitol ([0026]), a buffering agent or amino acid ([0122]-[0123]), and an antioxidant such as 10 mM methionine ([0021], [0026], [0082]-[0083]), as well as a surfactant such as 0.01% to 0.1% PS80 ([0027], [0040]), and having a pH of about 5 to 7, and in particular about 6 ([0027]).
Luisi teaches that in addition to mannitol, sucrose, trehalose and glycine are taught as alternative, acceptable tonicity agents (see [0126]). Such tonicity agents may be present in the formulation at about 2% to about 6% w/v, or about 3% to about 5% w/v ([0127]). Again, such teachings provide for recited limitations pertaining to the stabilizer in present claims 1, 6-7, 9, 13, and 24. The anti-oxidant may include L-methionine or an analog thereof (see [0015], [0020] and [0130]), and is present at a concentration of about 0.1 mM to about 20 mM, such as specifically about 5 mM, 6 mM, 7 mM, 8 mM, 9 mM, 10 mM, 11 mM, 12 mM, 13 mM, 14 mM, 15 mM, or about 12 mM to about 17 mM ([0131]), which addresses the limitations of present claims 17-19.
It would have been obvious to one of ordinary skill in the art at the time of filing to have substituted the stabilizer sucrose as taught by Sharma for one or more of trehalose, mannitol, sorbitol, L-arginine, L-proline or glycine as taught by Li and Luisi and thereby arrive at the presently claimed antibody formulation. This is because the artisan has good reason to pursue the known options within his or her technical grasp to achieve predictable results. In the instant case, this would amount to the simple substitution of functionally equivalent elements (i.e., stabilizers, lyoprotectants, tonicity agents) to arrive at a predictable outcome. In fact, Sharma even suggests that agents such as trehalose can be used in place of sucrose, and therefore it would have been obvious to have substituted the art-recognized equivalent stabilizer/tonicity agents according to the concentrations of Li and Luisi with a reasonable expectation of success.
Further, it would have been obvious to one of ordinary skill in the art at the time of filing to have included an anti-oxidant such as L-methionine, as taught by Luisi, in the antibody formulation of Sharma and thereby arrive at the presently claimed invention. Given the teachings of Li and Luisi, the skilled artisan would have recognized that the addition of antioxidants in an antibody formulation helps to prevent oxidation of the therapeutic polypeptides. Further, Luisi expressly suggests the inclusion of an anti-oxidant, such as 10 mM L-methionine, in therapeutic antibody formulations so as to prevent oxidation and thereby preserve the formulation (see [0129] and [0131] of Luisi). Given the extensive teachings of Sharma, Li and Luisi demonstrating various antibody formulations, the artisan would have had a reasonable expectation that the addition of L-methionine to the anti-PD-1 antibody formulation of Sharma would be successful in preventing oxidation of the antibody. Therefore, the combined teachings of the above prior art references render obvious the presently recited invention of claims 1-4, 6-7, 9-15 and 17-30.
8. Claim(s) 1-4, 6-15 and 17-30 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sharma et al. (US 9,220,776 B2) as evidenced by Wang et al. (Oncoimmunology, 2021, 10(1):1896643) and in view of Li et al. (WO 2017/054646 A12; Pub April 6, 2017 with priority to earlier filing date) and Luisi et al. (US 2006/0210557 A1) as applied to claims 1-4, 6-7, 9-15 and 17-30 above, and further in view of Hartl et al. (J Pharm Sci. 2013, 102:4121-4131) (all references listed on 10/01/2025 IDS).
The reasons why the combined teachings of Sharma, Li, and Luisi render obvious the invention of claims 1-4, 6-7, 9-15 and 17-30 is discussed above.
However, while Li et al. may teach that cyclodextrins are suitable stabilizers for antibody formulations, the references do not specifically teach that the cyclodextrin stabilizer is (2-hydroxypropyl)-b-cyclodextrin (HPbCD), as in claims 1, 8 and 24.
Hartl et al. teach that antibody solutions usually require the addition of suitable excipients, such as surfactants and polyols, to overcome stability problems under mechanical or thermal stress (see abstract). Hartl suggests that because cyclodextrins exhibit weak surface activity (similar to surfactants) and a sugar-based structure (like polyols), they can, in principle, stabilize proteins by a double mechanism. Hartl tested the stabilizing potential of various concentrations of HPbCD on two antibodies compared with polysorbate 80 or sucrose formulations as controls (see abstract). Hartl found that increasing concentrations of HPbCD lead to a gradual protein stabilization under mechanical stress, and generally performed better than sucrose in monomer recovery (see abstract and Fig. 1 at p. 4124). Hartl conclude that low concentrations of HPbCD (such as about 2.5 to 50 mM) can be a viable option to stabilize antibody solutions (see conclusion at p. 4130). Note that 6-8% w/v HPbCD is equivalent to about 40-60 mM.
It would have been obvious to one of ordinary skill in the art to have used HPbCD, as taught by Hartl, for the cyclodextrin stabilizer as taught by the combination of Li, and thereby arrive at the presently claimed antibody formulation. Given that Li teaches that cyclodextrins can reasonably be used as stabilizing agents in antibody formulations, and given that Hartl demonstrates that HPbCD performs similarly to sucrose (as taught in Sharma) for antibody stabilization, it would have been obvious to have substituted sucrose with HPbCD as presently claimed. This is because the artisan has good reason to pursue the known options within his or her technical grasp to achieve predictable results. In the instant case, this would amount to the simple substitution of functionally equivalent elements (i.e., stabilizing agents, HPbCD for sucrose) to arrive at a predictable outcome.
9. Claim(s) 1-4, 6-7, 14-16 and 20-30 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sharma et al. (US 9,220,776 B2) as evidenced by Wang et al. (Oncoimmunology, 2021, 10(1):1896643) as applied to claims 1-4, 6, 14 and 20-30 above, and in view of Kang et al. (BioProcess Intl. 2016, 14(4): 40-45) (all references listed on 10/01/2025 IDS).
The reasons why the teachings of Sharma et al. render obvious the invention of claims 1-4, 6, 14 and 20-30 is discussed above. Sharma teaches that sucrose and trehalose are examples of suitable sugars useful to provide stability in antibody formulations (col. 13 lines 32-41). Sharma teaches a formulation that comprises 7% sucrose. However, Sharma does not explicitly teach a formulation that comprises trehalose instead of sucrose, as in claim 7. And while Sharma teaches that the antibody formulation comprises polysorbate 80 (PS80) as a surfactant, the reference does not teach that the surfactant is polysorbate 20 (PS20) or poloxamer 188, as in claims 15 and 16, respectively.
Kang et al. provide a review of the excipients used in commercial monoclonal antibody formulations and teach that most (80%) formulations used one of three surfactants: polysorbate 80, polysorbate 20, or poloxamer 188. Kang also teaches that all commercial antibody formulations used one or a mixture of polyol/disaccharide/polysaccharide, such as mannitol, sorbitol, sucrose, trehalose, and dextran 40. Kang teaches that sucrose was the most popular excipient and was included in over 80% of lyophilized formulations, 15% of liquid formulations, and 35% of all monoclonal antibody (Mab) formulations (Table 1). Trehalose was the next most frequently used sugar in commercial preparations, with inclusion in 18% of lyophilized formulations, 12% of liquid formulations, and 14% of all Mab formulations (Table 1).
Accordingly, it would have been obvious for one of ordinary skill in the art at the time of filing to have substituted PS20 or poloxamer 188, as taught by Kang, for PS80 as taught by Sharma, and thereby arrive at the presently claimed antibody formulation. Similarly, it would have been obvious to have substituted the sucrose with trehalose, because they are both taught by Kang to be functionally equivalent stabilizing agents. This is because the artisan has good reason to pursue the known options within his or her technical grasp to achieve predictable results. In the instant case, this would amount to the simple substitution of functionally equivalent elements (i.e., surfactants; sugars) to arrive at a predictable outcome.
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.
10. Claims 1-4, 6-7 and 9-30 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 and 13 of U.S. Patent No. 9,220,776 in view of Li et al. (US 2018/0339045 A1), Luisi et al. (US 2006/0210557 A1), and Kang et al. (BioProcess Intl. 2016, 14(4): 40-45).
The patented ‘776 claims recite a stable antibody formulation comprising 25-100 mg/mL of antibody; about 70 mg/mL sucrose (which is about 7% w/v); 0.2 mg/mL polysorbate 80 (which is about 0.02% w/v); and about 10 mM histidine buffer at pH 5.0-6.0, wherein the antibody comprises a light chain and heavy chain sequences that are comprised by the antibody pembrolizumab as instantly claimed. However, the patented claims do not recite that the formulation comprises a different buffer (acetate or citrate), stabilizer (trehalose, mannitol, sorbitol, L-arginine, L-proline or glycine), or an antioxidant, such as L-methionine. The ‘776 patented claims also recite a method of treating cancer in a human subject comprising administering the anti-PD-1 antibody formulation, wherein the subject has melanoma.
The teachings of Li et al., Luisi et al., and Kang et al. are cumulative and are discussed above and provide for the use of alternative buffering agents, such as an acetate or citrate buffer ([0015] of Li; Kang), stabilizing agents (such as trehalose, mannitol, sorbitol, L-arginine, L-proline or glycine) (as in present claims 3-4, 7 and 9-13), as well as the addition of an anti-oxidant, such as 10 mM L-methionine, to be included in stable antibody formulations. Li teaches PS20 and PS80 as suitable surfactants, as in claims 14-15, and Kang teaches that poloxamer 188 is another suitable surfactant, as in claim 16. Each of the references teach that the addition of an anti-oxidant, such as methionine, to a formulation is beneficial in reducing oxidation of the antibody and for preventing the formation of aggregation and/or fragmentation of the antibody. Li additionally teaches that stable anti-PD-1 antibody formulations can be administered subcutaneously ([0064]), as in present claim 27.
Accordingly, it would have been obvious to have used a different buffer, such as citrate or acetate, one or more of the stabilizing agents, a different surfactant (PS20 or poloxamer 188), an antioxidant such as L-methionine, or to have administered the antibody subcutaneously and thereby arrive at the claimed invention. The prior art references provide both motivation to include the listed agents as well as a reasonable expectation that such substitution or addition to the formulation would be predictable or else improve the stability and reduce oxidation of the anti-PD-1 antibody contained therein.
11. Claim 5 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 and 13 of U.S. Patent No. 9,220,776 in view of Li et al. (US 2018/0339045 A1), Luisi et al. (US 2006/0210557 A1) and Kang et al. (BioProcess Intl. 2016, 14(4): 40-45) as applied to claims 1-4, 6-7 and 9-30 above, and further in view of Wang et al. (Mol. Pharmaceutics, 2015, 12, 4478-4487; hereinafter “Wang 2015”) and Barry et al. (US 2009/0060906 A1).
The reasons why the patented claims in view of Li, Luisi and Kang render obvious the invention of claims 1-4, 6-7 and 9-30 are discussed above. However, neither the patented claims nor the prior art teach that the composition further comprises L-arginine or a salt thereof as in claim 3.
The teachings of Wang 2015 and Barry et al. are discussed above and provide for the inclusion of L-arginine in an antibody formulation to improve viscosity.
Therefore, it would have been obvious to have included L-Arg in the antibody formulation of the patented ‘776 claims and thereby arrive at the presently claimed invention. The motivation to do so comes from the Wang and Barry references, and their teachings provide a reasonable expectation that the addition of L-arg to an antibody composition would be predictably beneficial.
12. Claim 8 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 and 13 of U.S. Patent No. 9,220,776 in view of Li et al. (US 2018/0339045 A1), Luisi et al. (US 2006/0210557 A1) and Kang et al. (BioProcess Intl. 2016, 14(4): 40-45) as applied to claims 1-4, 6-7 and 9-30 above, and further in view of Hartl et al. (J Pharm Sci. 2013, 102:4121-4131).
The reasons why the patented claims in view of Li, Luisi and Kang render obvious the invention of claims 1-4, 6-7 and 9-30 are discussed above. However, neither the patented claims nor the prior art teach that the composition comprises (2-hydroxypropyl)-b-cyclodextrin (HPbCD) as the stabilizer, as in claim 5.
The teachings of Hartl et al. are discussed above and provide for the use of HPbCD as a suitable stabilizing agent.
Given that Li teaches that cyclodextrins can reasonably be used as stabilizing agents in antibody formulations, and given that Hartl demonstrates that HPbCD performs similarly to sucrose (as recited in the ‘776 claims) for antibody stabilization, it would have been obvious to have substituted HPbCD for sucrose as presently claimed. This is because the artisan has good reason to pursue the known options within his or her technical grasp to achieve predictable results. In the instant case, this would amount to the simple substitution of functionally equivalent elements (i.e., stabilizing agents; HPbCD for sucrose) to arrive at a predictable outcome.
13. Claims 1-7 and 9-30 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7, 10-13, 16 and 18-21 of U.S. Patent No. 11,633,476 in view of Li et al. (US 2018/0339045 A1), Luisi et al. (US 2006/0210557 A1), and Kang et al. (BioProcess Intl. 2016, 14(4): 40-45).
The patented ‘476 claims recite a stable anti-human PD-1 antibody formulation comprising 100-200 mg/mL (or 125-200 mg/ml, or 165-170 mg/ml) of antibody; about 6% to 8% w/v sucrose; about 0.01% to about 0.1% w/v polysorbate 80; about 5 mM to about 20 mM histidine buffer at pH 5.0-6.0; and about 1 mM to about 20 mM L-methionine (or L-methionine HCl), wherein the antibody is pembrolizumab. The patented claims also recite that the formulation further comprises about 1% to about 3% w/v L-arginine. Finally, the patented claims recite a method for treating cancer in a human patient comprising administering the claimed antibody formulation, wherein the formulation is administered by subcutaneous administration.
However, the patented claims do not recite that the formulation comprises a different buffer (acetate or citrate), a different stabilizer (trehalose, mannitol, sorbitol, L-arginine, L-proline or glycine), different surfactants (PS20 or poloxamer 188), or that the cancer is one of the types of cancer listed in present claim 28.
The combined teachings of Li et al., Luisi et al. and Kang et al. are discussed above and provide for the use of alternative buffers (such as acetate or citrate), stabilizing agents (such as trehalose, mannitol, sorbitol, L-arginine, L-proline or glycine), and surfactants (such as polysorbate 20 or poloxamer 188) to be included in stable antibody formulations. Li additionally teaches that anti-PD-1 antibody formulations can be used in the treatment of cancer, such as breast cancer, lung cancer, stomach cancer, intestinal cancer, kidney cancer, or melanoma ([0035]-[0037]).
Accordingly, it would have been obvious to have used one or more of the alterative buffers, stabilizing agents, or surfactants as taught by Li, Luisi, and Kang, or to have treated a particular type of cancer as taught by Li, and thereby arrive at the presently claimed invention. This is because the artisan has good reason to pursue the known options within his or her technical grasp to obtain predictable results. Such would amount to the simple substitution of known equivalent elements (i.e., buffers, stabilizing agents, surfactants) to achieve a predictable outcome. Similarly, given the teachings of Li indicating that cancers such as breast, liver and lung cancers, etc. can be treated using anti-PD-1 antibodies, it would have been obvious and predictable to have applied the patented method of treating cancer to any of the specific types of cancer taught by Li.
14. Claim 8 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 11,633,476 in view of Li et al. (US 2018/0339045 A1), Luisi et al. (US 2006/0210557 A1), and Kang et al. (BioProcess Intl. 2016, 14(4): 40-45) as applied to claims 1-7 and 9-30 above, and further in view of Hartl et al. (J Pharm Sci. 2013, 102:4121-4131).
The reasons why the patented claims in view of Li, Luisi and Kang render obvious the invention of claims 1-7 and 9-30 are discussed above. However, neither the patented claims nor the prior art teach that the composition comprises (2-hydroxypropyl)-b-cyclodextrin (HPbCD) as the stabilizer, as in claim 8.
The teachings of Hartl et al. are discussed above and provide for the use of HPbCD as a suitable stabilizing agent.
Given that Li teaches that cyclodextrins can reasonably be used as stabilizing agents in antibody formulations, and given that Hartl demonstrates that HPbCD performs similarly to sucrose (as recited in the ‘476 claims) for antibody stabilization, it would have been obvious to have substituted HPbCD for sucrose as presently claimed. This is because the artisan has good reason to pursue the known options within his or her technical grasp to achieve predictable results. In the instant case, this would amount to the simple substitution of functionally equivalent elements (i.e., stabilizing agents; HPbCD for sucrose) to arrive at a predictable outcome.
15. Claims 1-30 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 and 19-30 of copending Application No. 19/346,648 in view of Kang et al. (BioProcess Intl. 2016, 14(4): 40-45).
The co-pending ‘648 claims recite an anti-human PD-1 antibody formulation comprising: pembrolizumab (5-100 mg/ml; 25 mg/ml; or 165-170 mg/ml); histidine buffer (5-20 mM), stabilizer (6-8% w/v trehalose or 2-hydroxypropyl-b-cyclodetrin; 3-5% w/v mannitol, sorbitol, L-Arg or L-Pro; 1.8-2.2% w/v glycine); surfactant (0.01-0.1% PS80, PS20 or poloxamer 188), additional agents (1-3% w/v L-Arg), and antioxidants (1-20 mM L-methionine) and the therapeutic subcutaneous administration of the formulation for the treatment of cancer. Further, co-pending claim 26 recites the same types of cancer that are recited in present claim 28. The only difference between the present claims and the co-pending ‘648 claims is that the present claims recite that the formulation comprises a different buffer: acetate or citrate.
Kang et al. teach that the most commonly used buffers in commercial antibody formulations to keep pH levels between 4.7 and 7.4 include acetate, citrate, histidine, succinate, phosphate, and Tris. Following histidine and phosphate, acetate and citrate buffers are the next most commonly used types of buffers (Table 1).
Accordingly, it would have been obvious to one of ordinary skill in the art to have substituted either acetate or citrate buffer as taught by Kang for histidine buffer as recited by the co-pending ‘648 claims and thereby arrive at the presently claimed invention. This is because the artisan has good reason to pursue the known options within his or her technical grasp to achieve predictable results. In the instant case, this would amount to the simple substitution of functionally equivalent elements (i.e., buffers) to arrive at a predictable outcome. This is a provisional nonstatutory double patenting rejection.
19. Claims 1-3, 5-15, 17-27 and 29 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11, 14-21, 23-26, 29-30, 33-43, 46-60 and 64-65 of copending Application No. 18/182,135 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because in each case the claims recite an anti-human PD-1 antibody liquid formulation comprising the same elements (pembrolizumab, acetate buffer, stabilizer, surfactant (PS20 or PS80), additional agents (L-arginine), and antioxidant (L-methionine)) at the same concentrations/amounts, and used in the treatment of cancer in a human patient. The only difference between the present claims and the co-pending ‘135 claims is that the present claims recite that the formulation comprises about 5 mg/ml to about 200 mg/ml antibody, and the co-pending claims recite that the formulation comprises about 100 mg/ml to about 200 mg/ml of antibody. However, the narrower range of the co-pending ‘135 application anticipates the more broadly claimed range of the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
20. Claims 4, 16, 28 and 30 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11, 14-21, 23-26, 29-30, 33-43, 46-60 and 64-65 of copending Application No. 18/182,135 in view of Kang et al. (BioProcess Intl. 2016, 14(4): 40-45) and Sharma et al. (US 9,220,776).
The reasons why the claims of the ‘135 application anticipate or render obvious present claims 1-3, 5-15, 17-27 and 29 are discussed above. However, the co-pending claims do not recite that the buffer is citrate, as in claims 4 and 30, surfactant is poloxamer 188 as in claim 16, the concentration of pembrolizumab is about 25 mg/ml, as in claims 22 and 25, or the types of cancer as in claim 28.
The teachings of Kang et al. are discussed above and provide for the use of citrate as a commonly used alternative buffer, and poloxamer 188 as an alternative suitable surfactant.
The teachings of Sharma et al. are also set forth above and provide for a liquid antibody formulation comprising pembrolizumab, wherein the concentration of the antibody is 25-100 mg/ml (col. 4 lines 1-4 and 49-51), or more specifically, 25 mg/ml (col. 19 lines 1-3). Consistent with Kang, Sharma indicates that citrate can be used as a suitable buffer (col. 13 lines 1-5). Sharma also teaches that pembrolizumab can be used in the treatment of the different types of cancer as recited in present claim 28 (col. 6 lines 51-67; col. 7 lines 7-20 and 30-38).
It would have been obvious to one of ordinary skill in the art to have used citrate buffer as taught by Kang and by Sharma, to have substituted poloxamer 188 for PS80 as recited by the ‘476 claims, and thereby arrive at the presently claimed antibody formulation. This is because the artisan has good reason to pursue the known options within his or her technical grasp to achieve predictable results. In the instant case, this would amount to the simple substitution of functionally equivalent elements (i.e., buffers, surfactants) to arrive at a predictable outcome.
It similarly would have been obvious to have used a lower concentration of pembrolizumab, or to treat a specific type of cancer, as taught by Sharma, and thereby arrive at the presently claimed invention. In particular, Sharma teaches the same antibody, pembrolizumab, and its formulation and therapeutic use, and therefore provides both motivation to use different antibody concentrations or treat specific types of cancer, but also a reasonable expectation that such concentrations/therapeutic applications would be successful. This is a provisional nonstatutory double patenting rejection.
21. Claims 1-30 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 and 19-30 of copending Application No. 19/346,623 in view of Kang et al. (BioProcess Intl. 2016, 14(4): 40-45).
The claims of the ‘623 co-pending application and the instant claims are both drawn to an anti-human PD-1 antibody formulation comprising the same amounts (5-200 mg/ml, 25-100 mg/ml, 25 mg/ml, 165-170 mg/ml) of the same antibody (pembrolizumab) and having the same stabilizing agents and amounts (trehalose, HPbCD, mannitol, sorbitol, L-Arg, L-Pro, glycine), non-ionic surfactants (0.01-0.1% w/v PS80, PS20, or poloxamer 188), and anti-oxidants (1-20 mM L-methionine HCl). The co-pending claims also recite a method of treating cancer in a human patient, comprising administering the aforementioned antibody formulation, wherein the type of cancer is the same as those recited in present claim 28, and administration is by subcutaneous administration. However, the ‘623 claims recite that the formulation comprises 5-20 mM histidine buffer, whereas the instant claims recite that the buffer is 5-20 mM acetate or citrate. The present claims also recite that the stabilizer is sucrose.
Kang et al. provide a review of the excipients used in commercial monoclonal antibody formulations and teach that six commonly used buffers keep pH levels between 4.7 and 7.4: acetate, citrate, histidine, succinate, phosphate, and Tris. Following histidine and phosphate, acetate and citrate buffers are the next most commonly used types of buffers (Table 1). Kang further teaches that sucrose is the most commonly used sugar stabilizing agent.
Therefore, it would have been obvious to have substituted to acetate or citrate buffer, as taught by Kang for the histidine buffer of the ‘623 application, or to have substituted sucrose for trehalose, and thereby arrive at the presently claimed invention. This is because the artisan has good reason to pursue the known options within his or her technical grasp to achieve predictable results. In the instant case, this would amount to the simple substitution of functionally equivalent elements (i.e., common buffers or sugar stabilizers) to arrive at a predictable outcome. This is a provisional nonstatutory double patenting rejection.
22. Claims 1-7 and 9-30 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7, 10-20, 23-24 and 27-35 of copending Application No. 18/182,097 (reference application) in view of Li et al. (US 2018/0339045 A1), Luisi et al. (US 2006/0210557 A1) and Kang et al. (BioProcess Intl. 2016, 14(4): 40-45).
The co-pending ‘097 claims recite a stable anti-human PD-1 antibody formulation comprising 100-200 mg/mL (or 125-200 mg/ml, or 165-170 mg/ml) of antibody; about 6% to 8% w/v sucrose; about 0.01% to about 0.1% w/v polysorbate 80; about 5 mM to about 20 mM histidine buffer at pH 5.0-6.0; and about 1 mM to about 20 mM L-methionine (or L-methionine HCl), wherein the antibody is pembrolizumab. The co-pending claims also recite that the formulation is a reconstituted solution (i.e., a liquid) and that it further comprises about 1% to about 3% w/v L-arginine. Finally, the co-pending ‘097 claims recite a method for treating cancer in a human patient comprising administering the claimed antibody formulation, wherein the formulation is administered by subcutaneous administration.
However, the co-pending claims do not recite that the formulation comprises a different buffer (acetate or citrate), different stabilizer (trehalose, mannitol, sorbitol, L-arginine, L-proline or glycine), or that the cancer is one of the types of cancer listed in present claim 28.
The teachings of Li et al., Luisi et al. and Kang et al. are discussed above and provide for the use of alternative buffers (such as acetate or citrate), stabilizing agents (such as trehalose, mannitol, sorbitol, L-arginine, L-proline or glycine), and surfactants (PS20 or poloxamer 188) to be included in stable antibody formulations. Li additionally teaches that anti-PD-1 antibody formulations can be used in the treatment of cancer, such as breast cancer, lung cancer, stomach cancer, intestinal cancer, kidney cancer, or melanoma ([0035]-[0037]).
Accordingly, it would have been obvious to have used one or more of the alternative buffers, stabilizing agents or surfactants as taught by Li, Luisi and Kang, or to have treated a particular type of cancer as taught by Li, and thereby arrive at the presently claimed invention. This is because the artisan has good reason to pursue the known options within his or her technical grasp to obtain predictable results. Such would amount to the simple substitution of known equivalent elements (i.e., buffers, stabilizing agents, surfactants) to achieve a predictable outcome. Similarly, given the teachings of Li indicating that cancers such as breast, liver and lung cancers, etc. can be treated using anti-PD-1 antibodies, it would have been obvious and predictable to have applied the claimed co-pending method of treating cancer to the treatment of any of the specific types of cancer taught by Li.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
23. Claim 8 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7, 10-20, 23-24 and 27-35 of copending Application No. 18/182,097 (reference application) in view of Li et al. (US 2018/0339045 A1), Luisi et al. (US 2006/0210557 A1) and Kang et al. (BioProcess Intl. 2016, 14(4): 40-45) as applied to claims 1-7 and 9-30 above, and further in view of Hartl et al. (J Pharm Sci. 2013, 102:4121-4131).
The reasons why the co-pending ‘097 claims in view of Li, Luisi and Kang render obvious the invention of claims 1-7 and 9-30 are discussed above. However, neither the co-pending claims nor the prior art teach that the composition comprises (2-hydroxypropyl)-b-cyclodextrin (HPbCD) as the stabilizer, as in claim 8.
The teachings of Hartl et al. are discussed above and provide for the use of HPbCD as a suitable stabilizing agent.
Given that Li teaches that cyclodextrins can reasonably be used as stabilizing agents in antibody formulations, and given that Hartl demonstrates that HPbCD performs similarly to sucrose (as recited in the ‘097 claims) for antibody stabilization, it would have been obvious to have substituted HPbCD for sucrose or trehalose as presently claimed. This is because the artisan has good reason to pursue the known options within his or her technical grasp to achieve predictable results. In the instant case, this would amount to the simple substitution of functionally equivalent elements (i.e., stabilizing agents; HPbCD for sucrose) to arrive at a predictable outcome. This is a provisional nonstatutory double patenting rejection.
Conclusion
24. No claims are allowed.
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/KIMBERLY BALLARD/Primary Examiner, Art Unit 1675
1 This document is in Chinese; however, US 2018/0339045 A1 is the English language equivalent of the WO document (PCT/CN2016/098982) and therefore reference and citations within this rejection will be made with respect to the ‘045 publication.
2 This document is in Chinese; however, US 2018/0339045 A1 is the English language equivalent of the WO document (PCT/CN2016/098982) and therefore reference and citations within this rejection will be made with respect to the ‘045 publication.