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, Amendment and/or Claims
1. Claims 1, 6, 24 and 28 have been amended, claims 3-4, 7-13, 16, 20-22, 25 and 29-30 have been canceled, and new claims 31-33 have been added as requested in the amendment filed May 4, 2026. Following the amendment, claims 1-2, 5-6, 14-15, 17-19, 23-24, 26-28 and 31-33 are pending in the present application.
2. Claims 1-2, 5-6, 14-15, 17-19, 23-24, 26-28 and 31-33 are under examination in the current office action.
Information Disclosure Statement
3. The information disclosure statement (IDS) filed 05/04/2026 has been considered and the references therein are of record.
Withdrawn Claim Rejections
4. Any objection or rejection of record pertaining to any of canceled claims 3-4, 7-13, 16, 20-22, 25 or 29-30 is rendered moot by applicant’s amendment.
5. The terminal disclaimer filed on May 4, 2026 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of U.S. Patent No. 11,633,476 and any patent granted on any of U.S. Patent Application Nos. 19/346,648, 19/346,623, 18/182,135 and 18/182,097 has been reviewed and is accepted. The terminal disclaimer has been recorded.
Accordingly, the non-statutory double patenting rejections over the claims of the patent and patent applications have been overcome.
6. The objection to claim 28 for minor informalities is withdrawn in view of applicant’s amendment to the claim.
7. The rejection of claim 28 under 35 U.S.C. 112(b)(indefiniteness), as set forth at section 4 of the 02/02/2026 office action, is withdrawn in view of applicant’s clarifying amendment to the claim.
8. The rejection of claims 1-2, 6, 14-15, 17-19, 23-24 and 26-28 under 35 U.S.C. 103 as being unpatentable over Sharma et al. (US 9,220,776) as evidenced by Wang et al. (2021) and in view of Li et al. (WO 2017/054646 A1), Luisi et al. (US 2006/0210557 A1), as set forth at section 7 of the previous office action, is withdrawn in view of applicant’s claim amendments.
9. The rejection of claims 1-2, 6, 14-15, 17-19, 23-24 and 26-28 under 35 U.S.C. 103 as being unpatentable over Sharma et al. (US 9,220,776) as evidenced by Wang et al. (2021) and in view of Li et al. (WO 2017/054646 A1), Luisi et al. (US 2006/0210557 A1) and Hartl et al. (J Pharm Sci. 2013, 102:4121-4131), as set forth at section 8 of the previous office action, is withdrawn in view of applicant’s amendments to the claims. In particular, claims and/or limitations containing elements taught by Hartl have been canceled and/or deleted, and therefore this rejection is no longer necessary.
10. The rejection of claims 1-2, 6, 14-15, 17-19, 23-24 and 26-28 under 35 U.S.C. 103 as being unpatentable over Sharma et al. (US 9,220,776) as evidenced by Wang et al. (2021) and in view of Kang et al. (BioProcess Intl. 2016, 14(4): 40-45), as set forth at section 9 of the previous office action, is withdrawn in view of applicant’s claim amendments.
11. The rejection of claims 1-2, 4, 6, 14-15, 17-19, 23-24 and 26-28 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 set forth at section 10 of the previous office action, is withdrawn in view of applicant’s claim amendments.
Maintained and New Claim Rejections, Necessitated by Amendment
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.
12. Claim(s) 1-2, 6, 14, 23-24, 26-28 and 31 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). The rejection is maintained for reasons of record and as discussed below.
The basis of this rejection has been set forth previously and therefore will not be fully reiterated here (see section 5 of the 02/02/2026 office action). As amended, the claims are now directed to an anti-human PD-1 antibody formulation, or a method of treating cancer comprising administering an anti-human PD-1 antibody formulation, the formulation comprising: a) 100 mg/mL to about 200 mg/mL of an anti-human PD-1 antibody; b) about 5 mM to about 20 mM acetate buffer; c) about 6% to about 8% w/v sucrose; and d) about 0.01% to about 0.10% non-ionic surfactant, wherein the non-ionic surfactant is polysorbate 80 or polysorbate 20, and wherein the antibody is pembrolizumab and the formulation is a liquid.
As discussed previously, 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) and methods for treating various cancers in a human patient in need thereof using these stable formulations of anti-human PD-1 antibodies (see col. 3, lines 24-30; col. 4 lines 56-59; and col. 6 lines 47-49). Sharma teaches that the PD-1 blocking antibody is h409A11 (see col. 4 lines 49-50), which is evidenced by Wang et al. to alternatively be called pembrolizumab or MK3475 (see figure legend for Figure 2D at p. 7). 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. Such cancer can include non-small cell lung cancer (col. 7 line 12), which is on point to new claim 31.
Sharma teaches that liquid formulations may comprise antibody at a concentration of about 25 mg/ml to 100 mg/ml or higher concentrations such as 150 mg/ml or 200 mg/ml (col. 19 lines 1-4), which teach and suggest an antibody concentration within the range of 100 mg/mL to about 200 mg/mL as in present claims 1 and 24, and suggest an antibody concentration as in claims 23 and 26 (about 165 mg/ml to about 170 mg/ml). Sharma indicates that high concentrations are particularly useful where subcutaneous delivery of the reconstituted formulation is intended (col. 19 lines 41-43). In particular, 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), which address claim 27.
In addition to the antibody, Sharma discloses that liquid formulations may include a buffer to control the pH of the liquid within the range of about 5.0 to about 6.0 (the formulation has a pH between 5.0 and 6.0 (claim 2)), about 70 mg/ml sucrose, which is 7% w/v sucrose (about 6% to about 8% w/v sucrose (claims 1, 24); about 7% w/v sucrose (claim 6)), and 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 1, 14, 24). Sharma teaches that the term “buffer” includes succinate, gluconate, histidine, citrate and other organic acid buffers. In particular, 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 by Sharma to perform better than the citrate system (col. 13, lines 1-14). Thus, Sharma teaches and suggests that histidine and acetate are suitable buffers and functionally equivalent for liquid formulations containing the anti-PD-1 antibody.
Accordingly, it would have been obvious to one of ordinary skill in the art at the time of filing to have substituted acetate buffer for histidine buffer and to have increased the concentration of antibody in the exemplary formulation taught by Sharma and thereby arrive at the presently claimed invention. Sharma teaches that these buffers (acetate and histidine) are 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 acetate as a buffer in a liquid antibody formulation as claimed. Thus, the substitution of histidine with acetate 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.
Additionally, it would have been obvious to modify the concentration of the antibody within the liquid formulation to arrive at the presently claimed invention. In particular, Sharma clearly teaches that antibody concentrations higher 100 mg/mL, such as 150 mg/mL or 200 mg/mL, may be desired for subcutaneous administration of the antibody, which is also taught by the reference. Thus, the use of a higher antibody concentration would have been obvious and predictable, or at the very least would have amounted to optimization of an antibody formulation. A particular parameter must first be recognized as a result-effective variable, i.e., a variable, which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation. In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977). In the instant application, the concentration of antibody within a formulation is clearly a recognized result-effective variable that a person of ordinary skill in the art would routinely optimize (see MPEP § 2144.05). In fact, the disclosure of Sharma states that the antibody concentration can range from about 10 mg/mL to as high as about 500 mg/mL, wherein the higher concentrations may be useful for subcutaneous delivery (col. 19 lines 37-43). Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal concentration of antibody within a formulation. Thus, absent some demonstration of unexpected results from the claimed parameters, this optimization of antibody concentration would have been obvious at the time of Applicants’ invention.
Response to Arguments
13. In the response filed 05/04/2026, Applicant argues that Sharma focuses on antibody formulations containing lower antibody concentrations (25-100 mg/mL), and that there is no mention that acetate would be useful with a higher concentration of pembrolizumab (100-200 mg/mL). Applicant asserts that one of skill in the art could not predict that the claimed formulation comprising 100 to about 200 mg/mL pembrolizumab in combination with the other excipients would have had a reasonable expectation of success.
According to applicant, the instant specification demonstrates in Example 2 that a formulation containing a high concentration of pembrolizumab (160 mg/mL), acetate, sucrose and polysorbate 80 (formulation 5) was stable at 5°C and did not exhibit oxidation of Met-105 at this temperature, which results were not predictable from Sharma or Wang.
14. Applicant’s arguments have been considered but are not persuasive. In contrast to applicant’s arguments, Sharma provides for all elements of the presently claimed invention as well as sufficient disclosure and motivation to modify an exemplified formulation (i.e., comprising 25-100 mg/mL pembrolizumab, 10 mM histidine buffer, pH 5.5, 7% w/v sucrose, and 0.02% polysorbate 80) to include a disclosed higher concentration of antibody (i.e., 100 to about 200 mg/mL) and a different disclosed buffer (i.e., acetate). There is nothing within the Sharma reference, nor within the general art at the time of filing, to indicate that such an antibody formulation (i.e., higher antibody concentration, acetate buffer, sucrose, polysorbate 80) could not be combined, or to otherwise teach away from the presently claimed invention. In contrast, Sharma teaches that both histidine and acetate buffers were relatively equivalent and that both performed better than citrate buffer.
Further, applicant’s arguments regarding the formulations in Example 2 of the instant specification are not persuasive because the results described by Example 2 support the conclusion that histidine and acetate buffers perform equivalently. In particular, formulations 1 and 5 of this example are otherwise identical (160 mg/mL antibody, 7% sucrose, 0.02% PS80) except that formulation 1 contains histidine buffer and formulation 5 contains acetate buffer. The instant specification states and Fig. 1A shows that all five formulations tested were stable over the testing period (12 weeks) when stored at 5°C. Further, “[n]o differences were observed among results for the five formulations at 25°C” and there were “no differences in charge profile among the five formulations at any of the temperatures for the length of the testing period.” While increased Met-105 oxidation was observed in all five formulations at 40°C, there was no significant difference in oxidation levels between formulations 1 and 5 (Fig. 1C).
Therefore, in contrast to applicant’s argument, formulations containing either acetate buffer or histidine buffer performed similarly in terms of their stability as measured by the percentage of antibody oxidation at met-105, thus evidencing the predictability of successfully substituting one buffer for another in this antibody formulation. Accordingly, the rejection of claims 1-2, 6, 14, 23-24, 26-28 and 31 as being obvious over the teachings of Sharma is maintained.
15. Claim(s) 1-2, 5-6, 14, 23-24, 26-28 and 31 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 1-2, 6, 14, 23-24, 26-28 and 31 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 rejection is maintained for reasons of record and as discussed below.
The basis of this rejection has been set forth previously (see section 6 of the previous office action) and therefore will not be reiterated here.
Response to Arguments
16. Applicant traverses the above rejection and argues that Wang 2015 does not remedy the deficiency noted above of failing to teach or suggest the claimed formulation. It is asserted that Wang discussion of the viscosity lowering effects of amino acids on high concentration antibody solutions does not suggest combining a high concentration of pembrolizumab with acetate buffer, sucrose and a non-ionic surfactant. Applicant argues that Wang does not teach pembrolizumab at all, but rather two different IgG1 antibodies, and therefore does not provide guidance on the function of a particular excipient for use with a different antibody such as the IgG4 antibody pembrolizumab. It is similarly argued that Barry teaches formulations comprising anti-IL-13 antibodies, and therefore neither Wang 2015 nor Barry render the claimed invention obvious.
17. Applicant’s arguments have been considered but are not persuasive. Applicant’s arguments regarding Sharma have been addressed above. Regarding Wang, it is not necessary that Wang teaches formulations containing pembrolizumab specifically because this teaching is provided by Sharma. Wang’s teachings are relied upon to generally describe what was known in the art at the time of filing pertaining to the addition of arginine in antibody formulations. In particular, Wang teaches that formulations comprising high concentrations of antibody can benefit from the addition of arginine, which can reduce viscosity and improve stability. Similarly, Barry describes stable antibody formulations that include a high antibody concentration (100 mg/ml), buffer, sucrose, PS80 and 0.01% to 5% arginine, and in particular 2% arginine. Therefore, the combined teachings of Wang 2015 and Barry provide guidance as to the use and benefits of including amino acids, such as arginine, in antibody formulations.
In contrast to applicant’s arguments, the skilled artisan would have recognized that the components routinely used within the formulation of antibody compositions, such as buffering agents, viscosity modifying agents, surfactants, bulking agents, anti-oxidants, etc., all have well-established functions and effects, with the ultimate goal of improving the stability of the antibody within the formulation. These stabilizing effects are generally applicable to most therapeutic protein compositions, and antibody formulations in particular. As such, there would have been a reasonable expectation that the inclusion of arginine, as taught by Wang and Barry, would have predictably improved the stability of the antibody formulation comprising pembrolizumab as taught by Sharma. The combined reference teachings therefore still render obvious the presently claimed invention.
18. Claim(s) 1-2, 5-6, 14-15, 17-19, 23-24, 26-28 and 31 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 1-2, 6, 14, 23-24, 26-28 and 31 above, and in view of Li et al. (US 2018/0339045 A1), Yang et al. (EP 3049441 B1; filed 26 Sep 2014) and Luisi et al. (US 2006/0210557 A1; of record).
The reasons why the teachings of Sharma et al. render obvious the invention of claims 1-2, 6, 14, 23-24, 26-28 and 31 is discussed above. However, Sharma does not teach that the surfactant may be polysorbate 20 (claim 15), or that the formulation may further comprise about 1 mM to about 20 mM of an anti-oxidant (claim 17), wherein the anti-oxidant is L-methionine (claim 18) or L-methionine HCl (claim 19).
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 teaches that an anti-PD-1 antibody formulated in 10 mM sodium acetate had a better thermal stability was better than when the antibody was formulated with succinate, citrate, or disodium hydrogen phosphate buffers (Example 2, [0090]-[0095]). Thus, Li suggests that sodium acetate is a suitable buffer for an anti-PD-1 antibody formulation. Li also teaches that polysorbate 20 or polysorbate 80 are appropriate surfactants ([0018] and [0027]). Further, Li suggests that a stable anti-PD-1 antibody formulation may comprise an antioxidant, such as methionine.
Yang et al. teach antibody formulation comprising anti-PDL1 antibodies, wherein PDL1 is the ligand for the PD-1 receptor. Therefore, inhibition of the PD-L1/PD-1 interaction using antibodies targeting either the receptor or the ligand has been proposed for the treatment of cancer ([0004]). Yang teaches antibody formulations may comprise: 60 mg/ml to 125 mg/ml antibody ([0007]), or from about 25 mg/ml to about 150 mg/ml ([0191]); histidine acetate or sodium acetate buffer at a concentration of about 15 mM to 25 mM; sucrose at a concentration of 60 nM to 240 mM, such as about 170 mM (~6% w/v), about 200 mM (~7% w/v), or about 230 mM (~8% w/v) ([0913]); polysorbate in a concentration of 0.005% (w/v) to 0.06% (w/v), wherein such polysorbates include polysorbates 20 or 80 ([0195]); and a pH 5.0 to 6.3 ([0092]). A particular formulation may comprise 125 mg/ml antibody, 20 mM histidine acetate, 240 mM sucrose (which is about 8% w/v sucrose), 0.02% polysorbate 20, and having a pH of 5.5 ([0014]). Such teachings are on point to limitations in claims 1 and 24 regarding antibody concentration (100 mg/ml to about 200 mg/ml), buffer (about 5 mM to about 20 mM acetate buffer), stabilizer (about 6% to about 8% w/v sucrose), and non-ionic surfactant (about 0.01% to about 0.10%; polysorbate 20), claim 2 (pH between 5.0 and 6.0), and claim 15 (polysorbate 20).
Yang further teaches that in addition to antibody, buffer, sucrose, and surfactant, the formulation may also contain anti-oxidants such as methionine ([0196]).
Consistent with the teachings of Yang 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 an antioxidant such as 10 mM methionine ([0021], [0026], [0082]-[0083]). 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 included an anti-oxidant such as L-methionine, as taught by Li, Yang and Luisi, in the antibody formulation of Sharma and thereby arrive at the presently claimed invention. Given the teachings of Li, Yang 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, Yang 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.
Further, given the teachings of Yang, it would have been obvious to have substituted polysorbate 20 for polysorbate 80 in the antibody formulation of Sharma, particularly when used in combination with a higher antibody concentration, acetate buffer and sucrose stabilizer. Yang recognized that certain hydrogen peroxide impurities contained within polysorbate 20 raw material can cause tryptophan and methionine oxidation within the antibody, and that L-histidine can exacerbate this oxidation risk. Yang found that even at higher concentrations of polysorbate 20 (0.06%) and L-histidine buffer (25 mM), the did not produce a significant oxidation risk ([0226]). Given this information, the artisan would have had a reasonable expectation that the inclusion of PS20 and an acetate buffer, such as sodium acetate or histidine acetate, particularly in combination with the anti-oxidant L-methionine, would have resulted in a stable antibody formulation with minimal oxidation risk. Accordingly, the combined teachings of the above prior art references render obvious the presently recited invention of claims 1-2, 5-6, 14-15, 17-19, 23-24, 26-28 and 31.
19. Claim(s) 1-2, 6, 14, 23-24, 26-28 and 31-32 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 Gray et al. (Breast Cancer Res. 2016, 18:50, 14 pages).
The reasons why the teachings of Sharma et al. render obvious the invention of claims 1-2, 6, 14, 23-24, 26-28 and 31 is discussed above. Sharma discloses that the anti-PD-1 antibody (pembrolizumab) can be used for the treatment of various cancers which include, among others, breast cancer (col. 6 lines 51-67; col. 7 lines 7-20). However, Sharma does not teach that the cancer is triple negative breast cancer as in claim 32.
Gray et al. teach that the anti-tumorigenic activity of anti-PD-1 antibody therapy is enhanced when used in combination with a phosphatidylserine-targeting antibody, and that this combination can be used for the treatment of triple-negative breast cancer (TNBC) (see abstract and p. 3 left column). While Gray found that PD-1 therapy alone did significantly reduce tumor volume (Fig. 2) and enhance the survival of TNBC mice (Fig. 3), combining PS-targeting antibody and anti-PD-1 antibody therapies increased the levels of tumor infiltrating lymphocytes (TILs) more than either treatment alone, and this increase correlated with greater anti-tumor growth effects and better overall survival in TNBC (see paragraph spanning columns at p. 12). Accordingly, Gray’s teachings both demonstrate and suggest that anti-PD-1 antibodies can be utilized for the treatment of TNBC.
It would have been obvious to one of ordinary skill in the art at the time of filing to have applied the therapeutic method of treating breast cancer using pembrolizumab, as taught by Sharma, to the treatment of triple-negative breast cancer (TNBC) as suggested by Gray 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. In the instant case, Gray demonstrates that anti-PD-1 antibody therapy alone is effective for the treatment of TNBC, and in combination with anti-PS antibody therapy provides an enhanced anti-tumorigenic response. Therefore, the skilled artisan would have had a reasonable expectation that treating a subject having TNBC with pembrolizumab would be therapeutically beneficial and successful. The combined reference teachings thus render obvious the invention of present claims 1-2, 6, 14, 23-24, 26-28 and 31-32.
20. Claim(s) 1-2, 6, 14, 23-24, 26-28, 31 and 33 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 Penfold (“Primary Mediastinal Large B-cell Lymphoma: incidence, survival, immunophenotype, and molecular characteristics”, LymphomaHub, pub. Feb 2, 2017; retrieved 06/08/26).
The reasons why the teachings of Sharma et al. render obvious the invention of claims 1-2, 6, 14, 23-24, 26-28 and 31 is discussed above. Sharma also discloses that the anti-PD-1 antibody (pembrolizumab) can be therapeutically administered for the treatment of various cancers which include, among others, lymphoma (col. 6 lines 51-67; col. 7 lines 7-20). However, Sharma does not teach that the cancer is primary mediastinal large B-cell lymphoma as in claim 33.
Penfold teaches that primary mediastinal large B-cell lymphoma (PMBCL) is an uncommon lymphoma that occurs worldwide. Penfold also discloses that there is an ongoing phase II clinical trial using a humanized anti-PD-1 antibody (nivolumab) for the treatment of patients with relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) including PMBCL who are ineligible for transplant.
Accordingly, it would have been obvious to one of ordinary skill in the art at the time of filing to have substituted pembrolizumab for nivolumab for the treatment of PMBCL and thereby arrive at the presently claimed invention. In particular, Sharma discloses that pembrolizumab is useful for the treatment of lymphoma, and Penfold suggests that anti-PD-1 immunotherapy can be used for the treatment of PMBCL, which is a type of lymphoma. Therefore, the substitution of one anti-PD-1 antibody for another would have been obvious. This is because the artisan has good reason to pursue the known options within his or her technical grasp to obtain predictable results. This amounts to the simple substitution of one known functional equivalent for another (i.e., anti-PD-1 antibodies) to achieve a predicable outcome. The combined teachings of the prior art references thus render obvious the invention of present claims 1-2, 6, 14, 23-24, 26-28, 31 and 33.
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.
21. Claims 1-2, 4, 6, 14-15, 17-19, 23-24 and 26-28 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), Yang et al. (EP 3049441 B1; filed 26 Sep 2014) and Luisi et al. (US 2006/0210557 A1; of record).
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 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., Yang et al. and Luisi et al. are cumulative and are discussed above and provide for the use of alternative buffering agents, such as an acetate, alternative surfactant such as polysorbate 20, and the addition of an anti-oxidant, such as 10 mM L-methionine, to be included in stable antibody formulations. Li also teaches that anti-PD-1 antibody formulations can be administered subcutaneously ([0064]).
Accordingly, it would have been obvious to have used a different buffer, such as acetate, a different surfactant (PS20), 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.
22. 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 Li et al. (US 2018/0339045 A1), Yang et al. (EP 3049441 B1; filed 26 Sep 2014) and Luisi et al. (US 2006/0210557 A1), as applied to claims 1-2, 4, 6, 14-15, 17-19, 23-24 and 26-28 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 ‘776 claims in view of Yang and Luisi render obvious the invention of claims 1-2, 4, 6, 14-15, 17-19, 23-24 and 26-28 is discussed above. The patented claims do no recite that the formulation further comprises 1-3% w/v L-arginine as in claim 5.
The teachings of Wang et al. and Barry et al. are also 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.
Conclusion
23. No claims are allowed.
24. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/KIMBERLY BALLARD/Primary Examiner, Art Unit 1675
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