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 .
1. The Amendment filed May 13, 2026 in response to the Office Action of February 13, 2026, is acknowledged and has been entered. Claims 1-3, 14-18, 20, 22, 23, 26-33 are pending. Claims 4-13, 19, 21, 24, 25 are canceled. Claims 1, 22, 26-28, 30 are amended. Claims 31-33 are new. Claims 14-18, 22, 23, 26, 28-33 remain/are withdrawn. Claims 1-3, 20, 27 are currently being examined as drawn to the species of:
A. Stabilizer trehalose;
B. Non-ionic surfactant poloxamer 188;
C. formulation further comprising L-arginine (claim 3);
D. formulation NOT further comprising anti-oxidant (withdraw claims 14-16);
E. formulation NOT further comprising metal chelator (withdraw claims 17-18); and
F. low dose pembrolizumab concentration of 25 mg/ml (claim 20).
Claims 1 and 27 are amended and altered in scope to require the non-ionic surfactant be only poloxamer 188 and the formulation be liquid. Claim 1 is also amended and altered in scope to require stabilizer trehalose.
Maintained Rejection
(the 35 USC 103 rejections from the prior office action are combined to address the amendments combining claim limitations)
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.
2. Claim(s) 1-3, 20, and 27 remain rejected under 35 U.S.C. 103 as being unpatentable over US Patent 9,220,776, Sharma et al, issued December 2015; in view of US Patent Application Publication 2016/0304607, Sadineni et al; CA 2999079, Li et al, published April 6, 2017; US Patent Application Publication 2016/0145341, Cosenza et al; US Patent Application Publication 2011/0256149, Bishop et al; Connolly et al (American Pharmacists Association J Pharm Sci 104:4170–4184, 2015); and Khan et al (European Journal of Pharmaceutics and Biopharmaceutics; Volume 97, Part A, November 2015, Pages 60-67).
Sharma teaches an aqueous (liquid) pharmaceutical formulation of anti-PD-1 antibody comprising:
(i) 25 mg/ml or 25-100 mg/ml anti-PD-1 antibody;
(ii) 70 mg/ml sucrose stabilizer;
(iii) about 1.55 mg/ml or 10 mM histidine buffer;
(iv) ~ 0.2 mg/ml (= 0.02 %) non-ionic surfactant polysorbate 80; and
(v) pH 5.0-6.0;
wherein the anti-PD-1 antibody is h409A11 comprising heavy and light chain SEQ ID NOs:31 and 36, which is also known as MK-3475 or pembrolizumab (col. 23, lines 45-56; claims 1-6; Tables 3-6; Example 1).
Sharma teaches cryoprotectants and lyoprotectants of the antibody formulation can be sucrose or trehalose (col. 13, lines 17-41).
Sharma additionally suggests adding amino acid arginine to the composition as a cryoprotectant that provides stability to the protein against freezing-induced stresses (col. 13, lines 24-25).
Sharma does not teach substituting in about 6% - about 8% weight/volume (w/v) trehalose for the sucrose stabilizer into the formulation.
Sharma does not teach the composition comprises about 1% to about 3% w/v L-arginine.
Sharma does not teach substituting the non-ionic surfactant poloxamer 188 for the non-ionic surfactant polysorbate 80.
Sadineni suggest a pharmaceutical formulation comprising:
(i) an anti-PD-1 antibody
(ii) trehalose stabilizer ([21]; [163]; claim 39);
(iii) histidine at about 5mM to about 20 mM or at 20 mM (claims 31, 55, 57);
(iv) non-ionic surfactant polysorbate 80 at about 0.01% to about 0.10% ([23]; [163]; [167]; claims 41, 48, 49, 55); and
(v) pH about 5.0 to about 6.0 (claims 35, 55, 57);
wherein the anti-PD-1 antibody is pembrolizumab (MK-3475) ([9]; [111]; [119]; [135-137]; [148-149]; claim 3).
Sadenini additionally suggests adding arginine to the formulation as a stabilizing agent ([21]; claim 39).
Li teaches a pharmaceutical formulation comprising:
(i) an anti-PD-1 antibody in the range of 20-50 mg/ml (p. 7);
(ii) trehalose stabilizer in the amount of 60 to 90 mg/ml (= 6% to 9% w/v) (p. 3-4; p. 6; p. 8; Example 1, 4, 5, 6, 8);
(iii) histidine buffer 10 mM to 30 mM (p. 7);
(iv) non-ionic surfactant polysorbate 80 or polysorbate 20 or poloxamer (p. 3-4; p. 7; Examples 1, 4, 5, 6, 8); and
(v) pH in the range of 5.2 – 6.0 (p. 3-4; p. 7; Examples 1, 4, 5, 6, 8).
Li teaches (p. 18):
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Li further suggests adding amino acids including arginine at amounts of about 100 mM to about 150 mM (= 1.742% w/v to 2.613% w/v) (p. 8, lines 21-28).
Cosenza teaches an aqueous antibody pharmaceutical formulation comprising:
(i) a therapeutic antibody in the range of 20-150 mg/ml;
(ii) trehalose stabilizer at 120 (4% w/v) or 220 mM (7.5% w/v);
(iii) histidine buffer at 20 mM;
(iv) non-ionic surfactant polysorbate 20 or poloxamer 188 at 0.01% to 0.1% or 0.04%;
(v) pH in the range of 5.5 – 6.0; and
(vi) amino acid arginine-HCl (L-Arginine) at 50 mM (= 0.871% w/v).
See claims 1-24 and 35; Tables 5 and 16; paragraphs [9-63].
Cosenza teaches arginine-HCl functions as a stabilizer and buffer ([109]; [114]).
Bishop teaches an aqueous antibody pharmaceutical formulation comprising:
(i) a therapeutic antibody in the range of 10 mg/ml, 20 mg/ml, to 100 mg/ml;
(ii) trehalose stabilizer at 5%, 8% or 10%;
(iii) histidine buffer at 20 or 25 mM;
(iv) non-ionic surfactant polysorbate 80, polysorbate 20, or poloxamer 188 at 0.01 to 0.1%;
(v) pH in the range of 5.5 – 6.0; and
(vi) amino acid arginine-HCl (L-Arginine) at ([126]).
Also see paragraphs [30]; [32]; [48]; Figure 1; [85-109]; [114-117]; [127-129]; [137-148]; [452- 453]; claims 1, 5-9.
Bishop additionally teaches arginine is commonly added as an excipient that imparts beneficial physical property to the formulation ([30]).
Connolly established the stabilizing function of trehalose and optimizing effective ranges of trehalose for a monoclonal antibody composition, wherein the composition comprised 25 mg/ml antibody or 100 mg/ml antibody, 20 mM histidine at pH 6.0, and a range of trehalose from about 3.4% to about 6.8% w/v (Formula Composition p. 4171, col. 2; Table 3 and 4). Connolly teaches sucrose is a known alternative to trehalose (p. 4183, col. 1) and demonstrates comparing antibody composition stability with trehalose or sucrose (Figure 2).
Khan teaches the known and established function of polysorbate 80 and poloxamer 188 (P188) as non-ionic surfactants for reducing protein-protein interactions, reducing protein aggregates, and stabilizing protein or antibody formulations (Table 1; Figures 1 and 2). Khan also teaches methods for determining optimal concentration of surfactant are established. Khan teaches: “The most extensively used surfactants in biologics formulations are poly-oxy-ethylene (PEO) based surfactants, such as polysorbates 20 and 80 and poloxamer 188 (Fig. 1)” (section 2). Khan further teaches: “Typically, polysorbates are used in the range of 0.001–0.1% (w/v). The choice and concentrations of the surfactant are usually determined by screening for the lowest effective concentration which stabilizes the therapeutic protein upon interfacial stress. These concentrations are determined by stress studies generating air– water and/or ice–water interfaces, such as shaking, stirring or freezing/thawing at varied surfactant concentrations followed by aggregate and particulate analysis. The concentration chosen is usually significantly above the edge of failure to provide a sufficient safety margin and protection during real-time stress such as transportation, stirring, and freeze–thaw” (section 2).
Trehalose stabilizer at about 6% to about 8% w/v:
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to substitute trehalose stabilizer at 6-8% w/v for the sucrose stabilizer in the pembrolizumab composition of Sharma. One would have been motivated to, and have a reasonable expectation of success to because: (1) Sharma suggests using trehalose as a stabilizer; (2) all of Sharma, Sadineni, Li, Cosenza, Bishop, and Connolly teach and establish trehalose is a known stabilizer alternative to sucrose for antibody compositions and they are functional equivalents; (3) Li, Cosenza, Bishop, and Connolly teach or demonstrate known effective stabilizing amounts of trehalose in antibody compositions at about 6% to about 8% w/v; and (4) Sadineni, Li, Cosenza, Bishop, and Connolly teach or successfully demonstrate combining trehalose as the stabilizer with antibody, histidine buffer, non-ionic surfactant polysorbate or poloxamer; and at pH 5.0-6.0 to arrive at a stable antibody composition.
L-arginine at about 1% to about 3% w/v:
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to add amino acid L-arginine to the composition of Sharma and at about 1% to about 3% w/v. One would have been motivated to, and have a reasonable expectation of success to because: (1) Sharma suggests adding amino acid arginine to the composition as a stabilizer; and (2) Sadineni, Li, Consenza, and Bishop also teach additionally adding amino acid arginine or L-Arginine to the antibody composition as a common excipient, wherein Cosenza teaches arginine-HCl functions as a stabilizer and buffer and teaches adding Argining-HCl in the amount of about 1% w/v.
Non-ionic surfactant poloxamer 188 at about 0.01% to about 0.10% w/v:
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to substitute in poloxamer 188 as the non-ionic surfactant in the antibody composition of Sharma and the combined references. One would have been motivated to, and have a reasonable expectation of success to because: (1) the combined references all teach formulating antibody pharmaceutical compositions with non-ionic surfactant; (2) Li, Cosenza, and Bishop teach formulating monoclonal antibody therapeutic compositions with non-ionic surfactant poloxamers and poloxamer 188 specifically and at 0.01 to 0.1%; and (3) Khan teaches the functional equivalence of non-ionic surfactants polysorbate 80 and poloxamer 188 for reducing aggregation and enhancing protein stability in antibody formulations.
Response to Arguments
3. Applicants argue that the cited references do not provide motivation to modify the composition of Sharma to substitute in trehalose for sucrose as the stabilizer, substitute poloxamer 188 in for polysorbate 80 as the non-ionic surfactant, and add L-arginine. Applicants argue that it is known in the art that biological formulations have to be evaluated on a case-by-case basis while also evaluating factors including viscosity, aggregation, and stability, and therefore, one of skill in the art would not turn to the combination of cited references in seeking to formulate the specific anti-human PD-1 antibody as recited in claim 1 and claim 27.
Applicants argue that a result of the different amino acid sequences of each antibody, researchers who want to formulate a given antibody would not be able to predict whether a formulation that was useful for one antibody would also be successful in formulating a different antibody having a different structure. Applicants argue the Office Action fails to identify any reason to deviate from the formulations in Sharma and arrive at the presently claimed formulation which comprises trehalose and poloxamer 188. Applicants argue that the claims should be evaluated as a whole rather than limitation by limitation.
Applicants argue that of the references cited in the current rejection, only Sharma exemplifies pembrolizumab, and although Sadineni discloses pembrolizumab in the summary of the invention and detailed description, no examples are provided of a pembrolizumab formulation. Instead, all exemplified formulations in Sadineni contain nivolumab and ipilimumab antibodies. Applicants argue that there is no evidence that the formulations disclosed in Sadineni would work with pembrolizumab. Applicants argue that Li only touches on a non-pembrolizumab anti-PD-1 antibody and Cosenza and Bishop do not teach or suggest anti-PD-1 antibodies at all. Therefore, one of ordinary skill in the art could not have predictably used the formulations of Sadineni, Li, Cosenza and Bishop in formulating pembrolizumab.
Applicants argue that with regard to trehalose, Examiner relied on hindsight reasoning to combine the cited references and arrive at trehalose in the composition of Sharma. Applicants argue Sharma discloses trehalose in the context of cryoprotectants and lyoprotectants while the presently amended claims are now directed to a liquid formulation, so this disclosure is not relevant. Applicants argue that Connolly is cited as teaching trehalose concentrations, but Connolly refers to trehalose crystallization in frozen solutions and is therefore also irrelevant to the presently claimed liquid formulation. Nevertheless, Connolly indicates in the introduction section that although trehalose has been established as an effective cryoprotectant for protein formulations, there have been reports of spontaneous trehalose crystallization during freezing, frozen storage, and lyophilization in recent years. Applicants argue that Connolly teaches away from using trehalose in a formulation as it states on page 4183 that "results from the excipient screen study also suggest that noncrystallizing stabilizers (e.g., sucrose) should be considered as an alternative to trehalose if optimal cooling and storage temperature conditions cannot be achieved." (See Connolly, page 4183). Applicants argue that Connolly undermines the Office's position by explaining that trehalose concentrations are highly dependent on the particular molecule and formulation and cannot simply be transferred from one to another. Connolly states on page 4183, "In similar systems, it is possible that the specific ratio range identified may be limited in application to the specific scale, freeze processes, storage temperature, formulations, and molecule types evaluated. Thus, determination of optimal ratio ranges across different conditions may necessitate independent evaluations." (See Connolly, page 4183).
4. The arguments have been considered but are not persuasive. Examiner maintains it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to substitute trehalose stabilizer at 6-8% w/v for the sucrose stabilizer in the pembrolizumab composition of Sharma. One would have been motivated to, and have a reasonable expectation of success to because: (1) Sharma suggests using trehalose as a stabilizer; (2) all of Sharma, Sadineni, Li, Cosenza, Bishop, and Connolly teach and establish trehalose is a known stabilizer alternative to sucrose for antibody compositions and they are functional equivalents; (3) Li, Cosenza, Bishop, and Connolly teach or demonstrate known effective stabilizing amounts of trehalose in antibody compositions at about 6% to about 8% w/v; and (4) Sadineni, Li, Cosenza, Bishop, and Connolly teach or successfully demonstrate combining trehalose as the stabilizer with antibody, histidine buffer, non-ionic surfactant polysorbate or poloxamer; and at pH 5.0-6.0 to arrive at a stable antibody composition.
Contrary to arguments, and as evidenced by the obviousness rationale above, Examiner did not rely on hindsight reasoning to arrive at the claimed liquid pebrolizumab antibody formulation. It must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). In the instant case, Sharma suggests either sucrose or trehalose can be used as a stabilizer and cryoprotectant in the pembrolizumab formulation and the secondary references teach and demonstrate liquid antibody formulations comprising trehalose as a stabilizer in the same claimed range (see rejection of record). Sadineni teaches ([21]; [163] and claim 39): “The stabilizing agent can be selected from the group consisting of sucrose, trehalose, raffinose, arginine; or any combination thereof.” Li teaches “The cryoprotectant is preferably a disaccharide”, and “The at least one stabilizer of the present invention is selected from saccharide or amino acid. Wherein the saccharide is preferably a disaccharide selected from the group consisting of sucrose, lactic acid, trehalose and maltose, preferably trehalose, most preferably a,a-trehalose dihydrate.” Cosenza provides numerous exemplary antibody formulations comprising sucrose or trehalose as the stabilizer and teaches ([220]): “The preferred pH is 6.0. The non-ionic stabilizer tested, Trehalose, is beneficial to the formulation stability”. Cosenza exemplifies an antibody formulation containing trehalose was superior to a formulation containing sucrose for stabilizing antibody formulation after storage at freezing temperatures ([265]; Table 39). Bishop teaches numerous exemplary liquid antibody formulations comprising trehalose and teaches either sucrose or trehalose function as a stabilizer ([104]; [716]; [718]). Connolly demonstrates either sucrose or trehalose are successfully utilized as a stabilizer and cryoprotectant in an antibody formulation and optimized the amount of trehalose for freezing. Therefore, the secondary references provide both the motivation and reasonable expectation of success to predictably utilize trehalose as a stabilizer and cryoprotectant, and to substitute trehalose stabilizer at 6-8% w/v for the sucrose stabilizer in the pembrolizumab composition of Sharma, therefore Examiner did not rely upon hindsight reasoning.
MPEP 2144.06 states:
II. SUBSTITUTING EQUIVALENTS KNOWN FOR THE SAME PURPOSE
In order to rely on equivalence as a rationale supporting an obviousness rejection, the equivalency must be recognized in the prior art, and cannot be based on applicant’s disclosure or the mere fact that the components at issue are functional or mechanical equivalents. In re Ruff, 256 F.2d 590, 118 USPQ 340 (CCPA 1958) (The mere fact that components are claimed as members of a Markush group cannot be relied upon to establish the equivalency of these components. However, an applicant’s expressed recognition of an art-recognized or obvious equivalent may be used to refute an argument that such equivalency does not exist.); Smith v. Hayashi, 209 USPQ 754 (Bd. of Pat. Inter. 1980) (The mere fact that phthalocyanine and selenium function as equivalent photoconductors in the claimed environment was not sufficient to establish that one would have been obvious over the other. However, there was evidence that both phthalocyanine and selenium were known photoconductors in the art of electrophotography. "This, in our view, presents strong evidence of obviousness in substituting one for the other in an electrophotographic environment as a photoconductor." 209 USPQ at 759.).
In the instant case, the cited references teach adding stabilizer to the antibody composition that can be in the form of sucrose or trehalose, and to serve the same function. The cited art establishes sucrose and trehalose are functional equivalents in antibody compositions. The cited art established trehalose is a known stabilizer alternative to sucrose for antibody compositions and they are functional equivalents, thereby providing a reasonable expectation of success to substitute one for the other in the antibody composition of Sharma.
Although Applicants argue that biological formulations have to be evaluated on a case-by-case basis while also evaluating factors including viscosity, aggregation, and stability, Applicants are arguing limitation not recited in the claims. There are no viscosity, aggregation, and stability requirements or limitations for the claimed antibody formulation.
Although Applicants opine that the formulations for antibodies in the cited secondary references would not be predictably extrapolated to the formulation of pembrolizumab having a different amino acid sequence, Applicants have not provided evidence or persuasive arguments that the trehalose, L-arginine, and poloxamer 188 in the antibody compositions taught by the secondary references would not function the same in the pembrolizumab antibody composition of Sharma. Contrary to arguments, the cited references teach and demonstrate it is established that sucralose and trehalose are both stabilizers in liquid antibody compositions, polysorbate 80 and poloxamer 188 are both non-ionic surfactants in liquid antibody compositions, and L-arginine is an established common excipient for stabilizing antibody formulations. Therefore, one of ordinary skill in the art could have predictably used the reagents interchangeably or added them and achieved the claimed liquid formulation of pembrolizumab with a reasonable expectation of success based on the teaching of the prior art.
Further, with regard to trehalose, Sharma teaches cryoprotectants and lyoprotectants of the antibody formulation can be sucrose or trehalose. Although Applicants argue that the claims recite a liquid formulation, the cited references teach that the liquid formulations can be frozen or lyophilized later for storage, requiring cryoprotectants and lyoprotectants like sucrose or trehalose, as suggested by Sharma, Cosenza, and Connolly.
Contrary to arguments, Connolly does not teach away from using trehalose as a stabilizer in an antibody composition, and instead, demonstrates the success of adding trehalose to liquid antibody formulations to act as a stabilizer when the formulation is frozen and stored. Connolly teaches sucrose is a known alternative to trehalose (p. 4183, col. 1) and demonstrates comparing antibody composition stability with trehalose or sucrose, wherein they serve the same function, providing for a reasonable expectation of success to substitute trehalose for the sucrose in the antibody composition of Sharma.
Contrary to arguments, the variable conditions (i.e., cooling process, temperature storage) used to freeze the antibody compositions taught by Connolly in order to observe the effects on antibody aggregation and stability do not teach away from utilizing trehalose as a stabilizer. Instead, Connolly successfully optimized the freezing and storage process of the liquid antibody formulation using trehalose, teaching (p. 4183, col. 2): “no increases in trehalose crystallization or protein aggregation were observed following 12-month storage at−40°C for any of the formulation compositions evaluated. These results suggest that trehalose crystallization and protein aggregation can also be prevented by storing formulations at or below the glass transition temperature.”
Contrary to arguments, Connolly does not teach the addition of trehalose to antibody liquid formulations is unpredictable, but rather, successfully demonstrates the stabilizing function of trehalose in liquid antibody formulations is predictable and demonstrates arriving at the optimal concentration or ratio of trehalose for a particular antibody is routine. Connolly successfully demonstrates arriving at an antibody composition comprising 25 mg/ml antibody or 100 mg/ml antibody, 20 mM histidine at pH 6.0, and a range of trehalose from about 3.4% to about 6.8% w/v.
Contrary to arguments, the disclosure of Connolly is relevant to the instant claims because it discloses trehalose and sucrose serve the same stabilizing function in liquid antibody formulations later frozen and stored, as suggested by Sharma.
5. Applicants argue that with regard to L-arginine, the Office relies on hindsight in stating that one would have been motivated to combine the cited references and would have had a reasonable expectation of success in developing the claimed formulation. Applicants argue that Sharma discloses L-arginine in the context of cryoprotectants and lyoprotectants while the presently amended claims are now directed to a liquid formulation, so this disclosure is not relevant. Applicants argue that Consenza teaches away from the use of arginine as Table 43 shows that the formulation containing arginine contains more particles at the initial time point as well as a larger increase in the particle count (i.e., comparing Formulation numbers 1 (not containing arginine) and 3 (containing arginine), recognizing that there is also a difference in sucrose concentrations between these formulations) at room temperature, especially for the larger particles. (See Consenza, page 24). Additionally, Table 44 shows in the underlined formulations that the arginine-containing formulation yielded a substantially higher number of particles (Formulation 1 compared to Formulation 3). (See Consenza, page 24-25). Table 44 is aligned with paragraphs 272 and 274 on page 24 of Consenza. Furthermore, the nephelometry data in Tables 17-19 also show consistently higher turbidities for the arginine-containing Formulation 3. (See Consenza, page 15). Cosenza also states that there are higher fragmentation levels for Formulation 3 based on SEC data. (See Table 26 of Consenza, page 17-18). Applicants argue that one of ordinary skill in the art would not have had a reasonable expectation of success based on the combined teachings of the cited art in developing the claimed formulations, absent the use of hindsight.
6. The arguments have been considered but are not persuasive. Examiner maintains it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to add amino acid L-arginine to the composition of Sharma and at about 1% to about 3% w/v. One would have been motivated to, and have a reasonable expectation of success to because: (1) Sharma suggests adding amino acid arginine to the composition as a stabilizer; and (2) Sadineni, Li, Consenza, and Bishop also teach additionally adding amino acid arginine or L-Arginine to the antibody composition as a common excipient, wherein Cosenza teaches arginine-HCl functions as a stabilizer and buffer and teaches adding Arginine-HCl in the amount of about 1% w/v. Therefore, Examiner did not rely upon hindsight reasoning to add L-Arginine to the composition of Sharma. The cited references teach the suggestion, motivation, and reasonable expectation of success to.
Applicants’ arguments that Sharma discloses L-arginine in the context of cryoprotectants while the presently amended claims are now directed to a liquid formulation, and that Sharma’s disclosure is not relevant, are not persuasive. As stated above, the cited prior art teaches that liquid antibody formulations can be frozen later for storage, requiring cryoprotectants like arginine, as suggested by Sharma. Further, the cited secondary references teach L-Arginine is a well-established, common excipient, buffer, and stabilizer in liquid antibody compositions, providing motivation and reasonable expectation of success to add it to the composition of Sharma.
Contrary to arguments, Cosenza does not teach away from adding L-arginine to the composition of Sharma. Applicants have argued data in Cosenza directed at testing the antibody sub-visible content after being subject to various conditions (storage at 25ºC for two months, agitation stress, freeze/thaw cycles, or prolonged light exposure) with results in Tables 43 and 44. Although applicants argue that one formulation comprising Arg (Formula 3 in Tables 43 and 44) has higher turbidity than those without, the arguments are not persuasive because the antibody composition argued by Applicants contain sucrose, not trehalose as required by the claims, and the conditions tested are not recited to be present in the claims. Tables 17, 18, 39 and 42-44 demonstrate that antibody formulations containing trehalose (Formula 2) and subject to various storage conditions including freezing, were superior in stability to that of the composition containing sucrose (Formula 1). Further, Table 42 demonstrates Formula 3 containing sucrose/Arg had less sub-visible content than Formula 1 containing sucrose/no Arg when subject to storage at 40ºC for one month and similar sub-visible content when subject to storage at 40ºC for two months (Table 42). Therefore, the other components in the antibody formulation, outside of Arg, influence the effects of antibody stability in various storage conditions. Contrary to arguments, Cosenza concludes that “all four formulations were very similar in terms of their stability profile” ([277]), therefore does not teach away from utilizing Arg. The cited prior art teach the established, predictable function of L-Arginine in liquid antibody formulations and motivation to add it to the composition of Sharma as a common excipient and stabilizer at about 1% to about 3% w/v with a reasonable expectation of success for the reasons of record.
7. Applicants argue that Examiner relies on hindsight reasoning to substitute poloxamer 188 as the non-ionic surfactant in the composition of Sharma. Applicants argue that Sharma does not disclose poloxamer 188. Applicants argue that Li and Bishop do not reference poloxamer 188, and the reference to poloxamer 188 in Cosenza specifies 0.3% poloxamer 188 in Table 5, which is outside of the range in the current claims. Applicants argue that Cosenza seems to conclude that polysorbate 20 is preferable, noting that polysorbate 20 is "beneficial to the stability of the formulation" in paragraph 220 and then only using polysorbate 20 in the subsequent screen in Table 16. Therefore, Cosenza teaches away from the use of poloxamer 188 and suggests instead using polysorbate 20.
Applicants argue that given the lack of any identified problems with the existing formulations in Sharma, the person of ordinary skill in the art would not have been motivated to pursue this untested ingredient in a pembrolizumab formulation. Applicants argue that Khan states that the most extensively used surfactants in biologic formulations are poly-oxy-ethylene (PEO) based surfactants, such as polysorbates 20 and 80 and poloxamer 88. (see Khan, page 61). Applicants argue that Khan noticeably excludes poloxamer 188 from the next sentence as it states "Polysorbate 20 (Tween®20) and Polysorbate 80 (Tween®80) are not only capable of preventing protein aggregation caused by exposure to air-water interfaces and freeze-thaw stress, but also inhibit adsorption to various surfaces such as sterilization filters and primary packaging (See Khan, page 61). Therefore, Applicants argue that there is no reason that one of ordinary skill in the art would be motivated by Khan to include poloxamer 188 in the claimed formulation. Applicants argue that one of ordinary skill in the art would not have had a reasonable expectation of success based on the combined teachings of the cited art in developing the claimed formulations, absent the use of hindsight.
8. The arguments have been considered but are not persuasive. Examiner maintains it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to substitute in poloxamer 188 as the non-ionic surfactant in the antibody composition of Sharma and the combined references. One would have been motivated to, and have a reasonable expectation of success to because: (1) the combined references all teach formulating antibody pharmaceutical compositions with non-ionic surfactant; (2) Li, Cosenza, and Bishop teach formulating monoclonal antibody therapeutic compositions with non-ionic surfactant poloxamers and poloxamer 188 specifically and at 0.01 to 0.1%; and (3) Khan teaches the functional equivalence of non-ionic surfactants polysorbate 80 and poloxamer 188 for reducing aggregation and enhancing protein stability in antibody formulations. Therefore, Examiner did not rely upon hindsight reasoning to substitute functionally equivalent non-ionic surfactant poloxamer 188 for the non-ionic surfactant polysorbate 80 in the composition of Sharma. The cited references provide the motivation and reasonable expectation of success to substitute one functional equivalent or another. See MPEP 2144.06.
Contrary to arguments, as stated in the rejection, Li suggests any of non-ionic surfactant polysorbate 80, polysorbate 20, or poloxamer can be used in the PD-1 antibody formulation as a surfactant to protect protein formulations against mechanical stresses like agitation and shearing.
Contrary to arguments, as stated in the rejection, Bishop does specifically suggest utilizing poloxamer 188 as the surfactant in antibody formulations, and teaches any of polysorbate 80, polysorbate 20, and poloxamer 188 function as surfactants in the antibody formulation. Bishop further teaches surfactant poloxamer 188 is commercially available as PF-68 (Pluronic F-68) and is added to reduce antibody aggregation ([114]).
Contrary to arguments, as stated in the rejection, Cosenza specifically teaches formulating liquid antibody composition with 0.01%-0.1% polysorbate 20 or poloxamer 188 as a surfactant. Like Sharma (col. 14, lines 12-42), Cosenza teaches the importance of reducing antibody aggregation in antibody formulations ([4-10]) and demonstrates that antibody compositions comprising either polysorbate 20 or poloxamer 188 as a surfactant successfully reduce aggregation products during agitation, freeze/thaw cycles, thermal stress, and different storage temperatures (Tables 5-13). Cosenza teaches the poloxamer 188 can be present in a concentration “between 0.01% and 0.1%” and demonstrates the success of poloxamer 188 stabilizing liquid antibody formulations in the Examples in a concentration of 0.3%, therefore providing both motivation and reasonable expectation of success to substitute the polysorbate surfactant of Sharma with poloxamer 188. The disclosure of polysorbate 20 as “preferable” in the Cosenza does not teach away from their explicit disclosure and success of using poloxamer 188 as a surfactant. MPEP 2123 states: Disclosed examples and preferred embodiments do not constitute a teaching away from a
broader disclosure or nonpreferred embodiments. MPEP 2123 further states: Furthermore, “[t]he prior art’s mere disclosure of more than one alternative does not
constitute a teaching away from any of these alternatives because such disclosure does
not criticize, discredit, or otherwise discourage the solution claimed….” In re Fulton,
391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004).
Similarly, contrary to arguments, the disclosure of alternative surfactants by Kahn does not teach away from their explicit disclosure of poloxamer 188 as a surfactant for antibody formulation. Khan teaches the functional equivalence of non-ionic surfactants polysorbate 80 and poloxamer 188 for reducing aggregation and enhancing protein stability in antibody formulations. Kahn further teaches: “The most extensively used surfactants in biologics formulations are poly-oxy-ethylene (PEO) based surfactants, such as polysorbates 20 and 80 and poloxamer 188 (Fig. 1)” (p. 61, col. 1).
Therefore, the cited references provide both the motivation and reasonable expectation of success to predictably substitute one functionally equivalent surfactant, poloxamer 188, for another, polysorbate 80, at the claimed concentration in the liquid antibody composition of Sharma, for the reasons of record.
Maintained Rejection
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.
5. Claims 1-3, 20, and 27 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of U.S. Patent No. 9,220,776 in view of US Patent Application Publication 2014/0234296, Sharma et al; US Patent Application Publication 2016/0304607, Sadineni et al; CA 2999079, Li et al, published April 6, 2017; US Patent Application Publication 2016/0145341, Cosenza et al; US Patent Application Publication 2011/0256149, Bishop et al; and Connolly et al (American Pharmacists Association J Pharm Sci 104:4170–4184, 2015); and Khan et al (European Journal of Pharmaceutics and Biopharmaceutics; Volume 97, Part A, November 2015, Pages 60-67).
U.S. Patent No. 9,220,776 claims:
1. A stable lyophilized pharmaceutical formulation of an anti-human PD-1 antibody, wherein the formulation made by lyophilizing an aqueous solution comprising:
a) 25-100 mg/mL of the anti-human PD-1 antibody;
b) about 70 mg/mL sucrose;
c) about 0.2 mg/mL polysorbate 80; and
d) about 10 mM Histidine buffer at about pH 5.0-pH 6.0, and
wherein the antibody, comprises:
i) a light chain comprising amino acid residues 20 to 237 of SEQ ID NO: 36; and
ii) a heavy chain comprising amino acid residues 20 to 466 of SEQ ID NO: 31.
2. The stable lyophilized pharmaceutical formulation of claim 1, wherein the anti-human PD-1 antibody is present at about 25 mg/mL in the aqueous solution.
3. The stable lyophilized pharmaceutical formulation of claim 1, wherein the aqueous solution has a pH of about 5.5.
4. The stable lyophilized pharmaceutical formulation of claim 1, wherein the aqueous solution comprises 25.0 mg/ml of the anti-human PD-1 antibody, 1.55 mg/ml histidine, 0.2 mg/ml polysorbate 80, 70 mg/ml sucrose, and has a pH of 5.5.
5. A stable liquid pharmaceutical formulation of an anti-human PD-1 antibody, comprising:
a) 25-100 mg/mL of the anti-human PD-1 antibody;
b) about 70 mg/mL sucrose;
c) about 0.2 mg/mL polysorbate 80; and
d) about 10 mM histidine buffer at pH 5.0-6.0,
wherein the antibody comprises:
i) a light chain comprising amino acid residues 20 to 237 of SEQ ID NO: 36; and
ii) a heavy chain comprising amino acid residues 20 to 466 of SEQ ID NO:31, and
wherein the liquid formulation has not been previously lyophilized.
6. The stable liquid pharmaceutical formulation of claim 5, which comprises 10 mM histidine, pH 5.5, 7% sucrose, 0.02% polysorbate 80, and 25.0 mg/ml of the anti-human PD-1 antibody.
7. A method of treating cancer in a human subject in need thereof, the method comprising administering an effective amount of a pharmaceutical formulation of an anti-human PD-1 antibody comprising:
a) 25-100 mg/mL of the anti-human PD-1 antibody, or antigen binding fragment thereof;
b) about 70 mg/mL sucrose;
c) about 0.2 mg/mL polysorbate 80; and
d) about 10 mM histidine buffer at pH 5.0-6.0,
wherein the antibody comprises:
i) a light chain comprising amino acid residues 20 to 237 of SEQ ID NO: 36; and
ii) a heavy chain comprising amino acid residues 20 to 466 of SEQ ID NO:31, and
wherein the pharmaceutical formulation is reconstituted from a stable lyophilized formulation or is a stable liquid formulation has not been previously lyophilized.
The US Patent does not claim the liquid pharmaceutical formulation of an anti-human PD-1 antibody comprises about 6% to about 8% w/v trehalose stabilizer, poloxamer 188 non-ionic surfactant, or further comprises about 1% to about 3% w/v L-arginine.
US Patent Application Publication 2014/0234296, Sharma, teaches an aqueous (liquid) pharmaceutical formulation of anti-PD-1 antibody comprising:
(i) 25 mg/ml or 25-100 mg/ml anti-PD-1 antibody;
(ii) 70 mg/ml sucrose stabilizer;
(iii) about 1.55 mg/ml or 10 mM histidine buffer;
(iv) ~ 0.2 mg/ml (= 0.02 % w/v) non-ionic surfactant polysorbate 80; and
(v) pH 5.0-6.0;
wherein the anti-PD-1 antibody is h409A11 comprising heavy and light chain SEQ ID NOs:31 and 36, which is also known as MK-3475 or pembrolizumab ([23-26]; [31-33]; claims 31-42; Tables 3-6; Example 1).
Sharma teaches cryoprotectants and lyoprotectants of the antibody formulation can be sucrose or trehalose ([76-78]).
Sharma additionally suggests adding amino acid arginine to the composition as a cryoprotectant that provides stability to the protein against freezing-induced stresses ([76]).
Sadineni, Li, Bishop, Connolly, and Khan teach as set forth above.
Trehalose stabilizer at about 6% to about 8% w/v (claims 1, 27):
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to substitute trehalose stabilizer at 6-8% w/v for the sucrose stabilizer in the pembrolizumab composition of U.S. Patent No. 9,220,776. One would have been motivated to, and have a reasonable expectation of success to because: (1) all of Sharma, Sadineni, Li, Cosenza, Bishop, and Connolly teach and establish trehalose is a known stabilizer alternative to sucrose for antibody compositions and they are functional equivalents; (3) Li, Cosenza, Bishop, and Connolly teach or demonstrate known effective stabilizing amounts of trehalose in antibody compositions at about 6% to about 8% w/v; and (4) Sadineni, Li, Cosenza, Bishop, and Connolly teach or successfully demonstrate combining trehalose as the stabilizer with antibody, histidine buffer, non-ionic surfactant polysorbate 80; and at pH 5.0-6.0 to arrive at a stable antibody composition.
L-arginine at about 1% to about 3% w/v (claim 3):
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to add amino acid L-arginine to the composition of U.S. Patent No. 9,220,776 and at about 1% to about 3% w/v. One would have been motivated to, and have a reasonable expectation of success to because: (1) Sharma suggests adding amino acid arginine to the composition as a stabilizer; and (2) Sadineni, Li, Consenza, and Bishop also teach additionally adding amino acid arginine or L-Arginine to the antibody composition as a common excipient, wherein Cosenza teaches arginine-HCl functions as a stabilizer and buffer and teaches adding Argining-HCl in the amount of about 1% w/v.
Non-ionic surfactant poloxamer 188 at about 0.01% to about 0.10% (claims 1, 27):
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to substitute poloxamer 188 for polysorbate 80 as the non-ionic surfactant in the antibody composition of U.S. Patent No. 9,220,776. One would have been motivated to, and have a reasonable expectation of success to because: (1) U.S. Patent No. 9,220,776 claims formulating the antibody composition with a non-ionic surfactant at 0.02% w/v (0.2 mg/ml polysorbate 80); (2) Sharma, Sadineni, Li, Consenza, and Bishop all teach formulating antibody pharmaceutical compositions with non-ionic surfactant; (3) Li, Cosenza, and Bishop teach formulating monoclonal antibody therapeutic compositions with non-ionic surfactant poloxamers and poloxamer 188 specifically and at 0.01 to 0.1%; and (4) Khan teaches the functional equivalence of non-ionic surfactants polysorbate 80 and poloxamer 188 for reducing aggregation and enhancing protein stability in antibody formulations.
Response to Arguments
10. Applicants reiterate arguments above that the claims are not obvious over Sharma. Applicants argue that the deficiency of teaching the claimed invention is not remedied by Sadineni, Li, Cosenza, Bishop and Connolly and Khan.
11. The arguments have been considered but are not persuasive for the reasons stated above with regard to the rejection under 35 USC 103.
12. All other objections and rejections recited in the Office Action mailed February 13, 2026 are hereby withdrawn in view of claim amendments. The rejection of claims under obviousness double patenting are withdrawn in view of the terminal disclaimers filed over copending applications 18/182,135; 18/182,097; 19/346,623; and 19/346,638; and over US Patents 11,633,476; 11,845,798; 12,319,735.
13. Conclusion: No claim is allowed.
Conclusion
14. 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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/Laura B Goddard/Primary Examiner, Art Unit 1642
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