DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.
Claims 1-22 are pending and under examination.
.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. §119 as follows:
The disclosure of the prior-filed application, Application No. 61/913172, fails to provide adequate support or enablement in the manner provided by the first paragraph of 35 U.S.C. 112 for one or more claims of this application.
Particularly, claims 1-20 are not supported by the prior-filed application because the disclosure of DMSO is present at a concentration of 1-4%” is not supported in the prior-filed application US Patent Application NO. 61/913172. Thus, claims 1-20 are is hereby assigned the priority date of December 5, 2014, the filing date of the PCT application, PCT/US2014/068893 which is the PCT application of the instant national stage application 15/102129.
35 USC § 103 rejections withdrawn
The rejections of claims 1-22 under 35 U.S.C. 103 as being unpatentable over Fritsch et al (WO 2015/085233, published June 11, 2015, IDS) in view of Georges (US 9962453, issued 8 May 2018, effective filing date 2 December 2013, IDS) and Fassihi et al (US 2003/0219480, published November 27, 2003) are withdrawn in view of Applicant’s amendments to claim 1 resulting in a change in the priority date of the present claims.
35 USC § 103 rejections maintained
The rejections of claims 1, 2 and 4-21 under 35 U.S.C. 103 as being unpatentable over Hacohen et al (US 2011/0293637, 1 December 2011, IDS), Randolph et al (US 20100158951, published 24 June 2010, IDS) and Cleland et al (US 6821515, 23 November 2004, IDS) in view of Walensky et al (US 2010/0286057, published 11 November 2010, IDS), Nash et al (US 2011/0223149, published 15 September 2011, IDS), Georges (US 9962453, issued 8 May 2018, effective filing date 2 December 2013, IDS) and Fassihi et al (US 2003/0219480, published November 27, 2003, cited previously) are maintained.
The claims are drawn an aqueous pharmaceutical composition suitable for administration to a human subject comprising:
(a) an aqueous component that does not comprise phosphate buffered saline (PBS),
wherein the aqueous component comprises:
(i) water;
(ii) 1 mM to 10 mM succinic acid or a pharmaceutically acceptable salt thereof;
(iii) a pharmaceutically acceptable carrier, wherein the pharmaceutically
acceptable carrier comprises DMSO, wherein the DMSO is present at a concentration of 1-4%; and
(iv) a tonicity adjusting agent selected from the group consisting of 3.6% to 5%
dextrose, 10% trehalose and 10% sucrose; and
(b) a plurality of peptides or pharmaceutically acceptable salts thereof, wherein each
peptide of the plurality of peptides or pharmaceutically acceptable salts thereof, (i) is soluble in the aqueous component;
(ii) is present in the pharmaceutical composition at a concentration of about 300
μg/mL or about 400 μg/mL;
(iii) has a length of from 15 to 35 amino acids consisting of standard L-amino acids joined by standard peptide bonds with an amine group at the amino terminus and a carboxylic acid group at the carboxyl terminus; and
(iv) has a hydrophobic fraction of less than 0.45.
Hacohen et al discloses pharmaceutical compositions for intravenous and intraperitoneal injection comprising at least 2 peptides (24-40 amino acids in length) and adjuvants (paragraphs 16, 117, 140, 145, 146). The suspensions can be aqueous (in water) or in buffered carriers, can contain pH adjusting agents and tonicity adjusting agents (paragraph145). Hacohen disclose peptides having a hydrophobic fraction of less than 0.45.
Randolph discloses peptide compositions for vaccination comprising at least one aluminum salt, at least one buffer system (succinate or citrate), at least one glass forming agent (sucrose or trehalose) and an adjuvant (paragraphs 9, 21-22). Randolph discloses peptides having 15 to 35 amino acids that have a hydrophobic fraction of less than 0.45, wherein the hydrophobic fraction is the total number of hydrophobic amino acids in a peptide divided by the total number of amino acids in the peptide, wherein the hydrophobic amino acids are alanine, leucine, isoleucine, valine, methionine, phenylalanine and tryptophan (Table 2).
Cleland discloses preparing protein formulations for intravenous vaccination comprising 1-20 mM succinate, citrate, sucrose, trelahose and/or dextrose (column 9, lines 62-65; col. 15, lines 30-50; col. 18, lines 3-20). Cleland et al discloses lyophilized protein formulations which contain 1 mM to about 20 mM succinate, citrate, sucrose, trelahose and/or dextrose for reconstitution (col. 15, lines 30-50; column 18, lines 3-11). Cleland disclose that proteins include the α chain (21 amino acids) and β chain (30 amino acids) of insulin (column 6 line 53 to column 7, line 28).
One of ordinary skill in the art would have been motivate to apply Hacohen’s peptide composition and Cleland’s peptide composition comprising 1-20 mM succinate to Randolph’s peptide compositions because Hacohen, Randolph, and Cleland all disclose peptide compositions for eliciting immune responses in humans. Additionally, since Cleland et al discloses that stable lyophilized protein formulations which contain 1 mM to about 20 mM succinate, citrate, sucrose, trelahose or dextrose for reconstitution, it also would have been obvious and within the purview of one skilled in the art to use any of the known solutions such as succinate, citrate, sucrose, trehalose in the vaccine composition for lyophilization and then reconstituting with an aqueous solution comprising citrate and dextrose.
Furthermore, the court has held that it is obvious to combine two compositions, in order to form a third composition, when each of the two compositions is taught by the prior art to be useful for the same purpose. (In re Kerkhoven, 626, F.2s 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). The idea of combining them flows logically from their having been individually taught in the prior art (MPEP 2144.06). Combining prior art elements according to known methods to yield predictable results is an exemplary rationale for a prima facie case of obviousness. MPEP2143. Thus, it would have been would have been prima facie obvious to combine Randolph’s peptide compositions comprising peptides having a having a hydrophobic fraction of less than 0.45 with Hacohen’s peptide composition and Cleland’s peptide composition comprising 1-20 mM succinate along with sucrose, trelahose and/or dextrose to have a aqueous peptide composition of a plurality of peptides having a hydrophobic fraction of less than 0.45 at with a pH modifier, wherein the pH modifier is 2mM to 5mM succinate solution and a tonicity adjusting agent such as sucrose, trelahose and/or dextrose.
Neither Hacohen, Randolph, nor Cleland disclose a pharmaceutical composition comprising a 300 ug/ml peptide, 1-4% DMSO and 5% glucose.
Walensky disclose pharmaceutical compositions comprising 22 amino acid BIM peptides in dispersing agent, citrate buffer, isotonic agent and 2.5% DMSO/D5W. (paragraphs 266- 268, 277, 317; Figures 8-11). Walensky disclose 22 amino acid BIM peptides having a having a hydrophobic fraction of less than 0.45 (Figures 8-11).
Nash disclose that IV dose formulations are prepared by dissolving peptide in 5% DMSO/D5W to achieve a 10 or 3 mg/Kg dose and administered at 10 mL/kg per single injection (paragraph 276).
Georges disclose measuring hydrophobicity of immunogenic peptides (column 2, lines 46-52). Georges discloses that peptides may have an amino acid sequence in which 45% or less of the amino acid residues have a hydrophobic sidechain (column 8, lines 60-63). Georges disclose that since the amino acid residues can have different pKa values, the solubility can be manipulated by varying the pH and/or ionic concentration of the solution (column 9 line 66 to column 10, line 2). In addition, Fassihi disclose that the hydrophobic amino acids include alanine, leucine, isoleucine, valine, methionine, phenylalanine and tryptophan (Table 1).
One of ordinary skill in the art would have been motivated to apply Walensky and Nash’s peptide compositions comprising a plurality of peptides having a having a hydrophobic fraction of less than 0.45 in citrate buffer and 2.5% DMSO/D5W to Sahin, Randolph, Hacohen and Cleland’s aqueous peptide composition comprising a plurality of peptides having a hydrophobic fraction of less than 0.45 in succinate or citrate buffer with sucrose, trelahose and/or dextrose because Hacohen Randolph, Cleland, Walensky and Nash all disclose peptide compositions that are to be administered in humans. Furthermore, the court has held that it is obvious to combine two compositions, in order to form a third composition, when each of the two compositions is taught by the prior art to be useful for the same purpose. (In re Kerkhoven, 626, F.2s 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). The idea of combining them flows logically from their having been individually taught in the prior art (MPEP 2144.06). Combining prior art elements according to known methods to yield predictable results is an exemplary rationale for a prima facie case of obviousness. MPEP 2143. Furthermore, it would have been obvious to adjust the pH modifier and tonicity agent to enhance the solubility of the peptides based on Georges disclosure that the solubility of peptides can be manipulated by varying the pH and/or ionic concentration of the solution. It would have been prima facie obvious to combine Hacohen, Randolph, and Cleland’s peptide composition with Walensky and Nash’s aqueous composition comprising 300 ug/ml peptides in 5% DMSO/D5W in citrate buffer to have a aqueous peptide composition of a plurality of peptides having a having a hydrophobic fraction of less than 0.45 at a concentration of 300 ug/ml with a pH modifier, wherein the pH modifier is 2mM to 5mM succinate solution, a tonicity adjusting agent such as 5% dextrose and DMSO at a concentration of 1-4%.
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 to determine the optimal amount of each ingredient needed to achieve the desired results. Thus, absent some demonstration of unexpected results from the claimed parameters, the optimization of ingredient amounts would have been obvious at the time of applicant's invention.
The principle of law states from MPEP 2144.05: "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."(Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382); Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
It has been held that discovering an optimum value of a result effective variable involves only routine skill in the art. In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980). "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation." Application of Aller, 220 F.2d 454, 456, 105 USPQ 233, 235-236 (C.C.P.A. 1955). Hence the claimed invention as a whole is prima facie obvious absence unexpected results. When optimizing solubility of peptides in solution, one must take into account the length of the peptide, the concentration of the peptide and the presence or absence of other components and their concentration in the solution. As discussed previously, the salting out of a small number of peptides in PBS at a pH of 7.4 would not be sufficient to demonstrate unexpected results.
One of ordinary skill in the art would have had a reasonable expectation of success given that making pharmaceutical compositions comprising peptides with the claimed agents were well known in the art.
It has been interpreted that the art doesn’t have to explicitly indicate that the pharmaceutical composition does not comprise PBS but only that other tonicity agents such as dextrose, sucrose or trehalose may be used in the alternative. This is consistent with what was disclosed in the present specification.
The rejections of claims 1-22 under 35 U.S.C. 103 as being unpatentable over Hacohen et al (US 2011/0293637, 1 December 2011, IDS, cited previously), Randolph et al (US 20100158951, published 24 June 2010, IDS, cited previously) in view of Cleland et al (US 6821515, 23 November 2004, IDS, cited previously), Walensky et al (US 2010/0286057, published 11 November 2010, IDS, cited previously), Nash et al ( US 2011/0223149, published 15 September 2011, IDS, cited previously), Georges (US 9962453, issued 8 May 2018, effective filing date 2 December 2013, IDS, cited previously) and Fassihi et al (US 2003/0219480, published November 27, 2003, cited previously) in further view of Sun et (US 7572821, issued 11 August 2009, IDS, cited previously) and Du et al (US 8648104, issued, 11 February 2014, filed 22 May 2008, IDS, cited previously) are maintained.
Neither Hacohen, Randolph, Cleland, Walensky, Nash nor Georges disclose a tonicity adjusting agent is 3.6-3.7% dextrose.
Sun disclose a pharmaceutical composition for treating cancer by intravenous injection comprising 3.6% dextrose column 276, lines 9-15).
Du disclose a pharmaceutical composition for treating cancer by intravenous or intraperitoneal injection comprising 3.6% dextrose column 359, line 65 to column 360, line 5; column 361, lines 30-38).
One of ordinary skill in the art would have been motivated to apply Sun and Du’s pharmaceutical composition comprising 3.6% glucose to Hacohen, Randolph, Cleland, Walensky, Nash and Georges pharmaceutical composition comprising 5% glucose because Hacohen, Randolph, Cleland, Walensky, Nash, Sun and Du all disclose pharmaceutic compositions that may be administered to humans. It would have been prima facie obvious to substitute Sun and Du’s 3.6% glucose for the 5% glucose in Hacohen, Randolph, Cleland, Walensky and Nash’s pharmaceutic composition because both concentrations have been shown to be suitable for administration in vivo. Furthermore, as discussed above, the principle of law states from MPEP 2144.05: "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."(Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382); It has been held that discovering an optimum value of a result effective variable involves only routine skill in the art. In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980). "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation." Application of Aller, 220 F.2d 454, 456, 105 USPQ 233, 235-236 (C.C.P.A. 1955). Hence the claimed invention as a whole is prima facie obvious absence unexpected results.
A.
Applicant argues that the problem of peptide solubility was previously unappreciated and not obvious in view of the cited references. Applicant argues that at the priority date of the present invention, neoantigenic peptide technology was still quite new and little experimental work had been done to investigate the formulation of these
peptides into pharmaceutical compositions. Applicant argues that none of the cited references by the Office recognized the problem of neoantigenic peptide solubility. Applicant argues that none of the cited references teaches or suggests providing a pharmaceutical composition having improved solubility of peptides having the characteristics of claim 1 for administration to a human subject. Applicant argues that since the solubility problem of neoantigenic peptides having the structural and functional characteristics of claim 1, had not been previously appreciated until the present invention, there would have been no reason to incur additional time and expense to solve the problem of neoantigenic peptide solubility. Applicant argues that none of the cited references, alone or in combination, teaches or suggests the problem addressed by the claimed invention, which is providing aqueous pharmaceutical compositions having improved solubility of peptides suitable for administration to a human subject.
Applicant argues that Hacohen fails to mention any solubility problem of neoantigenic peptides or recognize the problem of solubility of neoantigenic peptides. Applicant argues that as Hacohen is not concerned with providing formulations having improved solubility, Hacohen cannot be considered to be directed to recognizing the problem of peptide solubility.
Applicant further argues that none of Randolph, Cleland, Walensky, Nash, Georges, Sun, or Du, alone or in combination, remedy the deficiencies in the teachings of Hacohen at least because (1) these secondary references do not seek to solve the problem of providing a pharmaceutical composition having improved solubility of peptides having the characteristics of claim 1, and (2) even if the skilled person were to combine the secondary references with Hacohen, he/she would still not arrive at the claimed subject matter. Applicant argues that Randolph, Cleland, Walensky, and Sun fail to mention improved solubility, let alone improved solubility of peptides having the
characteristics of claim 1. Applicant argues that the problem addressed in Sun is providing small molecule chemical compounds having the formulas of (I), (IA), (IB), (VA, (VIIA), (VIIIA), among other formulas corresponding to small molecules, which inhibit tubulin polymerization and/or target vasculature. Applicant argues that, Nash mentions solubility in the context of pharmaceutically acceptable derivatives including a chemical group but not improved solubility of peptides. Applicant argues that by contrast to Nash, claim 1 recites that each peptide "has a length of from 15 to 35 amino acids consisting of naturally occurring amino acids," and thus, are not "pharmaceutically acceptable derivatives including a chemical group".
In addition, Applicant argues that Georges is directed to "use of a peptide to reduce the solubility and to increase the adjuvanticity of an immunostimulant in extracellular fluid, wherein the peptide is covalently linked to the immunostimulant." In Georges, the immunostimulant can be a TLR7, TLR8, or NLR agonist, among other agonists. Applicant argues that Georges does not seek to improve the solubility of peptides, but suggests the exact opposite, i.e., using a peptide to reduce solubility so that the composition, when injected, stays in place without distributing throughout
the body. Lastly, Du mentions solubility in the context of "biohydrolyzable amide "biohydrolyzable ester", "biohydrolyzable carbamate", "biohydrolyzable carbonate",
"biohydrolyzable ureide" and "biohydrolyzable phosphate analogue", all of which are not
peptides having the characteristics of claim 1.
Applicant also argue that the problem addressed in Du is providing chemical compounds which inhibit the activity of Hsp90, or for treating c-Met associated cancers. Applicant argues that collectively, none of the cited references, alone or in combination, teaches or suggests the problem addressed by the claimed invention, which is providing aqueous pharmaceutical compositions having improved solubility of peptides suitable for administration to a human subject.
Applicant’s arguments have been considered but are not persuasive. The problem of peptide solubility was previously appreciated. Peptide insolubility was well known prior to Applicant’s filing of the current application. In most cases, to administer peptides to a subject, the peptides must be soluble in the pharmaceutical composition. Applicant have not supplied any evidence to support their argument that peptide solubility was unappreciated at the filing date of the present application.
Applicant does demonstrate the solubility of peptides having a length of 20-33 amino acids with hydrophobic fractions between 0.4 and 0.43 at a peptide concentration of 2 mg/ml were soluble in the succinate acid, 4% DMSO and 5% dextrose, using a specific protocol. It is not clear what is the pH of the succinate buffer. As discussed previously, all the parameters for the pharmaceutical composition listed in the claims are recited in the art. Thus, the issues are whether the specific parameters listed in the claims involve unexpected results and whether the initial solubilization of the peptides in 100% DMSO had any effect on the solubilization of the peptides. As recited previously, Georges disclose that since the amino acid residues can have different pKa values, the solubility can be manipulated by varying the pH and/or ionic concentration of the solution. Thus, methods for enhancing the solubility of peptides were known in the art.
In response to Applicant argument that none of the cited references by the Office recognized the problem of neoantigenic peptide solubility, the fact that the intended use of the peptides discussed in the art required that the peptides be soluble necessarily means that peptide solubility was recognized as a problem to be solved in order for the functioning of the peptides. Furthermore, as discussed previously, Georges disclose that the solubility of peptides can be manipulated by varying the pH and/or ionic concentration of the solution. Furthermore, the solubility of a peptide is primarily a feature of the amino acid sequence of the peptide. It is not clear why the solubility of a neoantigenic peptide would be distinct from any other peptide with a similar amino acid sequence. One of ordinary skill in the art would not recognize that a peptide was a neoantigenic peptide based solely on the amino acid sequence of the peptide.
In response to Applicant’s argument that that none of the cited references by the Office recognized the problem of neoantigenic peptide solubility, it is not clear why the solubility of a neoantigenic peptide would be any different than the solubility of a wild-type peptide. The solubility of a peptide would be determined by it’s amino acid content, not whether one of the amino acids is different from the wild-type peptide. As discussed previously, Georges disclose that since the amino acid residues can have different pKa values, the solubility can be manipulated by varying the pH and/or ionic concentration of the solution.
In response to Applicant’s argument that Georges does not seek to improve the solubility of peptides, but suggests the exact opposite, i.e., using a peptide to reduce solubility so that the composition, when injected, stays in place without distributing throughout the body, George teaches that changing the pH and ionic concentration of a particular solution would result in peptide solubility. Furthermore, Georges was concerned with the solubility and insolubility of peptides with low and high hydrophobic amino acid content. Thus, the teaching in Georges could be used to optimize the solubility of peptides in various solutions. As stated previously, Georges disclose that since the amino acid residues can have different pKa values, the solubility can be manipulated by varying the pH and/or ionic concentration of the solution.
Given that the function of the aqueous pharmaceutical composition comprising peptides of the present claims is to treat cancer, both Sun and Du are from the same field of endeavor as the claimed invention, administering anti-cancer agents to cancer patients. It is noted that the art already disclose the use of dextrose in pharmaceutical compositions comprising peptides for use in cancer treatment. One of skill in the art would have looked to the art to identify pharmaceutical compositions comprising 3.6% dextrose capable of treating cancer.
B.
Applicant further argues that a person of ordinary skill in the art would not be
motivated to combine the teachings of the cited references, to arrive at the compositions
according to the amended claims with any reasonable expectation of success at least because the compositions disclosed in the secondary references differ structurally and functionally from the plurality of peptides having the characteristics recited in claim 1.
i
Applicant argues that a person of ordinary skill would not have been able to predict with any reasonable expectation of success that the formulations disclosed in Randolph and Cleland, which were useful for large proteins would apply similarly for the 15-35 amino acid-long peptides in Hacohen. Applicant argues that certain conditions, such as significant heating, exposes regions of the protein that are typically shielded by other regions of the protein and causes aggregation and precipitation. Applicant argues that peptides, which are 15 to 35 amino acids long as claimed, are not part of a larger,
carefully folded structure, and so are unprotected by the remainder of the protein, and thus they are very sensitive to their chemical environment. Applicant argues that in light of these structural differences individual large proteins and individual peptides which are 15 to 35 amino acids long can behave differently in similar chemical environments.
In addition, Applicant argues that given that Walensky discloses stapled peptides that are clearly different from the peptides recited in the claims, a person of ordinary skill in the art would not expect that a solution used to maintain solubility of peptides engineered (by 'stapling') to maintain a biologically active structure dependent on solubility and containing non-natural amino acids would be useful or applicable to solubilize the non-stapled, all naturally-occurring amino acids peptides recited in the claims, much less improve the solubility of such non-stapled, all naturally occurring peptides.
Applicant argues that given that Nash discloses peptidomimetic macrocycles that are clearly different from the peptides having lengths of 15 to 35 amino acids consisting of naturally occurring amino acids, and directs a person away from using such peptides, a person of skill in the art would have no motivation to combine the teachings of Nash with the cited references to produce an aqueous pharmaceutical composition having improved peptide solubility. Applicant argues that Example 2 and Figure 2 of Nash shows that the peptides disclosed in Nash all contain at least two non-naturally occurring crosslinks. Applicant argues that Nash discloses that "unmodified peptides often suffer from poor metabolic stability, poor cell penetrability, and promiscuous binding due to conformational flexibility. Applicant argues that given that Nash discloses peptidomimetic macrocycles that are clearly different from the peptides having lengths of 15 to 35 amino acids consisting of standard L-amino acids joined by standard peptide bonds with an amine group at the amino terminus and a carboxylic acid group at the carboxyl terminus, and directs a person away from using such peptides, a person of skill in the art would have no motivation to combine the teachings of Nash with the cited references to produce an aqueous pharmaceutical composition having improved peptide solubility. Applicant argues that a person of ordinary skill in the art would not reasonably expect that the formulations disclosed in Nash as useful for solubilizing peptidomimetic macrocycles to apply similarly to solubilizing peptides having lengths of 15 to 35 amino acids consisting of standard L-amino acids joined by standard peptide bonds with an amine group at the amino terminus and a carboxylic acid group at the carboxyl terminus, much less improve the solubility of such peptides as claimed.
Applicant argues that the claims at question in Kerkhoven involve the combination of two spray detergents to form a third spray detergent. According to Kerkhoven and the MPEP, it is only when equivalent compounds are combined that the "idea of combining them flows logically from their having been individually taught in the prior art (MPEP 2144.06)." Applicant argues that the pending claims formulate an aqueous solution that is not equivalent to the compositions cited in the art, with the pending claims reciting a plurality of peptides with standard L-amino acids joined by standard peptide bonds with an amine group at the amino terminus and a carboxylic acid group at the carboxyl terminus and add carefully chosen elements, such as a pH modifier and a tonicity adjusting reagent, with different purposes that, when combined, create a solution that is suitable for administration to a human subject.
In addition, Applicant argue that the isothiazole derivatives and the peptides recited in the claims are structurally different, a person of ordinary skill in the art would not reasonably expect that the formulations disclosed in Sun as useful for solubilizing isothiazole derivatives to apply similarly to solubilizing peptides having lengths of 15 to 35 amino acids consisting of naturally occurring amino acids, much less improve the solubility of such peptides as claimed. There is no structural overlap between the compositions described in Sun and the peptides in the present invention. Applicant argues that such peptides pose a different technical problem than isothiazole derivatives compounds that are synthetically modified to comprise strained ring structures with different hydrophobicity, charge, and stability issues. Applicant argues that as isothiazole derivatives and the peptides recited in the claims are structurally different, a person of ordinary skill in the art would not reasonably expect that the formulations disclosed in Sun as useful for solubilizing isothiazole derivatives to apply similarly to solubilizing peptides having lengths of 15 to 35 amino acids consisting of standard L-amino acids joined by standard peptide bonds with an amine group at the amino terminus and a carboxylic acid group at the carboxyl terminus, much less improve the solubility of such peptides as claimed.
Applicant also argues that the structural and functional differences between the compositions described in Du and the compositions of the present invention are significant. Applicant argues that such peptides pose a different technical problem than small molecule compounds comprising a triazole that are synthetically modified to comprise strained ring structures with different hydrophobicity, charge, and stability issues. a person of ordinary skill in the art would not reasonably expect that the formulations disclosed in Du as useful for solubilizing small molecule compounds comprising a triazole to apply similarly to solubilizing peptides having lengths of 15 to 35 amino acids consisting of standard L-amino acids joined by standard peptide bonds with an amine group at the amino terminus and a carboxylic acid group at the carboxyl terminus, much less improve the solubility of such peptides as claimed.
Applicant arguments have been considered but are not persuasive. Hacohen discloses the invention provides methods of inducing a tumor specific immune response in a subject by administering one or more peptides or polypeptides identified
according to the methods of the invention and an adjuvant (paragraph 10). Hacohen disclose that the compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions, such as pH adjusting and buffering agents, tonicity adjusting agents, wetting agents and the like (145). The peptides would necessarily have to be soluble in the pharmaceutically acceptable compositions in order to be administered to the patients. Hacohen, like Ott, doesn’t list the specific buffering agents, tonicity adjusting agents, wetting agents or their concentrations but one of skill in the art would have looked to other references to provide the pH modifier and tonicity adjust agents and their concentrations. Hacohen Randolph, Cleland, Walensky and Nash all disclose compositions that are to be administered in humans which would require that the peptides to be soluble. While the length of the peptides may differ, Applicant has not supplied any evidence that one of skill in the art would not have looked at the components and concentrations in pharmaceutical compositions comprising larger peptides to use in the pharmaceutical compositions used in administering peptides to a subject. Applicant has not provided any objective evidence demonstrating the peptides recited in Hacohen Randolph, Cleland, Walensky and Nash would not have been soluble in DMSO/D5W.
The specification discloses that a number of peptides with a hydrophobic fraction greater than or equal to 0.4 were not soluble in DMSO/D5W (paragraph 384). The specification discloses that a number of these can be solubilized by addition of succinate. The specification discloses that 3 of 4 of these peptides had hydrophobic
fractions between 0.4 and 0.43. The specification discloses that four peptides became less soluble upon addition of succinate. This data is consistent with Georges disclosure that since the amino acid residues can have different pKa values, the solubility can be manipulated by varying the pH and/or ionic concentration of the solution. Given that the claims do not recite a particular pH it appears that the claims are leaving out a critical factor for determining solubility. The specification recites that depending on the peptide pool and the concentration of succinate buffer used, pH for the peptide solutions in DSW /succinate ranged from about 4.64 to about 6.96.
In response to Applicant’s argument that the pending claims formulate an aqueous solution that is not equivalent to the compositions cited in the art, with the pending claims reciting a plurality of peptides with standard L-amino acids joined by standard peptide bonds with an amine group at the amino terminus and a carboxylic acid group at the carboxyl terminus and add carefully chosen elements, such as a pH modifier and a tonicity adjusting reagent, with different purposes that, when combined, create a solution that is suitable for administration to a human subject, the claimed pH modifier, the claimed pharmaceutically acceptable carrier and a tonicity adjusting reagent, along with the concentrations were known in the art. Furthermore, there was ample motivation to combine the different references because they all concern pharmaceutical compositions for polypeptides. In addition, the claims do not recite the pH of the pharmaceutical composition which would be important factor in improving the solubility of the peptides. Georges disclose that since the amino acid residues can have different pKa values, the solubility can be manipulated by varying the pH.
In response to Applicant’s arguments concerning the peptides of Walensky and Nash, as discussed previously, both the BIM-SAHB molecule and the peptidomimetic macrocycles would be considered to be peptides which comprise primarily naturally occurring amino acids. The peptides have been modified to increase stability in vivo. It is not clear why either Walensky or Nash would be considered to be non-analogous art given that they are made of amino acids and Applicant has not supplied any evidence that the peptides of Nash and Walensky would have different solubility properties in an aqueous pharmaceutical composition than a peptide having unmodified amino acids. It is noted that Walensky identifies the listed compounds as peptides. One of skill in the art would look to the aqueous compositions of Walensky and Nash for their disclosure of aqueous pharmaceutical compositions comprising peptides suitable for administration to a human subject. It is noted that Hacohen, Randolph and Georges all disclose peptides comprising all naturally-occurring amino acids.
It is not clear why Applicant argues that the cited references do not provide a reasonable expectation of success to arrive at the pending claims. Methods for solubilizing peptides were well known in the art and as Georges recites, changing the pH and ionic concentration of a particular solution would result in peptide solubility. As discussed above, the pH of the pharmaceutical composition likely has a role in the solubility of the peptides.
ii DMSO Concentration
In addition, Applicant argues that the cited references do not provide the requisite motivation to arrive at a composition comprising a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier comprises DMSO, wherein the DMSO is present at a concentration of 1-4%.
Applicant argues that Tjernberg in discussing the concentration of DMSO solutions used in assays is silent as to the inclusion of DMSO in a formulation for administration to a human. Applicant argues that Tjernberg is concerned with the problems that DMSO can cause in solutions of proteins, concluding, for example, that "DMSO at relatively low concentrations can change the properties of proteins in solution, leading to protein denaturation, aggregation, or degradation" and these phenomena occur in "many other protein systems. Applicant states that Fig. 5 of Tjernberg shows significant increase in protein degradation in the presence of 0.5% DMSO. As Tjernberg notes, "the rate of degradation is highly dependent on the
presence of 0.5% DMSO." Applicant states that Table 2 of Tjernberg shows substantial increase in protein aggregation in the presence of 0.5% DMSO. In discussing this table, Tjernberg explains that "DMSO resulted in complete disappearance of the protein monomer peak at 2.6 nm. Applicant argues that at the same time, the content of the large-size aggregates clearly increased." These concentrations of DMSO are
lower than recited in the pending claims. Applicant argues that when Tjernberg attempted to use 1 % DMSO the aggregation issue was further exacerbated. Applicant argues that a person having ordinary skill in the would have thus been dissuaded from attempting to include the claimed 1-4% DMSO in a peptide formulation because of the problems protein degradation and aggregation described by Tjernberg.
Applicant argues that for its experiments, Tjernberg used the proteins human growth hormone receptor (hGHbp) and the phosphatase domain of PFKFB 1 (BPase ), i.e., proteins composed of natural amino acids, like those claimed. Applicant argues that in contrast, Walensky and Nash employed peptides that had been chemically modified to increase stability. Applicant argues that a person having ordinary skill in the art would not have considered Tjernberg's findings on the deleterious impact of DMSO upon protein aggregation and stability to be negated by examples in the cited references utilizing DMSO in conjunction with chemically stabilized peptides (or small molecules, in the case of Sun and Du).
Applicant argues that Applicant respectfully submits that the cited references would not have guided a person having ordinary skill in the art to a peptide formulation as claimed. Applicant argues that the art taught away from including DMSO in a formulation for peptides consisting of standard amino acids.
Applicant’s arguments have been considered but are not persuasive. Tjernberg disclose that assay concentrations of DMSO are normally from 0.1 % to 5% DMSO. Tjernberg also disclose that DMSO is often one of the principal additives in assay buffer. Thus, Tjernberg reinforces the premise that for most solutions the concentrations of DMSO are normally from 0.1 % to 5%. This is consistent with what was disclosed in Walensky that disclose pharmaceutical compositions comprising 22 amino acid BIM peptides in dispersing agent, citrate buffer, isotonic agent and 2.5% DMSO/D5W. Tjernberg does disclose that at concentrations of 3% DMSO can result in a change in properties of proteins leading to protein denaturation or aggregation for the phosphatase domain of PFKFB1 (BPase). Tjernberg also disclose DMSO can change the apparent binding properties of the proteins. Tjernberg disclose that in the presence of DMSO the temperature gradient of the heat capacity of BPase was higher than in DMSO-free Tris-CL which resulted in an increase in the number of dimers and trimers (Fig 6.). Thus, Tjernberg does disclose that the use of DMSO in buffers may cause aggregation of protein which may be caused by protein unfolding. Protein unfolding would expose hydrophobic regions which would bind together causing the proteins to clump. However, it is not clear the relevance of Tjernberg for the use of DMSO in peptide solutions. The problems associated with proteins containing highly hydrophobic regions that denature and then aggregate in DMSO would not be relevant in most peptides consisting of 15 -35 amino acids. In addition, Tjernberg does not indicate that the buffer used was consequential in determining the aggregation of BPase. Importantly, Tjernberg does not argue against the use of DMSO in protein solutions, let alone for the use of DMSO in peptide solutions comprising peptides of 15 -35 amino acids. Furthermore, it is not clear what relevance Tjernberg's findings on the deleterious impact of DMSO upon protein aggregation and stability with reference to Walensky, Nash, Sun and Du given that the peptides in Walensky, Nash, Sun and Du do not have highly hydrophobic regions which would be exposed in solutions of DMSO.
Furthermore, as stated previously, the Specification disclose that the peptides were dissolved in DMSO at high concentration, diluted with 5% dextrose in water (D5W) The Specification disclose that a final concentration of 4% DMSO was used to solubilize peptides (paragraph 440). It does not appear that different concentrations of DMSO were used to determine optimal concentrations of DMSO for each peptide.
In response to Applicant’s argument that in contrast to the proteins of Tjernberg, the peptides of the claimed aqueous pharmaceutical composition had improved peptide solubility in 1-4% DMSO, this is because the peptides of the claimed aqueous pharmaceutical composition have a hydrophobic fraction of less than 0.45. A 15 to 35 amino acid peptide having a very high hydrophobicity, like some regions in the Tjernberg’s BPase protein, would not be soluble in 1-4% DMSO.
C.
Applicant continues to argue that a person of ordinary skill in the art would have had no reasonable expectation that the claimed pharmaceutical composition containing 1-4% DMSO, a pH modifier, a tonicity adjusting agent, and an aqueous component lacking PBS, could successfully solubilize a plurality of peptides that would be suitable for administration to a human subject. Applicant argues that as the field of peptide solubility was unpredictable at the priority date of the application, a person of ordinary skill in the art would have had no reasonable expectation that the claimed pharmaceutical composition containing 1-4% DMSO, a pH modifier, a tonicity adjusting agent, but lacking PBS, could successfully solubilize a plurality of peptides, having the structural and functional characteristics as claimed, that would be suitable for administration to a human subject.
Applicant argues that in a chemical environment having low concentrations of 1-5% DMSO conditions, large proteins like those in Randolph and Cleland behave differently than peptides which are 15 to 35 amino acids long. Applicant argues that the the conditions that maintain stability and solubility of any individual peptides bear no correlation to conditions that might stabilize and solubilize any individual large proteins. Applicant argues that given that individual large proteins and individual peptides can behave differently under similar chemical conditions, a person of skill in the art (i) would not reasonably expect the formulations disclosed in Cleland and Randolph as useful for larger proteins to apply similarly for peptides as recited in the claims, and (ii) would move away from using low DMSO concentrations. In addition, since all the formulations disclosed in Hacohen, Cleland and Randolph do not teach or suggest 1-4% DMSO, there would be no reasonable expectation of success that combining the 15-35 amino acid-long peptides in Hacohen to any of the formulations described in Cleland and Randolph would result in an aqueous pharmaceutical composition having improved peptide solubility. Applicant argues that in a chemical environment having low concentrations of 1-5% DMSO conditions, large proteins like those in Randolph and Cleland behave differently than peptides which are 15 to 35 amino acids long. Applicant argues that since all the formulations disclosed in Hacohen, Cleland and Randolph do not teach or suggest 1-4% DMSO, there would be no reasonable expectation of success that combining the 15-35 amino acid-long peptides in Hacohen to any of the formulations described in Cleland and Randolph would result in an aqueous pharmaceutical composition having improved peptide solubility.
Applicant’s arguments have been considered but are not persuasive. It is not clear the relevance of formulations disclosed in Cleland and Randolph to the claimed aqueous pharmaceutical composition having improved peptide solubility in 1-4% DMSO. It appears that Applicant is arguing that the buffers recited in Cleland and Randolph would somehow affect the improved peptide solubility in 1-4% DMSO. However, the Specification does appear to disclose any relationship between the buffers used in Cleland and Randolph and improved peptide solubility in 1-4% DMSO. Neither Clealand nor Randolph disclose formulation including DMSO. However, both Walensky and Nash disclose pharmaceutical compositions for comprising 2.5% DMSO/D5W and 5% DMSO/D5W, respectively, for administration to a patient.
It is worth noting that the specification discloses that of the 5 peptides tested four of them were soluble in D5W without DMSO. (paragraph 421). Thus, DMSO was required for the solubility of a subset of peptides. Furthermore, the Specification disclose that the peptides are weighed, dissolved in DMSO at high concentration, diluted with 5% dextrose in water (D5W) and sodium succinate (4.8- 5 mM) It is not clear what role the initial high concentrations of DMSO had on the solubility of the peptides. Thus, it appears that Applicant is arguing unexpected results based on the findings that some peptides required DMSO to be solubilized. However, as previously, discussed, it has been held that discovering an optimum value of a result effective variable involves only routine skill in the art. In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980). "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation." Application of Aller, 220 F.2d 454, 456, 105 USPQ 233, 235-236 (C.C.P.A. 1955). Given that Tjernberg disclose that assay concentrations of DMSO are normally from 0.1 % to 5% DMSO and Walensky and Nash disclose pharmaceutical comprising 2.5% DMSO/D5W and 5% DMSO/D5W, respectively, it would have been obvious to include DMSO in a pharmaceutical composition for administration to a patient.
In addition, Applicant continues to argue that the complex structures of the stapled peptides, like BIM-SAHB, in Walensky, and the peptidomimetic macrocycles in Nash, are structurally different than the linear structure of the plurality of peptides having a length of from 15 to 35 amino acids consisting of naturally occurring amino acids. Applicant continues to argue that the stapled peptides in Nash contain a
hydrocarbon chain staple that is very hydrophobic. Applicant argues that this would change the physical properties and solubility of a peptide greatly, and a skilled artisan would understand this and know that formulations useful for peptides with a hydrocarbon chain staple that is very hydrophobic would likely not be useful to solubilize peptides without such a hydrocarbon chain staple. Applicant argues that as described above in section B., the stapled peptides in Walensky and the peptidomimetic macrocycles in Nash are structurally different from the peptides recited in the
claims. Applicant argues that a person of ordinary skill in the art would not reasonably expect that the formulations disclosed in Walensky as useful for solubilizing stapled peptides, or the formulations disclosed in Nash as useful for solubilizing peptidomimetic macrocycles, to apply similarly to solubilizing peptides having lengths of 15 to 35 amino acids consisting of naturally occurring amino acids, much less be suitable for administration to a human subject.
Applicant’s arguments have been considered but are not persuasive. Both the BIM-SAHB molecule and the peptidomimetic macrocycles would be considered to be peptides which comprise primarily naturally occurring amino acids. The peptides have been modified to increase stability in vivo. It is not clear why either Walensky or Nash would be considered to be non-analogous art given that they are made of amino acids and Applicant has not supplied any evidence that the peptides of Nash and Walensky would have different solubility properties in an aqueous pharmaceutical composition than a peptide having unmodified amino acids. It is noted that Walensky identifies the listed compounds as peptides. One of skill in the art would look to the aqueous compositions of Walensky and Nash for their disclosure of aqueous pharmaceutical compositions comprising peptides suitable for administration to a human subject.
In response to Applicant’s argument that DMSO is not mentioned in Nash's discussion of liquid pharmaceutical formulations, Nash disclose that IV dose formulations are prepared by dissolving peptide in 5% DMSO/D5W to achieve a 10 or 3 mg/Kg dose and administered at 10 mL/kg per single injection (paragraph 276).
In response to Applicant’s argument that only place that Walensky mentions DMSO is in its Example 8, 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).” Art is art, not only for what it expressly teaches, but also for what it would reasonably suggest to the skilled artisan, including alternative or non-preferred embodiments. MPEP § 2123.
In response to Applicant’s argument that the mice administered DMSO in Example 8 of Walensky are promptly euthanized after administration and tissues are examined for apoptotic activity and are not to formulate or evaluate solutions suitable for administration to humans, but to evaluate the activity of the BIMSAHB stapled peptide, Applicant appears to be arguing that the 2.5% DMSO/D5W might be toxic or somehow deleterious to humans. However, Applicant has not provided any evidence to support this suggestion. As previously discussed, Walensky disclose that compounds, pharmaceutical compositions, and regimens of the invention can be tested in suitable animal model systems prior to use in humans (paragraph 199). Thus, Walensky plans to use the composition comprising 2.5% DMSO/D5W for administration to humans. Animal models are routinely used as a guide for use in humans and examples of using animal models are seen as providing support for the claimed uses in humans. It also appears that DMSO is primarily used to solubilize peptides and not solely as a pharmaceutical composition for administration to a human subject.
Applicant further argues that Georges does not teach or suggest any peptide composition in DMSO, let alone 1-4% DMSO. Applicant argues that the preferred buffer in Georges is one containing PBS. Applicant argues that based on Georges, a skilled artisan would arrive at a conclusion that PBS was a suitable buffer for formulating peptides. Applicant argues that the pending claims specify "an aqueous component that does not comprise phosphate buffered saline (PBS)." Applicant argues that one of ordinary skill in the relevant art must have a reasonable expectation of success in light of the cited reference or references and the reasonable expectation of success must be found in the prior art, and may not be based on the Applicant's disclosure.
Applicant argues that the Examiner is not granting the appropriate weight to the explicitly claimed features of the pharmaceutical composition lacking PBS and instead
comprising 1-4% DMSO. Specifically, Applicant submits that the explicit exclusion of the PBS from the claimed pharmaceutical compositions cannot be considered routine optimization because PBS is not a "results effective" variable when solubilizing peptides. Applicant points the Examiner to MPEP 2144.05(Il)(B), which states 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). Applicant argues that the cited prior art does not recognize a clear nexus between PBS and solubility of peptides as claimed wherein the claimed parameter was not a recognized result-effective variable because the cited prior art did not recognize a clear nexus between the claimed parameter and the relevant property. Applicant argues that the specification as filed specifies that PBS is not suitable for solubilizing the peptides as claimed. Example 6 of the instant specification discloses that the present inventors conducted a study of solubility of peptides, including PBS. Applicant argues that precipitating out of
peptides was observed which caused a "visible cloudiness". Applicant argues that "from 40 peptides tested, that D5W was, unexpectedly, shown to be more effective than PBS (and that sucrose and trehalose were also found to be effective as alternatives to dextrose)." Applicant argues that according to the instant specification, solubility evaluations showed that "upon addition of the PBS pH 7.4, it was observed that one or more of the peptides had precipitated out. Applicant argues that this is contrary and
unexpected to what a skilled artisan would arrive at based on the teachings of Georges (that PBS was a suitable buffer for formulating peptides). Applicant argues that the specification demonstrates that PBS led to peptide precipitation, and that PBS would not be a suitable buffer for reconstitution. Applicant argues that a skilled artisan reading Georges would have had no reasonable expectation that the claimed pharmaceutical composition containing 1-4% DMSO, a pH modifier, a tonicity adjusting agent,
and an aqueous component lacking PBS, could successfully solubilize a plurality peptides that would be suitable for administration to a human subject
Applicant’s arguments have been considered but are not persuasive. Paragraph 418 of the Specification recites “Upon addition of the PBS pH 7.4, it was observed that one or more of the peptides had precipitated out”. Table 5 indicates that one out of five peptides precipitated out with PBS, pH 7.4. It does not appear that any other concentration of PBS nor any other pH was used to solubilize the peptides. As previous discussed, Georges discloses the solubility of peptides can be manipulated by varying the pH and/or ionic concentration of the solution. Thus, what the specification demonstrates is that one composition comprising PBS solubilized 80% of the listed peptides having 20-33 amino acids and a hydrophobicity of less than .45 while a 5% dextrose solution solubilized 100% of the peptides. It is noted that four of the peptides listed in Table 4 were not soluble in 5% glucose. It is not clear from the specification that the solubility of 40 peptides were determined using the composition comprising PBS solution. The Specification disclose that the peptides are weighed, dissolved in DMSO at high concentration, diluted with 5% dextrose in water (D5W) and sodium succinate (4.8- 5 mM) (paragraph 422). Applicant’s discovery is that the solubility of a small number of peptides in the claimed composition was greater than the solubility of the same subset of peptides in another solution that includes PBS. However, the pH of the composition comprising PBS nor the concentration of the PBS were altered to determine whether these factors increase the solubility of the peptides in the composition. Furthermore, the effect of altering the concentrations of DMSO, glucose or succinate on the solubility of the peptides is unknown. It is not known what the effect of the pH on the solubility of the peptides. It is not even clear whether the parameters of the clamed components in their pharmaceutical composition were optimized let alone whether the particular parameters of the pharmaceutical composition resulted in unexpected results.
As discussed previously, all the parameters for the pharmaceutical composition listed in the claims are recited in the art. Thus, the issues are whether the specific parameters listed in the claims involve unexpected results and whether the initial solubilization of the peptides in 100% DMSO had any effect on the solubilization of the peptides. As recited previously, Georges disclose that since the amino acid residues can have different pKa values, the solubility can be manipulated by varying the pH and/or ionic concentration of the solution. It is not clear why Applicant insists that the cited references do not provide a reasonable expectation of success to arrive at the pending claims. Methods for solubilizing peptides were well known in the art and as Georges recites, changing the pH and ionic concentration of a particular solution would result in peptide solubility.
In response to Applicant argument that the specification as filed specifies that PBS is not suitable for solubilizing the peptides as claimed, paragraph 192 of the specification discloses that exemplary pharmaceutically acceptable carriers include water, buffer solutions in water (such as phosphate buffered saline (PBS), and 5% dextrose in water (D5W) or 10% trehalose or 10% sucrose. Thus, Applicant’s own specification indicates that PBS is a suitable pharmaceutically acceptable carrier. What Applicant has discovered is that some peptides were not soluble in PBS at a specific concentration and pH.
In addition, Applicant argues that nothing in the cited references teaches or suggests that the peptide solutions comprising DMSO of Walensky and Nash would be suitable for administration to human patients. Applicant argues that the isothiazole derivatives in Sun, and the small molecule compounds comprising a triazole in Du, are structurally different from the peptides recited in the claims. A person of ordinary skill in
the art would not reasonably expect that the formulations disclosed in Sun as useful for
solubilizing isothiazole derivatives, or the formulations disclosed in Du as useful for solubilizing small molecule compounds comprising a triazole, to apply similarly to solubilizing peptides having lengths of 15 to 35 amino acids consisting of naturally occurring amino acids, much less be suitable for administration to a human subject.
Applicant argues that Sun and Du do not teach or suggest any peptide composition in DMSO, let alone 1-4% DMSO. Applicant argues that the preferred solution in Sun and Du is one containing 10% DMSO. Applicant argues that the small molecule compositions in Sun and Du are completely different from peptides as claimed. Applicant argues that even if a skilled artisan were to ignored the differences in composition and apply Sun and Du to the instant application, he/she would use a solution containing 10% DMSO, or even higher concentrations of DMSO
Applicant’s arguments have been considered but are not persuasive. Applicant argues as before that Sun and Du are not relevant to the present claims because they are concerned with small molecules rather than peptides. Given that the function of the aqueous pharmaceutical composition comprising peptides of the present claims is to treat cancer, both Sun and Du are from the same field of endeavor as the claimed invention, administering anti-cancer agents to cancer patients. It is noted that the art already discloses the use of dextrose in pharmaceutical compositions comprising peptides for use in cancer treatment. One of skill in the art would have looked to the art to identify pharmaceutical compositions comprising 3.6% dextrose capable of treating cancer.
In response to Applicant’s argument that Sun and Du do not teach or suggest any peptide composition in DMSO, let alone 1-4% DMSO, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Both Walensky and Nash disclose pharmaceutical compositions for comprising 2.5% DMSO/D5W and 5% DMSO/D5W, respectively, for administration to a patient.
As discussed previously, all the parameters for the pharmaceutical composition listed in the claims are recited in the art. Thus, the issues are whether the specific parameters listed in the claims involve unexpected results and whether the initial solubilization of the peptides in 100% DMSO had any effect on the solubilization of the peptides. It is not clear what role the initial high concentrations of DMSO had on the solubility of the peptides.
As recited previously, Georges disclose that since the amino acid residues can have different pKa values, the solubility can be manipulated by varying the pH and/or ionic concentration of the solution. It is not clear why Applicant argues that the cited references would not provide reasonable expectation that the claimed pharmaceutical composition containing 1-4% DMSO, a pH modifier, a tonicity adjusting agent, and an aqueous component lacking PBS, could successfully solubilize a plurality of peptides that would be suitable for administration to a human subject. Methods for solubilizing peptides were well known in the art and as Georges recites, changing the pH and ionic concentration of a particular solution would result in peptide solubility. Furthermore, the administration of peptides was also well known in the art. It is not clear why one of skill in the art would not expect that the claimed pharmaceutical composition containing 1-4% DMSO, a pH modifier, a tonicity adjusting agent, and an aqueous component lacking PBS would be suitable for administration to a human subject. It is not clear whether the parameters of the different components of the claimed pharmaceutical composition were optimized let alone whether the particular parameters of the pharmaceutical composition resulted in unexpected results.
In addition, Applicant argues that a skilled artisan would understand that at high concentrations of DMSO (low concentrations of water), the solubility of such peptides is high, whereas at low concentrations of DMSO (high concentrations of water) caused a decrease in peptide solubility. Applicant argues that even if the skilled artisan was seeking to optimize conditions to solve the problem of providing compositions having improved solubility of the peptides as claimed, there is clear teaching in Malavolta to use high concentrations of DMSO rather than low concentrations (1-4% DMSO). Applicant argues that A person of skill in the art would, reading Malavolta, would understand that at high concentrations of DMSO (low concentrations of water), the solubility of the tested peptides is high, whereas low concentrations of DMSO (high concentrations of water) caused a decrease in peptide solubility.
In response it is not clear how relevant the findings of Malavolta are given that Malavolta was attempting to solubilize an 8 amino acid peptide known to be insoluble. It is noted that Malavolta, like Georges, disclose that the solubility of some peptides was dependent on the pH of the medium (page 1481, 1st column). Thus, any relationship between the percent of DMSO in the medium and the solubility of a peptide must take into account the pH and/or ionic concentration of the medium, as well as the overall hydrophobicity of the peptides. It does not appear in the specification that either of these variable were taken into account when determining solubility of the peptides.
Furthermore, as stated previously, the specification disclose that the peptides were dissolved in DMSO at high concentration, diluted with 5% dextrose in water (D5W) The Specification disclose that a final concentration of 4% DMSO was used to solubilize peptides (paragraph 440). It does not appear that different concentrations of DMSO were used to determine optimal concentrations of DMSO for each peptide.
D.
Applicant further argues that the cited references do not reasonably provide an expectation of successfully achieving the unexpected and improved solubility of the peptides having the structural and functional characteristic as claimed that would be suitable for administration to a human subject. Applicant argues that the present invention relates particularly to non-obvious pharmaceutical compositions which have unexpectedly been found to provide improved solubility of neoantigenic peptides. Applicant argues that the combination of references does not guide one of skilled in the art to the invention as presently claimed nor does it provide guidance to allow one of skilled in the art to reasonably expect that such pharmaceutical compositions having improved solubility of peptides would be suitable for administration to a human subject.
Applicant argues that claim 1 is directed to a pharmaceutical composition which, for the first time, brings together (i) and (ii), and has unexpectedly been found to provide improved solubility of neoantigenic peptide. Such pharmaceutical compositions were suitable for administration to a human subject as demonstrated by the clinical results.
Applicant states that the following examples and cited paragraphs of the present
invention help illustrate such unexpected findings as follows
Example 6 of the application as filed: The present inventors are the first to have
conducted a study of the solubility of the genus of plurality of peptides.
Paragraph [00383], Table 4 on pages 111-118 of the application as filed show the results of solubility evaluations of 60 potential neoantigen peptides are shown.
In the specification at Examples 9-11, the soluble pharmaceutical compositions were functional
Paragraph [00416] of the application as filed recites that the conclusion drawn by the inventors is: "In general, it was found that peptides that are clear upon dilution to 2 mg/ml in D5W with succinate buffer retain clarity upon mixing with other peptides.
Paragraph [00384] shows additional results reported: It will further be noted from 40 peptides tested, that D5W was, unexpectedly, shown to be more effective than PBS.
(f) Paragraph [00419]: Similar to the above, another experiment states that: "Upon addition of the PBS pH 7.4, it was observed that one or more of the peptides had precipitated out.
As noted in the specification at paragraph [00176]: It has been unexpectedly found that a pharmaceutical composition comprising succinic acid or a pharmaceutically acceptable salt thereof (succinate) can provide improved solubility for the neoantigenic peptides.
In fact, recent clinical trials conducted after the priority date of the application utilized a vaccine that is commensurate in scope with the claimed pharmaceutical compositions and showed that such pharmaceutical compositions were suitable for administration to a human subject, as demonstrated by the clinical results.
Applicant argues that specifically,
a. Ott (2017) described a personal neoantigen vaccine study to treat melanoma
utilizing a vaccine commensurate in scope with the pharmaceutical composition
as claimed (see page 7, L. col., lines 9-17). As described in Ott (2017), all 6
patients showed enhanced multiepitope immunogenicity based on the use of a
large repertoire of mutated epitopes and revealed a profile of clinical success not
seen with prior vaccine efforts and all 6 patients were disease free at a median
follow-up of 25 months (range 20-32).
b. Applicant argues that the results in Ott showed that a vaccine commensurate in scope withthe pharmaceutical compositions as claimed was suitable for administration to a human subject, as demonstrated by the impressive clinical results
In summary, it was unexpected that:
(i) PBS diluent would result in visible cloudiness, which to one skilled in the art of
pharmaceutical formulations means that there was a 'precipitating out" of a
number of peptides;
(ii) Dextrose, sucrose, and trehalose could be more effective as a diluent than PBS;
(iii) A combination of "an agent for the adjustment of tonicity" (as exemplified by
dextrose, sucrose, and trehalose) and "a pH modifier that is a base" (as
exemplified by succinic acid or a pharmaceutically acceptable salt thereof, or
citric acid or a pharmaceutically acceptable salt thereof) as the diluent, as recited
in amended in the independent claims, might provide further improvement; and
(iv) Such pharmaceutical compositions showing improved solubility of the peptides
were suitable for administration to a human subject.
Applicant also argues that they have demonstrated unexpected and surprising results of improved peptide solubility in the claimed pharmaceutical compositions, which were suitable for administration to a human subject. Applicant argues that even if optimization was routine and a skilled artisan was seeking to solve the problem of solubilizing peptides having similar lengths and consisting of standard L-amino acids joined by standard peptide bonds with an amine group at the amino terminus and a carboxylic acid group at the carboxyl terminus as claimed, a skilled artisan would understand that at high concentrations of DMSO, the solubility of such peptides is high, whereas at low concentrations of DMSO caused a decrease in peptide solubility. Applicant argues that even if the skilled artisan was seeking to optimize conditions to solve the problem of providing compositions having improved solubility of the peptides as claimed, there is clear teaching in, for example, Malavolta to use high concentrations of DMSO rather than low concentrations ( 1- 4% DMSO). Applicant argues that as explained above in sections A. and C., a person of ordinary skill in the art would move away from using low DMSO concentrations in view of Tjemberg, given that the proteins of Tjemberg when exposed to low concentrations of 1-5% DMSO, led to protein denaturation, aggregation or degradation.
Applicant argues that as set forth above, Applicant has demonstrated unexpected and surprising results of improved peptide solubility in the claimed pharmaceutical compositions, which were suitable for administration to a human subject. Applicant argues that even if optimization was routine and a skilled
artisan was seeking to solve the problem of solubilizing peptides having similar lengths and consisting of standard L-amino acids joined by standard peptide bonds with an amine group at the amino terminus and a carboxylic acid group at the carboxyl terminus as claimed, a skilled artisan would understand that at high concentrations of DMSO (low concentrations of water), the solubility of such peptides is high, whereas at low concentrations of DMSO (high concentrations of water) caused a decrease in peptide solubility. Applicant argues that even if the skilled artisan was seeking to optimize conditions to solve the problem of providing compositions having improved
solubility of the peptides as claimed, there is clear teaching in, for example, Malavolta to use high concentrations of DMSO rather than low concentrations (1-4% DMSO). Applicant argues that as explained above in sections A. and C., a person of ordinary skill in the art would move away from using low DMSO concentrations in view of Tjemberg, given that the proteins of Tjemberg when exposed to low concentrations of 1-5% DMSO, led to protein denaturation, aggregation or degradation.
Applicant’s arguments have been considered but are not persuasive. As discussed previously, Applicant’s discovery is that the solubility of a small number of peptides was greater in the claimed composition than the solubility of the same subset of peptides in another composition that includes PBS. However, neither the pH of the composition comprising PBS nor the concentration of the PBS were altered to determine whether these factors increase the solubility of the peptides in the composition. It is likely that there are many pharmaceutical compositions which would have been capable of solubilizing the peptides listed in Table 4. The demonstration of a particular pharmaceutical composition capable of solubilizing the peptides does not establish unexpected results. Furthermore, as discussed previously, the peptides were initially solubilization in 100% DMSO. It was not demonstrated whether this initial solubilization had any effect on the solubilization of the peptides in the D5W.
In addition, as discussed previously, the solubility of the peptides in a pharmaceutical composition is necessary for the administration of the peptides to a subject. Thus, the peptides disclosed in the majority of the art had to be solubilized prior to the administration step. Only Georges discloses pharmaceutical compositions of peptides in the presence of an adjuvant were not soluble for therapeutic reasons. It is not evident from the specification that the discovery of a particular pharmaceutical composition capable of solubilizing a particular subset of peptides was unexpected, especially given the need to solubilize the peptides prior to administration to a subject and the numerous articles that disclose the use of soluble peptides in therapeutic treatments. It is almost certain that there would be many other pharmaceutical compositions besides the claimed pharmaceutical compositions that are capable of solubilizing the subset of peptides defined in the claims. The specification tested few pharmaceutical compositions to determine which compositions resulted in the solubility of the peptides having 15-35 amino acids with a hydrophobic fraction of less than 0.45. It is noted that several peptides having 15-35 amino acids with a hydrophobic fraction of less than 0.45 were not soluble in the claimed pharmaceutical composition (Table 4). Without comparing the claimed pharmaceutical composition with other pharmaceutical compositions it would be impossible to demonstrate unexpected results. The fact that the claimed pharmaceutical composition D5W at one pH and one ionic concentration was superior to PBS at one pH and one ionic concentration is not show unexpected results.
As Georges disclose since the amino acid residues can have different pKa values, the solubility can be manipulated by varying the pH and/or ionic concentration of the solution. Applicants have demonstrated that a particular pharmaceutical composition was capable of solubilizing a majority of peptides having 15-35 amino acids with a hydrophobic fraction of less than 0.45. Thus, what the specification demonstrates is that one composition comprising PBS solubilized 80% of the listed peptides having 20-33 amino acids and a hydrophobicity of less than .45 while a 5% dextrose solution solubilized 100% of the tested peptides. The specification only discloses that D5W at a specific concentration and pH was superior to PBS at a specific concentration and pH in solubilizing some peptides having 15-35 amino acids with a hydrophobic fraction of less than 0.45. The pH of the composition comprising PBS, the concentration of the PBS nor the percent DMSO were altered to determine whether these factors increase the solubility of the peptides in the composition. It is interesting to note that four of five peptides tested could be dissolved directly in D5W without any DMSO.
The specification appears to only examine the solubility of a handful of peptides out of the 40 peptides using the composition comprising the PBS solution. And onoly one pH and concentration of PBS were used. The specification disclose that the peptides are weighed, dissolved in DMSO at high concentration, diluted with 5% dextrose in water (D5W) and sodium succinate (4.8- 5 mM) (paragraph 422).
In response to Applicant’s argument that Malavolta used high concentrations of DMSO rather than low concentrations (1-4% DMSO), it is not clear how relevant the findings of Malavolta are given that Malavolta was attempting to solubilize an 8 amino acid peptide known to be insoluble. It is noted that Malavolta, like Georges, disclose that the solubility of some peptides was dependent on the pH of the medium (page 1481, 1st column). Thus, any relationship between the percent of DMSO in the medium and the solubility of a peptide must take into account the pH and/or ionic concentration of the medium, as well as the overall hydrophobicity of the peptides. It does not appear in the specification that either of these variable were taken into account when determining solubility of the peptides.
Furthermore, as stated previously, the specification disclose that the peptides were dissolved in DMSO at high concentration, diluted with 5% dextrose in water (D5W) The Specification disclose that a final concentration of 4% DMSO was used to solubilize peptides (paragraph 440). It does not appear that different concentrations of DMSO were used to determine optimal concentrations of DMSO for each peptide.
In response to Applicant’s argument that a person of ordinary skill in the art would move away from using low DMSO concentrations in view of Tjemberg, given that the proteins of Tjemberg when exposed to low concentrations of 1-5% DMSO, led to protein denaturation, aggregation or degradation, Tjernberg disclose that assay concentrations of DMSO are normally from 0.1 % to 5% DMSO. Tjernberg also disclose that DMSO is often one of the principal additives in assay buffer. Thus, Tjernberg reinforces the premise that for most solutions the concentrations of DMSO are normally from 0.1 % to 5%. This is consistent with what was disclosed in Walensky that disclose pharmaceutical compositions comprising 22 amino acid BIM peptides in dispersing agent, citrate buffer, isotonic agent and 2.5% DMSO/D5W. Tjernberg does disclose that at concentrations of 3% DMSO can result in a change in properties of proteins leading to protein denaturation or aggregation for the phosphatase domain of PFKFB1 (BPase). Tjernberg also disclose DMSO can change the apparent binding properties of the proteins. Tjernberg disclose that in the presence of DMSO the temperature gradient of the heat capacity of BPase was higher than in DMSO-free Tris-CL which resulted in an increase in the number of dimers and trimers (Fig 6.). Thus, Tjernberg does disclose that the use of DMSO in buffers may cause aggregation of protein which may be caused by protein unfolding. However, it is not clear the relevance of Tjernberg for the use of DMSO in peptide solutions. The problems associated with proteins containing highly hydrophobic regions that denature and then aggregate in DMSO would not be relevant in most peptides consisting of 15 -35 amino acids. In addition, Tjernberg does not indicate that the buffer used was consequential in determining the aggregation of BPase. Importantly, Tjernberg does not argue against the use of DMSO in protein solutions, let alone for the use of DMSO in peptide solutions comprising peptides of 15 -35 amino acids.
In response to Applicant’s argument in (c) that soluble pharmaceutical compositions were functional, it appears as if Examples 9-11 are prophetic examples.
In response to Applicant’s argument in (e) that paragraph [00384] shows additional results that from 40 peptides tested, that D5W was, unexpectedly, shown to be more effective than PBS, paragraph 384 does not appear to show the comparison between D5W and PBS for the 40 listed peptides.
With regards to (h) above, Ott does not disclose a particular pharmaceutical composition for solubilizing their peptides, nor that the reason for their results were due to the pharmaceutical composition comprising the peptides. It is highly likely that the results of Ott were due to the type of cancer treated, the specific peptides used as well as the specific pooling of peptides used in their experiments. It is unlikely that the specific pharmaceutical composition of the peptides was a significant factor in the results and the Ott reference does not disclose that the pharmaceutical composition played any role in the results. Thus, it is not clear if there was any nexus between the claimed pharmaceutical composition and the results demonstrated in Ott. It is likely that a different pharmaceutical composition that was capable of solubilizing the peptides used in Ott would be capable of producing the same results.
NEW REJECTIONS:
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.
Claims 1-22 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 and 18 recite the limitation “a plurality of peptides or pharmaceutically acceptable salts thereof, wherein each peptide of the plurality of peptides or pharmaceutically acceptable salts thereof has a hydrophobic fraction of less than 0.45”.
It is well known that there are various methods for calculating hydrophobicity. Fritsch discloses that hydrophobicity can be calculated in various ways. One way to calculate hydrophobicity is to look for regions of each peptide that are hydrophobic and to calculate an index for the degree of hydrophobicity of each region and find the region with the highest degree of hydrophobicity (paragraph 643). Kyte (J Mol Biol, 157:105-132, 1982, IDS) discloses a program that program uses a moving-segment approach that continuously determines the average hydropathy within a segment of predetermined length as it advances through the sequence (page 105, 1st paragraph; page 106, 4th paragraph spanning to page 107). Kyte et al discloses that hydrophilicity and hydrophobicity are no more than the two extremes of a spectrum, a term that defines that spectrum would be useful as either (page 107, footnote). Hopp (US 4,554,101, published 19 November 1985, IDS) discloses determining the point along a protein where there is greatest local average hydrophilicity (column 2, lines 22-27 and lines 58-61). Hopp discloses that this is done by assigning relative hydrophilicty values to each amino acid in the protein (column 2, lines 25-27 and lines 58-61). Biswas et al (J Chromoatog 1000:637-655, 2003). disclose that there is a wide range of hydrophobicity values that exist for each amino acid (page 647 1st column to page 651, 1st column). Some show a high hydrophobic ranking with one method while another method shows a high hydrophilic ranking for the same amino acid Thus, there are many ways for calculating the hydrophobicity of a peptide. It would be unclear to a skilled artisan if they are infringing on the metes and bounds of the claim since it would not be clear what formulation was being used to determine that the peptides had a hydrophobic fraction of less than 0.45.
It is noted that although the method for determining whether the peptides had a hydrophobic fraction of less than 0.45 was in the specification, that method is not recited in the claims. Narrow limitation contained in the specification cannot be inferred in the claims where the elements not set forth in the claims are linchpin of patentability. See In re Philips Industries, Inc. v. State Stove & Mfg. Co., 522 F.2d 1137, 186 USPQ 458 (CA6 1975), 237 PTJA A-12. While the claims are to be interpreted in light of the specification, it does not follow that limitations from the specification may be read into claims. On the contrary, claims must be interpreted as broadly as their terms reasonably allow. See Ex parte Oetiker, 23 USPQ2d 1641 (BPAI, 1992). Applicant is reminded that the claims define the subject matter of his invention and that the specification cannot be relied upon to read limitations into the claims.
Thus, providing the hydrophobic fraction of less than 0.45 without providing the method system for determining the hydrophobic fraction is insufficient, as one of skill in the art is not clear as to the metes and bounds of the claimed invention.
Summary
Claims 1-22 stand rejected.
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/MARK HALVORSON/ Primary Examiner, Art Unit 1646