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 .
Claims 1, 2 and 4-23 are pending and under examination.
Priority date of March 9, 2020 maintained
Applicant argues that the '172 application explicitly discloses that "the aqueous solvent further comprises dimethyl sulfoxide (DMSO), e.g., in an amount of about 1-4%, or 1-3%." Id. at p. 34. However, the paragraph on page 34, lines 8-14 as well as paragraph 193 of the specification recites “Exemplary pharmaceutically acceptable carriers include water, buffer solutions in water (such as phosphate buffered saline (PBS), and 5% dextrose in water (D5W). In certain embodiments, the aqueous solvent further comprises dimethyl sulfoxide (DMSO), e.g., in an amount of about 1-4%, or 1-3%”. Thus, it appears as if support for the limitation “DMSO at 1-4%” includes PBS as a buffer solution with DMSO at 1-4%. This is inconsistent with the present claim which recite that the “ an aqueous component that does not comprise phosphate buffered saline (PBS). Thus, claims 1, 2 and 4-23 are hereby assigned the priority date of March 9, 2020, the filing date of the parent case, 16/813,371.
35 USC § 112(b) rejections withdrawn
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35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter are withdrawn in view of Applicant’s amendments to claim1, 17 and 18.
35 USC § 103 rejections maintained
The rejections of claims 1, 2 and 4-21 and new claim 23. 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.
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). Randolph disclose succinate buffer at a pH of 5 (paragraph 83). Randolph disclose shelf temperatures of -20oC (paragraph 150).
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). Cleland disclose a pH of 5 with a succinate buffer (column 3, lines 45-53). Cleland disclose the protein may be present in a pH-buffered solution at a pH from about 5–7 (column 15, lines 39-50). Exemplary buffers include citrate (Id) Cleland further disclose that the lyophilized formulation was found to be stable at 40 C. for at least 3 months and stable at 30° C. for at least 6 months (Id).
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). Georges disclose that the peptides were freeze-dried and stored at -20oC (column 36, line 35; column lines 27-29)
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, 2 and 4-23 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.
Applicant argues that the Office has failed to establish a prima facie case of
obviousness with respect to previous claim 2. Applicant argues that the combination of references does not teach or suggest including each of at least 4 peptides or pharmaceutically acceptable salts thereof, each having a hydrophobic fraction of less than 0.45, solubilized in an aqueous pharmaceutical composition as instantly claimed. Applicant argues that that the amendments to claims 1, 17, and 18 overcome the
obviousness rejection by adding critical limitations to the aqueous component that are not taught or suggested by the cited prior art references, either individually or in combination.
Amended claim 1 now recites that the aqueous component has "1 mM to 10 mM citric acid or a pharmaceutically acceptable salt thereof" as recited in element (a)(ii). Additionally, amended claim 1 specifies "has a hydrophobic fraction of less than 0.45, wherein the hydrophobic fraction is the number of hydrophobic amino acids in the peptide divided by the total number of amino acids in the peptide" as recited in element (b)(iv). Claims 17 and 18 have been similarly amended. Applicant argues that this
specific combination of hydrophobic fraction and citric acid concentration with the other aqueous component elements is not disclosed or suggested by the cited references.
Additionally, amended claims 1, 17, and 18 now recite that each peptide "is stable for 24
weeks at -80°C." Applicant argues that none of the cited references teaches or suggests peptide stability for 24 weeks at -80°C. Applicant states that the specification demonstrates that the claimed pharmaceutical compositions provide this long-term stability, as disclosed in paragraph [00386]: "Two individual peptides were dissolved in
DMSO/D5W and placed on stability at two temperatures (-20°C and -80°C). These peptides were evaluated (RP-HPLC and pH and visual inspection) for up to 24 weeks. Both peptides are stable for up to 24 weeks." Applicant argues that this stability characteristic results from the specific combination of aqueous component features recited in the claims and further distinguishes the claimed compositions from the prior art.
Applicant argues that Hacohen does not disclose the specific hydrophobic fraction in combination with "1 mM to 10 mM citric acid or a pharmaceutically acceptable salt thereof" Applicant argues that Randolph discloses buffer systems including succinate, stating that "the buffer system is selected from either, or a combination of, a succinate and a phosphate buff er system. In one specific aspect, 25 mM sodium succinate, 15 mM sodium phosphate, at pH 5.0. In another specific aspect, the buffer system is 25 mM sodium succinate, pH 4.0." Applicant argues that Randolph does not
teach the specific combination of hydrophobic fraction with "1 mM to 10 mM citric acid or a pharmaceutically acceptable salt thereof," and the stability requirement that each peptide "is stable for 24 weeks at -80°C".
Applicant further argues that Cleland does not teach the specific combination of
hydrophobic fraction with "1 mM to 10 mM citric acid or a pharmaceutically acceptable salt thereof" in an aqueous component that does not comprise PBS, DMSO at 1-4%, and the stability requirement that each peptide "is stable for 24 weeks at -80°C". Applicant argues that Walensky does not disclose the specific hydrophobic fraction or the specific citric acid concentration of "1 mM to 10 mM," and the stability requirement that each peptide "is stable for 24 weeks at -80°C" as recited by amended claim 1. Applicant argues that Nash discloses DMSO/D5W formulations for peptidomimetic macrocycles but does not disclose the specific hydrophobic fraction or the specific citric acid concentration of "1 mM to 10 mM" in combination with the stability requirement that each peptide "is stable for 24 weeks at -80°C".
Applicants argue that regardless of whether the peptidomimetic macrocycles would be considered to be peptides which comprise primarily naturally occurring amino acids, the peptidomimetic macrocycles would not be considered to be peptides that "consist[] 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 comprise primarily naturally occurring amino acids" as recited in the instant claims. Applicant argues that unlike the stapled peptides of Walensky and Nash, the at least four peptides or pharmaceutically acceptable salts thereof of instant claims consist 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. Applicant argues that a skilled artisan would have had no expectation that any of stapled peptides
of Walensky and Nash, including the "22 amino acid BIM peptides having a having a hydrophobic fraction of less than 0.45" according to the Office, which contain a hydrocarbon chain staple that is very hydrophobic, could each be successfully solubilized in the claimed composition. Applicant argues that a skilled artisan would have readily understood that regardless of the computed hydrophobic fraction value of
the underlying amino acid sequence of the stapled peptides of Walensky and Nash, inclusion of a hydrocarbon chain staple on such peptides would greatly increase the hydrophobicity of such peptide such that the solubility of such peptides would not be comparable with the solubility of such peptides without the hydrocarbon chain staple.
Applicant argues that Georges discloses various buffer solutions but does not teach the specific hydrophobic fraction in combination with "1 mM to 10 mM citric acid or a pharmaceutically acceptable salt thereof" and an aqueous component that does not comprise PBS, DMSO at 1-4%, and the stability requirement that
each peptide "is stable for 24 weeks at -80°C".
Applicant argues that Fassihi discloses amino acid hydropathy characteristics but does not recite the specific hydrophobic fraction or citric acid concentrations for aqueous pharmaceutical compositions. Applicant argues that the specification demonstrates that hydrophobic fraction of less than 0.45 was a critical factor investigated by the inventors. Applicant argues that the inventors discovered through experimentation that the combination of citrate or succinate buffer with the other aqueous component elements provided improved peptide solubility: "[i]t was found that improved solubility was seen for 3 of 4 peptides which had solubility issues in D5W alone. Based on this initial observation, 19 additional peptides were evaluated with citrate or succinate, and 4 further peptides with succinate alone. It was found that solutions of 18 of the 19 tested peptides were clear when using either sodium citrate (where tested) or sodium succinate as buffer."
In addition, Applicant argues that Sun and Du are directed to small molecule compounds, not peptide formulations. Applicant argues that neither reference discloses the specific combination of the recited hydrophobic fraction with "1 mM to 10 mM citric acid or a pharmaceutically acceptable salt thereof" and the other aqueous component
elements as recited by amended claim 1. Applicant argues that a person of ordinary skill in the art would not have a reasonable expectation of success in applying formulations designed for small molecule compounds with 10% DMSO to peptide compositions requiring the specific combination of aqueous component features including "DMSO at 1-4%," "1 mM to 10 mM citric acid or a pharmaceutically acceptable salt thereof," and "hydrophobic fraction of less than 0.45," as recited by amended claim 1.
In addition, Applicant argues that none of the cited references teach or suggest the specific combination of hydrophobic fraction as defined with "1 mM to 10 mM citric acid or a pharmaceutically acceptable salt thereof" in an aqueous component that does not comprise PBS, DMSO at 1-4%, and the stability requirement that each peptide "is stable for 24 weeks at -80°C" as recited by amended claim 1. Applicant argues that the Examiner has not established a reasonable motivation to combine the cited references
to arrive at this specific combination of aqueous component features with the claimed hydrophobic fraction, citric acid concentration, and peptide stability.
Applicant’s arguments have been considered but are not persuasive. As an initial matter it is not clear how the hydrophobicity of peptides in Table 4 relate to the determination of hydrophobicity as recited in the current claims. The claims originally recited “a plurality of peptides… has 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. As previously discussed, one of skill in the art would not have known which of the hydrophobic amino acids would be included in Applicant’s subset of known hydrophobic amino acids. One would not have known that the hydrophobic amino acids glycine, proline and cysteine were not included in the group of hydrophobic amino acids used in the determination of hydrophobic fraction the subset of hydrophobic amino acids consist of alanine, leucine, isoleucine, valine, methionine, phenylalanine and tryptophan.
In addition, claims 1 and 18 recite either that the pH modifier is succinic acid or citric acid.
In response to Applicant argument that the combination of references does not teach or suggest including each of at least 4 peptides or pharmaceutically acceptable salts thereof, each having a hydrophobic fraction of less than 0.45, solubilized in an aqueous pharmaceutical composition 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). As discussed previously, all the parameters for the pharmaceutical composition listed in the claims are recited in the art and there is ample motivation to combine the different references.
Hacohen et al discloses pharmaceutical compositions for intravenous and intraperitoneal injection comprising at least 2 peptides and 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, Randolph disclose succinate buffer at a pH of 5 (paragraph 83). Randolph disclose shelf temperatures of -20oC (paragraph 150). Cleland discloses protein formulations comprising 1-20 mM succinate, citrate, sucrose, trelahose and/or dextrose. Cleland et al discloses lyophilized protein formulations which contain 1 mM to about 20 mM succinate, citrate, sucrose, trelahose and/or dextrose. Cleland disclose a pH of 5 with a succinate buffer (column 3, lines 45-53). Cleland disclose the protein may be present in a pH-buffered solution such as citrate at a pH from about 5–7. Cleland further disclose that the lyophilized formulation was found to be stable at 40 C. for at least 3 months and stable at 30° C. for at least 6 months (Id).
In response to Applicant’s argument that that Sun and Du are directed to small molecule compounds, not peptide formulations, 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.
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.
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.
With regards to Applicant’s argument that Cleland and Georges discloses various buffer solutions but does not teach the an aqueous component that does not comprise PBS. 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.
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 maintaining the stability of peptides for 24 weeks at -80°C.
Thus, the issue is whether the specific parameters listed in the claims involve unexpected results.
It appears as if Applicant is changing their argument for unexpected results from the argument that the pharmaceutical composition has improved solubility for peptides to their argument now that each peptide "is stable for 24 weeks at -80°C which results from the specific combination of aqueous component features recited in the claims. With respect to Applicant’s argument concerning unexpected results, paragraph 386 recites “Two individual peptides were dissolved in DMSO/D5W and placed on stability at two temperatures (-20°C and -80°C). These peptides were evaluated (RP-HPLC and pH and visual inspection) for up to 24 weeks. Both peptides are stable for up to 24 weeks. Thus, it appears that that the stability of peptides was examined in a composition that is different from the pharmaceutical composition as recited in claim 1.
MPEP 716.02(d) states
Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the “objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.” In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980) (Claims were directed to a process for removing corrosion at “elevated temperatures” using a certain ion exchange resin (with the exception of claim 8 which recited a temperature in excess of 100C). Appellant demonstrated unexpected results via comparative tests with the prior art ion exchange resin at 110C and 130C. The court affirmed the rejection of claims 1-7 and 9-10 because the term “elevated temperatures” encompassed temperatures as low as 60C where the prior art ion exchange resin was known to perform well. The rejection of claim 8, directed to a temperature in excess of 100C, was reversed.). See also In re Peterson, 315 F.3d 1325, 1329-31, 65 USPQ2d 1379, 1382-85 (Fed. Cir. 2003) (data showing improved alloy strength with the addition of 2% rhenium did not evidence unexpected results for the entire claimed range of about 1-3% rhenium); In re Grasselli, 713 F.2d 731, 741, 218 USPQ 769, 777 (Fed. Cir. 1983) (Claims were directed to certain catalysts containing an alkali metal. Evidence presented to rebut an obviousness rejection compared catalysts containing sodium with the prior art. The court held this evidence insufficient to rebut the prima facie case because experiments limited to sodium were not commensurate in scope with the claims.).
Applicant is arguing unexpected results based on a limited number of peptides in one concentration of DMSO/D5W, while the claims encompass a wide variety of different aqueous components.
Furthermore, regarding the interpretive “(v) is stable for 24 weeks at -80°C, the clause does not recite any additional steps or components, but simply states a characterization of those components of the aqueous components. As discussed above, the art discloses all the claim limitations. Therefore, the clause is not considered to further limit the method defined by the claim and has not been given weight in construing the claims. See Texas Instruments, Inc. v. International Trade Comm., 988 F.2d 1165, 1171, 26 USPQ2d 1018, 1023 (Fed Cir. 1993).
It is noted that the specification only discloses one pharmaceutical composition capable of remaining stable at -20oC and at -80oC. It is not clear how one can claim unexpected results from one pharmaceutical composition that remains stable for 24 weeks at -20oC and at -80oC. Given that Cleland disclose that the lyophilized formulation was found to be stable at 40 C. for at least 3 months and stable at 30° C. for at least 6 months, it would be expected that pharmaceutical compositions would be capable of remaining stable at -20oC and at -80oC for 24 weeks. In addition, Randolph disclose shelf temperatures of -20oC.
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).
It doesn’t appear that the concentrations of listed aqueous components for the pharmaceutical composition that are used to maintain stability for 24 weeks at -20oC and at -80oC are even optimized, let alone unexpected results.
With regards to the lack of Applicant’s argument that the art does not teach the specific combination of hydrophobic fraction with "1 mM to 10 mM citric acid or a pharmaceutically acceptable salt thereof" in an aqueous component that does not comprise PBS, DMSO at 1-4%, and the stability requirement that each peptide "is stable for 24 weeks at -80°C", paragraph recites “Exemplary pharmaceutically acceptable carriers include water, buffer solutions in water (such as phosphate buffered saline (PBS), and 5% dextrose in water (D5W). In certain embodiments, the aqueous
solvent further comprises dimethyl sulfoxide (DMSO), e.g., in an amount of about 1-4%, or 1-3%”. Thus, it appears as if support for the limitation “DMSO at 1-4%” includes PBS as a buffer solution with DMSO at 1-4%.
Paragraph 386 recites “Two individual peptides were dissolved in DMSO/D5W and placed on stability at two temperatures (-20°C and -80°C). These peptides were evaluated (RP-HPLC and pH and visual inspection) for up to 24 weeks. Both peptides are stable for up to 24 weeks.
NEW REJECTIONS:
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
Claim 23 is rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a new matter rejection.
There is not support in the specification for the limitation “pharmaceutical composition of claim 1, wherein the aqueous component has a pH of from about 4.6 to about 7.0. Paragraph 414 recites that “Concentrations of 2 mM to 5 mM succinate were found to be effective. Recovery of peptide was improved for one peptide in succinate buffer but not in citrate buffer. Depending the peptide pool and the concentration of succinate buffer used, pH for the peptide solutions in D5W /succinate ranged from about 4.64 to about 6.96. Thus, the pH from about 4.64 to about 6.96 referred to peptide solutions in D5W /succinate at concentrations of 2 mM to 5 mM succinate. However, claim 3 depends from claim 1 which also recites 1 mM to 10 mM citric acid.
Summary
Claims 1, 2 and 4-23 stand rejected.
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 extension fee 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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/MARK HALVORSON/Primary Examiner, Art Unit 1646
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