DETAILED ACTION
The present application is being examined under the pre-AIA first to invent provisions.
Priority
This application is a DIV of 14/407,174 (12/11/2014)
14/407,174 is a 371 of PCT/JP2013/068192 (06/26/2013)
and claims foreign priority to JAPAN 2012-144750 (06/27/2012).
Claim Status
Claims 32-52 are pending.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102 of this title, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 32-52 are rejected under 35 U.S.C. 103(a) as being unpatentable over Kajino et al. (WO 2007/026916) in view of Carstensen (“Kinetic pH Profiles,” Ch. 3 in Drug Stability: Principles and Practices, 3rd ed. (2000), p. 57-111) and Remington (“The Science and Practice of Pharmacy”, 21st ed., 2006, chs. 16-19, 41).
Regarding claim 32, Kajino teaches the following compound
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fumarate
in Example 8 (p. 163); claim 13 teaches the single compound; and Table 24 teaches the H+/K+-ATPase inhibitory activity of the compound. Kajino also teaches formulation for injection (p. 47, l. 18) with isotonizing agent including sodium chloride (p. 47; p. 49, l. 33) and buffers (p. 49, l. 35 – p. 50, l. 1). Kajino discloses the compound (Example 8 on page 163 = fumarate salt), a liquid preparation (p. 47, l. 9-19) that is “injectable” prepared “in accordance with a commonly known method” (p. 53, l. 10-14), with isotonizing agents and buffers for liquid preparations (p. 47, l. 29-30) which includes sodium chloride (p. 49, l. 33). Kajino teaches formulation for injection (p. 47, l. 18) with isotonizing agent including sodium chloride (p. 47; p. 49, l. 33) and buffers (p. 49, l. 35 – p. 50, l. 1) of the active compound (Example 8). Kajino teaches the compound as a salt with an organic acid including ascorbic acid (p. 32, lines 26-31: “Preferable examples of the salt with organic acid include a salt with … maleic acid”).
Kajino does not teach a specific embodiment where an organic acid is present in the composition. However, one of ordinary skill in the art would have considered preparing a formulation as taught by Kajino including adding sodium chloride salt as an isotonizing agent for injection to the compound as a maleic acid salt which Kajino teaches as a preferred embodiment. One of ordinary skill in the art would consider such a combination as routine optimization within the scope of Kajino’s teachings and arrive at the claimed invention with a reasonable expectation of success based on the specific teachings of Kajino. As per MPEP 2144.05:
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) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“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.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Lab. Inc., 874 F.2d 804, 809, 10 USPQ2d 1843, 1848 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989)(Claimed ratios were obvious as being reached by routine procedures and producing predictable results); In re Kulling, 897 F.2d 1147, 1149, 14 USPQ2d 1056, 1058 (Fed. Cir. 1990)(Claimed amount of wash solution was found to be unpatentable as a matter of routine optimization in the pertinent art, further supported by the prior art disclosure of the need to avoid undue amounts of wash solution); and In re Geisler, 116 F.3d 1465, 1470, 43 USPQ2d 1362, 1366 (Fed. Cir. 1997)(Claims were unpatentable because appellants failed to submit evidence of criticality to demonstrate that that the wear resistance of the protective layer in the claimed thickness range of 50-100 Angstroms was “unexpectedly good”); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree “will not sustain a patent”); In re Williams, 36 F.2d 436, 438, 4 USPQ 237 (CCPA 1929) (“It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions.”). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416, 82 USPQ2d 1385, 1395 (2007) (identifying “the need for caution in granting a patent based on the combination of elements found in the prior art.”).
In this case, in view of the teaching of the elements generally in the prior art one of ordinary skill in the art would have combined the elements taught by the prior art through routine optimization of the formulation and arrive at the claimed invention with a reasonable expectation of success.
Regarding claim 33, Kajino teaches formulation for injection.
Regarding claims 34-35, Kajino teaches the liquid preparation comprising the elements and is silent regarding the reaction product and the claimed “at not more than” amount. Almirall, LLC v. Amneal Pharm., 28 F.4th 265, 273 (Fed. Cir. 2022) (“"[A] reference need not state a feature's absence in order to disclose a negative limitation." AC Techs., S.A. v. Amazon.com, Inc. , 912 F.3d 1358, 1367 (Fed. Cir. 2019).”).
Regarding claim 36, the Kajino compound is nonpeptidic.
Regarding claim 37-38, the Kajino compound is within the scope of formula (I) and (II).
Regarding claim 39-40, the Kajino compound is listed in the claim, 1-{5-(2-fluorophenyl)-1-[(6-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine.
Regarding claims 41-42, Kajino teaches maleic acid within the scope of the claims.
Regarding claims 43-46, Kajino teaches sodium chloride within the scope of the claims.
Regarding claims 47-48, Kajino teaches the formulation is for injection which one of ordinary skill in the art would know to adjust to an appropriate pH within the scope of the claims.
Regarding claim 49, Kajino teaches the maleic acid salt which of the compound which would be within the scope of the claims.
Regarding claim 50, Kajino teaches administration for therapeutic effect which one of ordinary skill in the art would know the concentration is a results effective variable and optimize within the scope of the claims.
Regarding claim 51, Kajino teaches the compound is a proton pump inhibitor useful for gastric hyperacidity and acute stress ulcer (p. 6).
Regarding claims 52, Kajino teaches the liquid preparation comprising the elements of claim 32 and is silent regarding the reaction product. Almirall, LLC v. Amneal Pharm., 28 F.4th 265, 273 (Fed. Cir. 2022) (“"[A] reference need not state a feature's absence in order to disclose a negative limitation." AC Techs., S.A. v. Amazon.com, Inc. , 912 F.3d 1358, 1367 (Fed. Cir. 2019).”).
Remington is a reference text well-known to those of ordinary skill in the art and teaches that injected solutions should be isotonic and having 0.90 g sodium chloride in 100 mL (0.9 % w/v or 154 mmol/L (0.9 g/100mL / 58.44 g/mol * 1000 mmol/mol * 1000 mL/L)) (Remington pages 224-225, 250-252, 254: “When formulating parenterals, solutions otherwise hypotonic usually have their tonicity adjusted by the addition of dextrose or sodium chloride”; 802-805: Parenteral Preparations). Thus, suggesting to one of ordinary skill in the art the requirement for an injected formulation to be isotonic with sodium chloride at 154 mmol/L as in the claimed range.
Carstensen is a reference text well-known to those of ordinary skill in the art and teaches principles and practices for optimizing drug stability (Title & Contents). Carstensen teaches the importance of pH and Ionic Strength (sodium chloride – “NaCl for instance”) in optimization of drug stability in formulation (p. 58):
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Thus, Carstensen states that drug formulation in solution “must also address” pH and ionic strength effects.
The difference Kajino and the claims is the specific formulation. However, one of ordinary skill in the art of pharmaceutical formulation frequently optimizes salt, pH, and dosage for each pharmaceutical application and is explicitly taught by well-known texts of Remington and Carstensen (i.e. Remington p. 225: “it is desirable that solutions to be injected into the blood should be made isotonic”; p. 254: “parenterals, solutions otherwise hypotonic usually have their tonicity adjusted by the addition of dextrose or sodium chloride”; p. 229: “use of buffers to improve solubility is to create and maintain pH conditions”; p. 278: “Selection of Optimum pH, Buffer, and Solvent”, “Stability Testing of Pharmaceutical Products”) (Carstensen p. 58: “One of the tasks of stability scientists, particularly in the preformulation stage, is to establish the effect of pH on the stability of the drug”). One of ordinary skill in the art would consider routine and well within their technical grasp the process of testing a range of isotonizing salts, pH, and dosage to determine the optimum for formulation for injection and improve stability of the formulation. In addition, those of ordinary skill in the art would first look to known viable formulations in the art that share structural elements with the object of their endeavor.
Thus, Kajino discloses each and every feature including: the elected species (Example 8 on page 163 = fumarate salt), a liquid preparation (p. 47, l. 9-19) that is “injectable” prepared “in accordance with a commonly known method” (p. 53, l. 10-14), with isotonizing agents and buffers for liquid preparations (p. 47, l. 29-30) which includes sodium chloride (p. 49, l. 33). Kajino teaches the compound formulated in solution with sodium chloride and one of ordinary skill in the art following commonly known methods of formulation would readily arrive at the claimed invention including appropriate molar ratios.
Regarding purity limitations, one of ordinary skill in the art would have reasonably considered minimizing impurities in formulation as is routine in the art and arrive at the claimed invention. Regarding pH limitations, one of ordinary skill in the art would have reasonably considered optimizing the formulation for stability as well as parenteral formulation as is routine in the art and arrive at the claimed invention, particularly in view of the teaching of Remington. Regarding the intended use language such as “an agent for the prophylaxis or treatment of gastric ulcer …”, Kajino teaches such a utility as a proton pump inhibitor. Regarding the molar ratio language, Kajino teaches a fumarate salt of the compound which one of ordinary skill in the art would have considered and arrive at the claimed invention.
With each of the claims, the level of skill in the art is very high such that one of ordinary skill in the art would consider routine the combination of elements from the teaching of the art. One of ordinary skill in the art would have recognized that the results of the combination would be predictable due to the well-known nature and optimizations routinely performed in the art. Thus, one of ordinary skill in the art would have arrived at the invention as claimed with a reasonable expectation of success and the claims are prima facie obvious.
Considering the effects of NaCl (sodium chloride) suppressing reaction products as shown in Table 22 of the specification. The well-known text of Remington teaches that injected solutions should be isotonic and having 0.90 g sodium chloride in 100 mL (0.9 % w/v or 154 mmol/L (0.9 g/100mL / 58.44 g/mol * 1000 mmol/mol * 1000 mL/L)) (Remington pages 224-225, 250-252, 254: “When formulating parenterals, solutions otherwise hypotonic usually have their tonicity adjusted by the addition of dextrose or sodium chloride”; 802-805: Parenteral Preparations). Thus, suggesting to one of ordinary skill in the art the requirement for an injected formulation to be isotonic with sodium chloride at 154 mmol/L as in the claimed range. Similarly, Carstensen teaches that drug formulation in solution “must also address” pH and ionic strength effects in any consideration of drug stability (Carstensen page 104: “the presence of an ionic substance may affect the kinetics of decomposition”). Futhermore, Kajino teaches intravenous administration with isotonizing agents (p. 47) and specifically teaches the formulation with sodium chloride (p. 49):
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In this case one of ordinary skill in the art would consider a formulation with sodium chloride and improve the formulation for use as an IV composition and added stability, there was a reasonable expectation that formulating with sodium chloride would be successful.
Ordinary skill in the art would have known that salt affects stability of such a formulation as specifically taught by Carstensen (page 104: “the presence of an ionic substance may affect the kinetics of decomposition”) and be motivated to optimize the composition for stability or simply for formulation for injection (Remington: injected solutions should be isotonic and having 0.90 g sodium chloride in 100 mL (0.9 % w/v or 154 mmol/L)). As stated in MPEP 2144 IV:
The reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006) (motivation question arises in the context of the general problem confronting the inventor rather than the specific problem solved by the invention); Cross Med. Prods., Inc. v. Medtronic Sofamor Danek, Inc., 424 F.3d 1293, 1323, 76 USPQ2d 1662, 1685 (Fed. Cir. 2005) ("One of ordinary skill in the art need not see the identical problem addressed in a prior art reference to be motivated to apply its teachings."); In re Lintner, 458 F.2d 1013, 173 USPQ 560 (CCPA 1972) (discussed below); In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990), cert. denied, 500 U.S. 904 (1991).
Thus, it is not necessary that one of ordinary skill identify the same advantage as applicant and one of ordinary skill in the art would have had an expectation that pharmaceutical stability is affected by the salt content.
Close examination of Table 22 shows differences when salt is present in the formulation in amounts similar to that taught by the prior art and otherwise narrow ranges when compared to the full scope of the claim – i.e. any amount. Thus, even if there was any unexpected result, it is not commensurate in scope with the claims. Thus, the data presented in Table 22 show small changes in the amount of reaction product which is unclear what would be unexpected in view of the prior arts teaching of formulating with sodium chloride. Thus, weighing all of the relevant evidence of record results in the conclusion that based on a preponderance of the evidence the claims are obvious. This conclusion is reached by considering the well-known use of sodium chloride in pharmaceutical formulations, including for injection, Kajino’s specific teaching to use sodium chloride for formulating injection composition, Remington’s teaching of the requirement of isotonizing solutions for injection, and Carstensen teaching of optimizing formulations for stability in contrast to the data of Table 22 and as argued by Applicant. Thus, in considering all of the evidence, the claims are rejected as obvious
Conclusion
The claims are not in condition for allowance.
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/ROBERT H HAVLIN/Primary Examiner, Art Unit 1626