DETAILED ACTION
The present application is being examined under the pre-AIA first to invent provisions.
Request for Continued Examination (RCE)
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 12/8/2025 has been entered.
Status
The claims presented 5/23/2023 are under consideration wherein no claim amendments were made. Claims 2-4, 9-11, 15, 21-26, 28 and 30-31, 34, 37 are currently pending. Claims 9, 25, 26, 28, 30 are withdrawn.
Priority
This application is a 371 of PCT/JP2013/068192 (06/26/2013) and claims foreign priority to JAPAN 2012-144750 (06/27/2012).
Election/Restrictions
Applicant previously elected with traverse Group I (claims 1-8, 10-24, 27, 29, and 31) in the reply filed on 1/29/16. Applicant also elected the species of Example 14 comprising a fumarate of
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and sodium chloride as a salt, stated as reading on claims 1-8, 10-24, 27, 29, and 31. Now reading on pending claims 2-4, 10-11, 15, 21-24, 31, 34, 37.
As detailed in the following rejections, the generic claim encompassing the elected species was not found patentable. Therefore, the provisional election of species is given effect, the examination is restricted to the elected species only, and claims not reading on the elected species are held withdrawn. MPEP 803.02; Ex parte Ohsaka, 2 USPQ2d 1460, 1461 (Bd. Pat. App. lnt. 1987).
Should applicant, in response to this rejection of the Markush-type claim, overcome the rejection through amendment, the amended Markush-type claim will be reexamined to the extent necessary to determine patentability of the Markush-type claim. See MPEP 803.02.
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 2-4, 10, 11, 15, 21-24, 31, 34, 37 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 provided).
The instant claims read on the elected species of:
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, fumarate, and sodium chloride a product by process formulated as a liquid for injection having certain purity levels after time.
Kajino teaches the following compound (the same as the elected species) of
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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 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 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).
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.
Response to Remarks - 35 USC § 103
Applicant reiterates the argument that an unexpected result of NaCl (sodium chloride) suppressing reaction products is shown in Table 22 and now also points to Table 9 as supporting the full scope of the claims. The argument is essentially that one of ordinary skill in the art could not have predicted whether or not NaCl would contribute to stabilization of API preparations and cited to five references. None of the references cited and considered by the examiner establish that the use of NaCl generally unpredictably affects stabilization. In contrast, 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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MPEP 2145 states (citation added):
Absolute predictability is not a necessary prerequisite to a case of obviousness. Rather, a degree of predictability that one of ordinary skill would have found to be reasonable is sufficient. The Federal Circuit concluded that “[g]ood science and useful contributions do not necessarily result in patentability.” PharmaStem Therapeutics, Inc. v. Viacell, Inc., 491 F.3d 1342, 1364, 83 USPQ2d 1289, 1304 (Fed. Cir. 2007).
Thus, in this case although it may not have been absolutely predictable that a formulation with sodium chloride would be successful 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.
Applicant’s argument is also not persuasive because one of 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.
Regarding the proffered in support of an unexpected result, MPEP 2145 also states the requirement of a nexus:
Office personnel should avoid giving no weight to evidence submitted by applicant, except in rare circumstances. However, to be entitled to substantial weight, the applicant should establish a nexus between the rebuttal evidence and the claimed invention, i.e., objective evidence of nonobviousness must be attributable to the claimed invention.
…
In other words, in order for evidence of secondary considerations to be accorded substantial weight, there must be a nexus, i.e., a legally and factually sufficient connection or correspondence between the submitted evidence and the claimed invention.
And that it is Applicant’s burden to establish that the results are both statistically and practically significant – MPEP 716.02(b):
The evidence relied upon should establish “that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance.” Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992) (Mere conclusions in appellants’ brief that the claimed polymer had an unexpectedly increased impact strength “are not entitled to the weight of conclusions accompanying the evidence, either in the specification or in a declaration.”); Ex parte C, 27 USPQ2d 1492 (Bd. Pat. App. & Inter. 1992) (Applicant alleged unexpected results with regard to the claimed soybean plant, however there was no basis for judging the practical significance of data with regard to maturity date, flowering date, flower color, or height of the plant.). See also In re Nolan, 553 F.2d 1261, 1267, 193 USPQ 641, 645 (CCPA 1977) and In re Eli Lilly, 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) as discussed in MPEP § 716.02(c).
Consideration of the evidence of record including that of Table 22 and Table 9, shows that there is change from 0.10% to 0.14% without NaCl as measured by comparing integration of the HPLC curves (Comp. Ex. 2 in Table 9) a delta of +0.04%. Similarly, in Table 22, 0.13% to 0.25% (Comp. Ex. 1 in Table 22). Thus numerically, the delta number appears smaller when NaCl is present – i.e., in Ex. 6 (Table 9). However, the significance of these very small numbers measured from integrations of an HPLC curve where the main peak is more than 3 orders of magnitude larger is not clear from the description in the specification and there is no error analysis presented. Of significance is the fact that in Table 9, Ex. 9 shows a change from 0.11% to 0.10% or a delta of -0.01% which is a result that is more likely than not in indication of there being a lack of statistical significance in the very small numbers being compared in the tables.
Tables 9 and 22 shows differences when salt is present in the formulation vs. no salt:
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Thus, even if there was an alleged unexpected result, Applicant has not met their burden establishing how it is of a statistical and practical significance. Evaluating the statistical and practical significance of the data proffered shows that there is insufficient details to allow for a conclusion regarding the statistical significance of the data – for example what error analysis was performed on the reported results given these are very small differences of large numbers (~0.1%). The data presented in Tables 9 and 22 show small changes and in some cases are inconsistent (Ex. 9) in the amount of reaction product and thus it is unclear whether the results are statistically insignificant measurement errors.
Furthermore, the claims are to a variety of compounds of the claims, various concentration ranges, and pH values possible whereas the alleged unexpected result of the Tables are all very similar and limited in scope, for example, compound A, pH 3.6 or 4.0, and approximately the same concentration ~1.3 mg/mL
Applicant also points to WO2010013823 as establishing that improving stability by formulating with sodium chloride would have been difficult to conceive. This argument is not persuasive because formulation with sodium chloride was well-known and one of ordinary skill in the art optimizing the formulation with such an ingredient would have been considered routine. Furthermore, WO2010013823 specifically teaches the use of sodium chloride as an isotonicity agent just as in Kajino. Therefore, one of ordinary skill in the art would have conceived of the claimed invention because it was specifically suggested by the prior art.
To reiterate, Kajino teaches the same compound as in the instant claims and generically formulated in a manner (injectable with isotonizing agents including sodium chloride) that is identical to the claimed invention as evidenced by Remington (154 mmol/L sodium chloride). Kajino does not specifically teach the alleged unexpected result of stability due to sodium chloride, however, this was generally known in the art as an important factor as evidenced by Carstensen. Applicant’s alleged unexpected result does not have a clear statistical significance and is within what one of skill in the art would expect.
Regarding evaluating the alleged unexpected results, MPEP 2145 states:
Evidence pertaining to secondary considerations must be taken into account whenever it has been properly presented; however, it does not necessarily control the obviousness conclusion. See, e.g., Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1372, 82 USPQ2d 1321, 1339 (Fed. Cir. 2007) (“the record establish[ed] such a strong case of obviousness” that allegedly unexpectedly superior results were ultimately insufficient to overcome obviousness conclusion); Leapfrog Enterprises Inc. v. Fisher-Price Inc., 485 F.3d 1157, 1162, 82 USPQ2d 1687, 1692 (Fed. Cir. 2007) (“given the strength of the prima facie obviousness showing, the evidence on secondary considerations was inadequate to overcome a final conclusion” of obviousness); and Newell Cos., Inc. v. Kenney Mfg. Co., 864 F.2d 757, 768, 9 USPQ2d 1417, 1426 (Fed. Cir. 1988). Office personnel should not evaluate rebuttal evidence for its “knockdown” value against the prima facie case, Piasecki, 745 F.2d at 1473, 223 USPQ at 788, or summarily dismiss it as not compelling or insufficient. Office personnel should weigh all relevant evidence of record in order to determine whether the claims would have been obvious based on a preponderance (more likely than not) standard, and then explain their conclusions. See MPEP § 716 - § 716.10 for additional information pertaining to the evaluation of rebuttal evidence submitted under 37 CFR 1.132.
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 Applicant’s arguments and all of the evidence of record.
Therefore, none of applicant’s arguments as to the nonobviousness of the claims are persuasive and the rejection is maintained.
Conclusion
The claims are not in condition for allowance.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ROBERT H HAVLIN whose telephone number is (571)272-9066. The examiner can normally be reached on 9am - 6pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Lundgren can be reached on (571) 272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ROBERT H HAVLIN/Primary Examiner, Art Unit 1626