Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Status of claims
The amendment filed on June 16, 2025 is acknowledged. Claims 2-3 have been canceled and new claim 18 has been added. Claims 1 and 4-18 are under examination in the instant office action.
Applicants' arguments, filed on June 16, 2025, have been fully considered but they are not deemed to be persuasive. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application. Responses are limited to Applicants' arguments relevant to either reiterated or newly applied rejections.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 4-10 and 12-18 are rejected under 35 U.S.C. 103 as being unpatentable over US 2014/0235666 (hereafter, DAHLSTROM; cited in the IDS filed on 5/17/2023) in view of US 2008/0280944 (hereafter, Fernstrom) and US 2002/0064555 (hereafter, Cullen).
DAHLSTROM discloses a novel imidazopyridine derivative of the following structure:
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as inhibitors of gastric acid secretion ([0012], [0055], claim 11)). The compound is also known as X842 as evidenced by the specification (p1, lines 10-11).
DAHLSTROM further discloses the compound (X842) as a prodrug of linaprazan (
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) ([0023] and [0031]).
DAHLSTROM teaches that the compound is formulated in the form of dosage unit for oral administration, wherein the compound is mixed with solid, powdered ingredients known in the art, such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatine, or another suitable ingredient, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes ([0038]). DAHLSTROM further discloses that the mixture is then processed into granules or pressed into tablets using any suitable method known in the art ([0038]).
In addition, DAHLSTROM teaches the use of the compounds for treatment and/or prevention of gastric acid related diseases, gastrointestinal inflammatory diseases, heartburn, symptomatic GERD, erosive esophagitis, peptic ulcer disease, regurgitation, acid reflux diseases or nausea in human or nonhuman mammal ([0053] and claim 9-11).
DAHLSTROM does not specifically disclose an immediate release oral formulation comprising a surfactant such as sodium lauryl sulfate. Also, DAHLSTROM does not specifically disclose specific filler such as lactose monohydrate, a disintegrant such as croscarmellose, and glidant.
However, it was known in the art to prepare an immediate release oral formulation for linaprazan, which is the active metabolite of X842, and to use surfactants for such formulation as evidenced by Fernstrom cited below. Also, it was well known in the art of pharmaceutical formulations that immediate release formulations require that a drug dissolves rapidly and that surfactants are commonly employed in pharmaceutical compositions to increase the dissolution of active agents.
Fernstrom discloses an immediate-release pharmaceutical formulation comprising: an active ingredient such as linaprazan (2,3-dimethyl-8-(2,6-dimethylbenzylamino)-N-hydroxyethyl-imidazo[1,2-a]pyridine-6-carboxamide, and a pharmaceutically-acceptable diluent or carrier ([0047], [0077] , [0078], and [0079]). Fernstrom further discloses that immediate release may be provided for by way of an appropriate pharmaceutically-acceptable diluent (filler) or carrier, which diluent (filler) or carrier does not prolong, to an appreciable extent, the onset and/or rate of drug release/absorption ([0080]). Fernstrom further discloses that immediate-release formulations may release at least 70% (e.g., 80%) of active ingredient within 4 hours, such as within 3 hours, preferably 2 hours, more preferably within 1.5 hours, and especially within an hour (such as within 30 minutes) of administration ([0082]).
Fernstrom discloses that the immediate release formulation further comprises surfactants ([0088]). Fernstrom further discloses that the amount of additional excipients in such an oral formulation of the invention also depends upon factors, such as the nature and amount of the active ingredient that is employed, as well as the nature, and amounts, of any other constituents (e.g. diluents/carriers and/or other further excipients) that are present in the formulation, but, for lubricants and glidants is typically up to 5% (w/w), and for binders and disintegrants is typically up to 10% (w/w) of the final composition ([0098]).
Cullen describes a dosage form comprising a proton pump inhibitor such as omeprazole and lansoprazole), which is used for treating gastrointestinal conditions such as gastric and duodenal ulcers and gastroesophageal reflux disease (abstract and [0003]). Cullen discloses formulations which include sodium lauryl (dodesyl) sulfate as a surfactant, lactose monohydrate as filler, and sodium croscarmellose as disintegrant ([0014], [0038], and [0046]). Sodium dodecyl sulfate is present in an amount of about 12 wt% relative to the amount of the active agent in the exemplary compositions ([0038] and [0044]).
It would have been prima facie obvious to one of ordinary skill in the art to prepare an immediate release oral formulation comprising a linaprazan prodrug (X842) just like its active compound (linaprazan) using known excipients such as surfactant, filler, disintegrant, lubricant, and glidant as taught by Fernstrom and Cullen because of the following reasons. DAHLSTROM already teaches and suggests the use of one or more excipients such as diluent (filler), disintegrant and lubricant for oral formulation comprising linaprazan prodrug (X842). Also, Fernstrom teaches and suggest the use of excipients suitable for providing immediate release, including filler, surfactant, lubricants and glidants. In addition, it was well-known in the art that sodium dodecyl (lauryl) sulfate, lactose monohydrate, and croscarmellose sodium are suitable anionic surfactant, filler, and disintegrant, respectively for oral dosage forms comprising proton pump inhibitors as active agent as evidenced by Cullen. Thus, the skilled artisan would have been motivated to use such known surfactant, filler, and disintegrant for oral formulation of the linaprazan prodrug (X842) on the reasonable expectation that they would provide their known individual functions for preparing the oral formulation comprising X842. Generally, it is prima facie obvious to select a known material for incorporation into a composition based on its recognized suitability for its intended use. See MPEP 2144.07.
As to the concentrations of surfactant recited in claims 1 and 4 and new claim 18, it would have been obvious to one of ordinary skill in the art to determine suitable amount of the surfactant for preparing immediate formulations through routine or manipulative experimentation to obtain desired dissolution profile based on the overlapping ranges disclosed in Cullen and Fernstrom. And, in the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). The amount of a surfactant in this composition is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Thus, absent some demonstration of unexpected results from the claimed parameters, the optimization of the known surfactant concentration would have been obvious. Thus, the recitation of the concentration range of surfactant does not make the claims non-obvious since the references in combination already disclose the claimed surfactant and teach that immediate release dosage forms are prepared according to the known pharmaceutical technique with excipients such as sodium lauryl sulfate, filler, disintegrant, lubricant and glidant suitable for such pharmaceutical forms.
As to claims 12-15, DAHLSTROM is silent about the pharmacokinetic property such as dissolution profile and Cmin of linaprazan, which are intended results of the claimed formulation. However, the references in combination teach, suggest and motivate the same composition comprising the same components as the instant invention, thus such pharmacokinetic property is necessarily present in the resulting composition. “Products of identical chemical composition cannot have mutually exclusive properties.” A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir.1990). In the alternative, Fernstrom discloses dissolution profile of immediate release formulation of linaprazan, which encompasses those claimed. Thus, it would have been prima facie obvious to prepare an oral formulation of X842 for immediate release, which could provide similar dissolution profile with those taught by Fernstrom.
Claims 11 is rejected under 35 U.S.C. 103 as being unpatentable over US 2014/023566 (hereafter, DAHLSTROM) in view of US 2008/0280944 (hereafter, Fernstrom) and US 2002/0064555 (hereafter, Cullen) in further view of Dukic´-Ott et al. (European Journal of Pharmaceutics and Biopharmaceutics 67: 715–724, 2007).
The teachings of DAHLSTROM, Fernstrom and Cullen as applied supra are herein applied for the same teachings in their entirety.
The references do not teach that the formulation does not include microcrystalline cellulose (MCC).
However, it was known in the art that MCC-based pellets do not disintegrate and drug release occurs via diffusion through an insoluble inert matrix as evidenced by Dukic´-Ott et al. (p715, col 2, para 2). Dukic´-Ott et al. further teach that lack of disintegration of MCC-based pellets becomes very critical if an active component has poor solubility in water, since the drug release is prolonged (p719, col 1, para 1). Also, Fernstrom teaches and suggests the use of an appropriate pharmaceutically-acceptable diluent (filler) or carrier for providing immediate release. Thus, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention not to add MCC as filler to the immediate release oral formulation comprising a linaprazan prodrug (X842) because it would delay the release of the drug as evidenced by Dukic´-Ott et al.
Response to Applicant’s arguments
Applicant argued that the inventor had unexpectedly found that the combination of sodium dodecyl sulfate in an amount of 8.0 to 12% by weight relative to the amount of X842 results in good solubility of the X842 formulation. Applicant stated that the effect of X842 is to increase the pH value in the stomach (such as to pH 4 or higher), allowing for treatment of gastrointestinal inflammatory diseases or gastric acid related diseases, such as severe erosive gastroesophageal reflux disease (eGERD) and at the same time, X842 has a lower solubility at a higher pH, as shown in the specification on page 1, lines 20-28. Applicant further stated that this means that oral administration of a first dose of X842 has a negative impact on the solubility of subsequent doses of X842 by worsening the solubility conditions (i.e., increasing the pH) and it is therefore necessary to improve the solubility of the compound at the pH that is maintained during treatment (e.g., pH 4 or higher).
Applicant further argued that none of the cited references, alone or in combination, render amended claim 1 obvious: 1) US ‘666 discloses imidazopyridine derivatives, including the compound corresponding to X842. Sodium dodecyl sulfate, however, is not mentioned in US ‘666. Applicant further stated that claim 1 as amended differs from the disclosure of US ‘666 by (1) reciting SDS (ii) in a very specific amount, namely 8.0 to 12.0% by weight relative to the amount of X842, in (iii) an immediate release formulation. Also, Applicant argued that the skilled person would not consult US’555 for at least the following reasons: US ’555 discloses a delayed release capsule dosage form, as opposed to the claimed immediate release formulation and additionally, the benzimidazole compounds of US ‘555, such as omeprazole and lansoprazole, are proton pump inhibitors.
In response to applicant's arguments against the references individually, 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). It is important to note that in an obvious rejection, it is not necessary that one reference addresses any limitation in a particular claim but that the references, when combined, do so. The Courts have made clear that the teaching, suggestion, or motivation test is flexible and an explicit suggestion to combine the prior art is not necessary. The motivation to combine may be implicit and may be found in the knowledge of one of ordinary skill in the art, or, in some cases, from the nature of the problem to be solved. Id. at 1366, 80 USPQ2d at 1649. “[A]n implicit motivation to combine exists not only when a suggestion may be gleaned from the prior art as a whole, but when the improvement’ is technology-independent and the combination of references results in a product or process that is more desirable, for example because it is stronger, cheaper, cleaner, faster, lighter, smaller, more durable, or more efficient. Because the desire to enhance commercial opportunities by improving a product or process is universal-and even common-sensical-we have held that there exists in these situations a motivation to combine prior art references even absent any hint of suggestion in the references themselves. In such situations, the proper question is whether the ordinary artisan possesses knowledge and skills rendering him capable of combining the prior art references.” Id. at 1368, 80 USPQ2d at 1651.
In this case, while US‘666 (DAHLSTROM) does not specifically disclose the use of surfactant such as SDS for a formulation comprising X842, US‘666 reference teaches and suggests the use of one or more excipients such as diluent (filler), disintegrant and lubricant for oral formulation comprising linaprazan prodrug (X842). Also, it was known in the art to use an immediate release formulation for linaprazan, which is active metabolite of the claimed compound, for the same use (i.e., inhibiting gastric acid secretion) as evidenced by US ‘944 reference (Fernstrom). US‘944 reference further teaches and suggest the use of excipients suitable for providing immediate release, including surfactant, filler, lubricants and glidants. Thus, it would have been prima facie to one of ordinary skill in the art to prepare the prodrug of linaprazan (i.e., X842) in a similar immediate release formulation including surfactant with that of linaprazan for the treatment of the same condition. US ‘555 (Cullen) was cited for showing that it was well known in the art that sodium dodecyl (lauryl) sulfate, lactose monohydrate, and croscarmellose sodium are suitable anionic surfactant, filler, and disintegrant, respectively for oral dosage forms used for the same use (i.e., inhibiting gastric acid secretion). Especially, surfactant is a well-known excipient, which is used for increasing the solubility of insoluble compounds. As such, the claimed excipients are well known and commonly used for preparing immediate release formulation for the same indication and those excipients are used for their established functions in the immediate formulation and one of ordinary skill in the art would have reasonable expectation that adding those excipients in the amounts as claimed would provide a suitable immediate formulation by performing their established functions. When considering obviousness of a combination of known elements, the operative question is thus “whether the improvement is more than the predictable use of prior art elements according to their established functions.” Id. In this regard, there is no evidence that the claimed combination is more than the predictable use of prior art elements according to their established functions.
As to the argument that Applicant unexpectedly found that the combination of sodium dodecyl sulfate in an amount of 8.0 to 12% by weight relative to the amount of X842 results in good solubility of the X842 formulation, improving solubility of a drug is well known function of a surfactant such as SDS. Thus, it would not be unexpected result. It is noted that it is applicant's burden to demonstrate unexpected results over the prior art. See MPEP 716.02, also 716.02 (a) - (g). Furthermore, the unexpected results should be demonstrated with evidence 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). Moreover, evidence as to any unexpected benefits must be "clear and convincing" In re Lohr, 137 USPQ 548 (CCPA 1963), and be of a scope reasonably commensurate with the scope of the subject matter claimed, In re Linder, 173 USPQ 356 (CCPA 1972).
In addition, mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention. In re Wiseman, 596 F.2d 1019, 201 USPQ 658 (CCPA 1979) (Claims were directed to grooved carbon disc brakes wherein the grooves were provided to vent steam or vapor during a braking action. A prior art reference taught noncarbon disc brakes which were grooved for the purpose of cooling the faces of the braking members and eliminating dust. The court held the prior art references when combined would overcome the problems of dust and overheating solved by the prior art and would inherently overcome the steam or vapor cause of the problem relied upon for patentability by applicants. Granting a patent on the discovery of an unknown but inherent function (here venting steam or vapor) “would remove from the public that which is in the public domain by virtue of its inclusion in, or obviousness from, the prior art.” 596 F.2d at 1022, 201 USPQ at 661.); In re Baxter Travenol Labs., 952 F.2d 388, 21 USPQ2d 1281 (Fed. Cir. 1991) (Appellant argued that the presence of DEHP as the plasticizer in a blood collection bag unexpectedly suppressed hemolysis and therefore rebutted any prima facie showing of obviousness, however the closest prior art utilizing a DEHP plasticized blood collection bag inherently achieved same result, although this fact was unknown in the prior art.).“The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.” Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985) (The prior art taught combustion fluid analyzers which used labyrinth heaters to maintain the samples at a uniform temperature. Although appellant showed an unexpectedly shorter response time was obtained when a labyrinth heater was employed, the Board held this advantage would flow naturally from following the suggestion of the prior art.). See also Lantech Inc. v. Kaufman Co. of Ohio Inc., 878 F.2d 1446, 12 USPQ2d 1076, 1077 (Fed. Cir. 1989), cert. denied, 493 U.S. 1058 (1990) (unpublished — not citable as precedent) (“The recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention.”). In re Lintner, 458 F.2d 1013, 173 USPQ 560 (CCPA 1972) and In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990) discussed in MPEP § 2144 are also pertinent to this issue. In this case, such improvement of solubility would be inherent function of the surfactant and would flow naturally from following the suggestion of the prior art in combination.
As to the amounts of SDS, while US‘666 does not explicitly teach the claimed ranges, it is the position of the Examiner that it would have been obvious to one of ordinary skill in the art to determine suitable amounts of a known excipient such as SDS for preparing pharmaceutical formulations through routine or manipulative experimentation to obtain the best possible results, as these are variable parameters attainable within the art. The amount of a specific excipient in this composition is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. In addition, Cullen and Fernstrom disclose the overlapping ranges. Thus, absent some demonstration of unexpected results from the claimed parameters, the optimization of the amounts of known excipients would have been obvious at the time of applicant's invention.
For the foregoing reasons, Applicants' arguments have not been found to be persuasive.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 date of this final action.
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/BONG-SOOK BAEK/Primary Examiner, Art Unit 1611
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