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
Previous Rejections
Applicants' arguments, filed 09/15/25, have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.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.
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, 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 1-13 and 17-20 are rejected under 35 U.S.C. 103 as being unpatentable over Leigh et al. (WO 2007/054342A1) in view of Jogia et al. ("Evaluation of Dissolution Media Containing a Novel Synthetic Surfactant by In Vitro Testing of BCS Class II Drugs", DISSOLUTION TECHNOLOGIES, vol. 16, no. 3, 26 August 2009 (2009-08-26), pages 14-19, presented in IDS) and Arnot et al. (WO 2005/062041).
Leigh et al. discloses solid compositions or examining drug solubility comprising bile salts and phospholipids, optionally containing buffer components suitable for preparation of intestinal media that simulate the composition of the intestinal fluids in fasted and fed states, see abstract. The reference teaches use of buffering agent and osmotically active agent, lines 20-25 on page 4. Method for preparing gastrointestinal media is taught on page 7, lines 15-25. Leigh et al. discloses a biorelevant dissolution medium resembling gastrointestinal fluid comprising: a micellar solution comprising a bile salt (sodium taurocholate), a surfactant (phospholipid), and buffer components and an osmotic agent; wherein the bile salt and the phospholipid have a mole ratio between about 1:1 and 10:1, (see page 4, line 26, page 5, line 4, pages 7-12 and page 13, lines 26-30). Use of buffers and osmoregulators such as bicarbonates, HCl, NaOH, phosphate, citrate salts and KCl to adjust pH and osmolality are taught on page 14, lines 21-31. Since the reference teaches generic molar amounts, it would be within skill of an artisan to manipulate the molar amounts and ratio to make a dissolution medium for poorly soluble or sparingly soluble drugs.
Leigh et al. does not teach use of phosphonocholic acid salt and polysorbate in the dissolution medium.
Jogia et al. discloses the use of "synthetic surfactant that has structural similarity to bile acids" , see pages 14-17. The objective of Jogia study was to employ a tailor-made, surface-active agent (phosphonobile acid) in the design of dissolution media that more closely reflect various luminal fluid physicochemical parameters such as buffer capacity, osmolarity, surface tension, and ph. According to Jogia, the proposed media are simple to prepare and use, and thus can be explored for routine application. Three BCS H drugs, glimepiride dipyridamole, and ibuprofen, were selected for the study in vitro dissolution profiles obtained with the proposed media were compared with profiles obtained in FaSSIF and FeSSIF media using the f2 similarity factor. Dissolution in the proposed media correlate well with the dissolution obtained in FaSSIF and FeSSIF media, see abstract.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have utilized phosphonocholic acid in place of bile salt, sodium taurocholate in the dissolution medium of Leigh et al. for having structural similarity to bile salts motivated by the teachings of Jogia et al.
Arnot et al. teaches use of polysorbates as surfactants, see (page 5, lines 4-7). Typical pH ranges from 4 to 8 or 6 to 8 of the dissolution media, see page 2, lines 24-25 and page 8, lines 3-10. Use of water for making dissolution media is taught on page 8, lines 28-30.
It would have been obvious to one of ordinary skill before the effective filing date of the claimed invention to have replaced one surfactant with another such as phospholipid with polysorbate for the known surfactant properties absent indication of unexpected results with the specific one claimed.
Applicant argues that those of ordinary skill had believed that the use bile acids and lipophilic surfactant was crucial to forming the mixed micelles which mimic in vivo characteristics, and the type of substitutions that the Examiner proposes would not produce useful formulations. As Applicants note in the instant specification, it had been known in the art to use biorelevant media contain natural bile acids as a primary surfactant along with natural lecithin as a secondary lipophilic surfactant to produce mixed micelles that are capable of solubilizing poorly water-soluble drugs in a manner resembling gastrointestinal fluids. According to Applicant, the instant specification, it had been known in the art to use biorelevant media contain natural bile acids as a primary surfactant along with natural lecithin as a secondary lipophilic surfactant to produce mixed micelles that are capable of solubilizing poorly water-soluble drugs in a manner resembling gastrointestinal fluids. According to Applicant, Those working in this field, however, had found that replacing lecithin with synthetic surfactants such as sodium lauryl sulfate (SLS) and polysorbates did not produce such micelles. Additionally, dissolution media comprising a phosphonocholic acid but no hydrophobic component such as lecithin had been found to not adequately mimic human intestinal fluid at least in that it could underestimate or overestimate in vivo dissolution, especially of poorly water-soluble drugs. In other words, those of ordinary skill in the art understood that replacing the two components of previously known biorelevant medium or using them individually did not provide the desired result.
Applicant’s arguments are fully considered but is not persuasive. Leigh et al. observed the drawback of the known previous methods to form biorelevant medium such as Coalescence of the dispersed globules in a binary emulsion system as the solvent is removed may result in a heterogeneous population of micelles and mixed micelles. Partitioned solvent between the resultant lipid micelles and mixed micelles and external aqueous phase is not easy to remove entirely. Residual solvent may affect solubility and dissolution profiling of lipophilic compounds which are poorly water soluble. For reproducible data, FaSSIF and FeS-SIF media and similar solutions which contain bile salts and phospholipids, as suggested in "Advanced Drug Delivery Reviews 50 (2001), pages 127-147", may not have sufficient shelf-life for storage and off-the-shelf use due to micelle aggregation, lipid oxidation, hydrolysis and microbial contamination, see page 2, first paragraph. In order to overcome such drawbacks, Leigh et al. teach a biorelevant dissolution medium resembling gastrointestinal fluid comprising: a micellar solution comprising a bile salt (sodium taurocholate), a surfactant (phospholipid), and buffer components and an osmotic agent; wherein the bile salt and the phospholipid have a mole ratio between about 1:1 and 10:1, (see page 4, line 26, page 5, line 4 and pages 7-12 and page 13, lines 26-30). Leigh et al. disclose in the background section, that dissolution media which simulate gastrointestinal fluid may include surfactants and solubilizers such as sodium dodecyl sulphate (SDS) and non-ionic surfactants. They mimic sink conditions for determining the dissolution profiles of poorly soluble compounds and drug formulations and further state that more relevant solubilisers such as lecithin, lysolecithin, bile salts, mono glycerides, fatty acids and mixed micelles thereof have been proposed to better simulate the fasted and fed states, see background section. Therefore, it can be interpreted and is apparent from the disclosure of Leigh et al. that surfactants and solubilizers (mainly for the poorly soluble drugs) play a critical role in forming a simulated intestinal medium especially bile salt (a surfactant).
The objective of Jogia study was to employ a tailor-made, surface-active agent (phosphonobile acid) in the design of dissolution media that more closely reflect various luminal fluid physicochemical parameters such as buffer capacity, osmolarity, surface tension, and ph. According to Jogia, the proposed media are simple to prepare and use, and thus can be explored for routine application. Three BCS H drugs, glimepiride dipyridamole, and ibuprofen, were selected for the study in vitro dissolution profiles obtained with the proposed media were compared with profiles obtained in FaSSIF and FeSSIF media using the f2 similarity factor. Dissolution in the proposed media correlate well with the dissolution obtained in FaSSIF and FeSSIF media, see abstract. Thus, the reference teaches importance of surfactants such as phosphonobile which is close to the luminal fluid and can be prepared to show dissolution of poorly soluble drugs such as ibuprofen and glimepiride as discussed above. Also, Jogia teaches that water-insoluble drugs or sparingly soluble drugs are most likely to be solubilized in the presence of naturally occurring surfactant and miceller media of gastrointestinal tract. Buri etal. demonstrated the similarity of natural surfactants sodium cholate and taurocholate to sodium lauryl sulfate for the purposes of drug solubilization and these reports suggest the importance of surfactants for in-vitro dissolution studies, see Introduction section, second paragraph.
Jogia explicitly teaches that surfactants like SLS, such as Span and Tween were also tested. Jogia further teaches that may or may not exhibit VIVE (4) To the best of our knowledge, synthetic surfactants with structural similarity to bile acids have not been reported, in the present work, our primary aim was to select a synthetic surfactant that has structural similarity to bile acids. 24-Phosphonobile acid (24-PBS) was selected as a suitable candidate. The use of 24-PB5 as a cholesterol gallstone solubilizer and its route of synthesis have been reported. The selected synthetic surfactant was used to design dissolution media that simulate the physiological properties of the luminal fluids such as buffer capacity, pH, osmolarity, and surface tension, see second column of Jogia et al. (Thus, Jogia explicitly teaches similarity of 24-PB5 with bile acids which ais the same as taught by Leigh et al).
Therefore, due to the structural similarity with bile salts and due to the surfactant properties and dissolution characteristics of the phosphonocholic acid as taught by Jogia et al., it would have been obvious to one of ordinary skill to have utilized phosphonocholic acid in place of bile salt, sodium taurocholate in the dissolution medium of Leigh et al. and come to the claimed invention.
Jogia et al. also teach similarity of surfactant SLS with Span and Tween and which were also tested for dissolution. Additionally, Arnot et al. teaches use of polysorbates as surfactants, see (page 5, lines 4-7). Typical pH ranges from 4 to 8 or 6 to 8 of the dissolution media, see page 2, lines 24-25 and page 8, lines 3-10. Therefore, it would have been obvious to one of ordinary skill before the effective filing date of the claimed invention to have replaced one surfactant with another such as phospholipid with polysorbate for the known surfactant and solubilizing propertied in a dissolution media and come to the claimed invention. The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
Applicant further discusses since the claimed dissolution medium is synthetic, it can be prepared in a simple, rapid and reproducible manner, and the raw materials can be obtained in high purity, making the biorelevant medium more consistent compared to classical biorelevant media comprising natural ingredients while nevertheless mimicking the properties of the existing dissolution media in fasted and fed gastrointestinal states (paragraph bridging pages 3 and 4 of the application as filed). This is in stark contrast to the previously known biorelevant media (such as those of Leigh) which are produced by labor-intensive processes from expensive raw natural materials (including lecithin and sodium taurocholate), and which often have variations in purity and drug dissolution results, as well as poor stability.
These arguments are not persuasive because no evidence has been provided to show labor-intensive processes from expensive raw natural materials (including lecithin and sodium taurocholate), and which often have variations in purity and drug dissolution results, as well as poor stability.
Action is final
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 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.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SNIGDHA MAEWALL whose telephone number is (571)272-6197. The examiner can normally be reached Monday thru Friday; 8:30 AM to 5PM.
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/SNIGDHA MAEWALL/Primary Examiner, Art Unit 1612
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