DETAILED ACTION
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 .
In view of the amendment, previous 112(b) rejection on claims 2-6 and 8-10 and previous 112(b) rejection on claim 14 are hereby withdrawn.
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.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim(s) 1-3, 7, 8, 11, 14 and 16-18 are rejected under 35 U.S.C. 103 as being unpatentable over Lynch (US 2019/0388345 A1).
Lynch teaches (abstract) a method for treating the gastro-intestinal system of a subject with prebiotic nutrients and probiotic bacteria. Lynch teaches ([0071]) that its invention is useful to nourish and supplement the microbiome of the human lower gastro-intestinal tract with desirable probiotic bacteria. Lynch further teaches ([0074]) a multi-chamber dosage form which can be taken orally, provided that the bacteria are enteric-coated or otherwise protected from the gastric juices of a subject’s body to thereby protect the viability of the probiotic bacteria until they reach the intestine of the subject. Thus, Lynch teaches a method of providing oral administration of an active substance (probiotic bacteria) to the intestine (the digestive tract) of the mammal.
With respect to instant delivery system, Lynch teaches (see Figure 1, [0076], [0079] and [0028]) its multi-chamber dosage form in a capsule form. As shown in Figure 1, an outer chamber defined by an outer chamber wall (instant outer capsule having an outer shell wall and an internal chamber) contains a matrix material containing prebiotic nutrients (for probiotic bacteria) and an inner chamber defined by an inner chamber wall (instant inner capsule having an exterior shell wall and an inner compartment) containing probiotic bacteria (instant active substance present in the inner compartment of the inner capsule). In the figure, it is shown that the inner chamber is located within the outer chamber (thus teaching instant limitation “inner capsule being located in the internal chamber of the outer capsule”).
Lynch further teaches ([0079]-[0080]) that both chambers in its multi-chamber dosage form, may optionally be enteric-coated to protect the probiotic bacteria from the strong acids of the upper digestive tract, and such multi-chamber dosage form is formulated to dissolve at a predetermined gastrointestinal location (in [0079], Lynch first teaches that when its multi-chamber dosage form is in a capsule form, “they may optionally be coated with an enteric coating to dissolve at a predetermined gastrointestinal location. Since Lynch’s multi-chamber dosage form comprises both an inner chamber containing probiotic bacteria and an outer chamber containing prebiotic nutrient (see [0041]-[0043]), it is the Examiner’s position that Lynch is teaching that both inner chamber and outer chamber may optionally be enteric-coated. The Examiner’s such position is also supported by Lynch’s own express teachings: Lynch expressly teaches ([0079]) that the outer wall forming the outer chamber may be formed from an enteric coating formulated to dissolve at a predetermined gastrointestinal location and also expressly teaches ([0070]) that the delayed release of the probiotic bacteria (relative to the prebiotic nutrients) can be effected by numerous techniques, such as enteric coating the probiotic bacteria (which is contained in the inner chamber of the inner capsule) to slow their release in the subject’s gastrointestinal tract). Based on Lynch’s teaching, it would be obvious to one skilled in the art to enterically coat both chambers (both instant outer and inner capsules) of its multi-chamber dosage form with a reasonable expectation of protecting the probiotic bacteria from the strong acids of the upper digestive tract and delivering probiotic bacteria at a predetermined gastrointestinal location. Thus, Lynch teaches instant limitation “said inner capsule being acid resistant” as recited in claim 1 as well as instant limitation “the outer capsule is an acid resistant capsule” as recited in claim 7.
Thus, Lynch renders obvious instant claims 1, 7 and 11.
With respect to instant claims 2, 3 and 8, Lynch teaches ([0159]) that its multi-chamber dosage form can be capsules where the capsule shell materials are selected from HPMC, pullulan or gelatin. Furthermore, Lynch teaches ([0079]) that the capsules may be hard or soft. It would have been obvious to one skilled in the art to make both inner and outer capsules in its multi-chamber dosage form to be HPMC hard capsules (with acid resistance as already discussed above). Thus, Lynch renders obvious instant claims 2, 3 and 8.
With respect to instant claim 14, Lynch teaches (Figure 3 and [0078]) that its multi-chamber dosage form can have an outer chamber that contains two inner chambers (i.e., instant more than one inner capsules). Thus, Lynch renders obvious instant claim 14.
With respect to instant claims 16-18, Lynch first teaches ([0003]) that one of the most important microbiomes is in the colon, and Lynch’s invention ([0035], [0065], [0071] and [0080]) provides a dosage form for the delivery of probiotic bacteria to the lower gastrointestinal tract to supplement and nourish the existing microbiome. Thus, it would be obvious to one skilled in the art to target the colon as the delivery site for the probiotic bacteria in Lynch’s inventive method. Furthermore, since Lynch teaches instant method of claim 1, the probiotic (instant active substance) would naturally be delivered to the colon in an amount which is at least 10 times greater (or at least 20 times greater or at least 30 times greater) than a capsule which dissolves in the stomach or small intestine as instantly recited in claims 16-18. Thus, Lynch renders obvious instant claims 16-18.
Claim(s) 4, 5, 9, 10, 12, 13 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Lynch (US 2019/0388345 A1) in view of Cade et al (US 2012/0288562 A1).
With respect to instant claims 4, 5, 9, 10, 12 and 13, Lynch does not teach instant gellan gum as its capsule material. Cade teaches ([0004]-[0005]) that the conventional way to provide acid-resistance to a capsule is by coating a non-acid resistant capsule with an enteric film. However, the methods of applying these coating solutions are complex, expensive, requires a high-level of expertise and may leave toxic solvent residues on the capsule after drying. Cade teaches (abstract and [0008]) a composition for a new acid-resistant hard capsule that has satisfactory mechanical properties and which can be manufactured by a cost-effective, environmentally friendly, healthy, safe and simple process. Cade’s acid-resistant hard capsule comprises an aqueous solvent, gellan gum and one or more water-soluble film-forming polymers, wherein the weight of the gellan gum to the one or more water-soluble film-forming polymers is between 4/100 to 15/100 (see [0009]). Cade further teaches ([0028]) that its preferred water-soluble film-forming polymers are HPMC and gellan. In its Fig.1, Cade shows the dissolution profile of its hard capsule of Example 6 comprising gellan gum and HPMC in a 5/100 ratio (see also [0057] and [0063]) under different pH conditions. After 1 hour at pH 1.2, the Example 6 capsule shows negligible dissolution. After 2 hours at pH 1.2, there is less than 10% dissolution and at pH 6.8, the capsule completely dissolves in 2 hours. Cade teaches ([0063]) that this dissolution profile meets the definition of enteric-release hard capsules according to the Japanese Pharmacopeia 2. Thus, Cade’s gellan gum/HPMC hard capsule has acid-resistance comparable to an enteric coating. Based on Cade’s teaching, it would be obvious to one skilled in the art to use Cade’s gellan gum/HPMC composition in a weight ratio of 5/100 to provide acid-resistance to Lynch’s inner and outer chambers (instead of Lynch’s enteric coating) with a reasonable expectation of achieving the advantages as taught by Cade and listed above. Cade’s Example 6 capsule teaches instant gellan gum/HPMC capsule of claims 4, 5, 9, 10, 12 and 13. Thus, Lynch in view of Cade renders obvious instant claims 4, 5, 9, 10, 12 and 13.
With respect to instant claim 15, Lynch does not expressly teach that its inner chamber is banded. Cade teaches ([0019], [0044] and [0050]) that hard capsules are typically sealed or banded according to conventional techniques in order to avoid leakage of contained substances and to make the capsules tamper-proof. Based on Cade’s teaching, it would be obvious to one skilled in the art to band Lynch’s inner chamber in order to prevent leakage of the probiotic bacteria and to make it tamper-proof. Thus, Lynch in view of Cade renders obvious instant claim 15.
Claim(s) 6 is rejected under 35 U.S.C. 103 as being unpatentable over Lynch (US 2019/0388345 A1) as applied to claim 2 above, and further in view of Cade et al (US 2012/0288562 A1) and Cade et al (US 2017/0087092 A1).
The Examiner established above (in relation to instant claim 2, from which claim 6 depends) that it would have been obvious to one skilled in the art to make both inner and outer capsules in Lynch’s multi-chamber dosage form to be HPMC hard capsules (with acid resistance as already discussed above). Lynch does not teach that its HPMC hard capsule comprises thermogelled HPMC. As evidenced by Cade’562 ([0013]-[0016]), it is known in the art that acid-resistant hard capsules are made by the process of dip-molding. As also evidenced by Cade’092 ([0007]), such process of dip-molding is conventionally known as thermogellation. It would be obvious to one skilled in the art to make Lynch’s HPMC hard capsules acid-resistant by dip-molding process (thermogellation) with a reasonable expectation of success. Thus, Lynch further in view of Cade’562 and Cade’092 render obvious instant claim 6.
Response to Arguments
Applicant first argue that Lynch is primarily directed to a dosage form that is administered via rectal, vaginal or urethral routes. Applicant argue that rather than relying on acid-resistant capsule structure, Lynch teaches ([0027] and [0076]) a matrix-based system in which the inner chamber is surrounded by a material that melts upon contact with mucosal tissue at body temperature and argue that such matrix is specifically designed to release contents upon contact with rectal or vaginal mucosa, not to withstand gastric acidity. The Examiner disagrees. First of all, in the abstract, Lynch clearly teaches that its products may be administered by oral, rectal, vaginal or urethral routes. Also, as evidenced by Lynch ([0007]-[0010]), one of three major ways of delivering healthy or desirable bacteria to the human to promote health is through oral ingestion of capsules and tablets containing probiotics. Lynch then teaches ([0080]) the following:
[0080] One method according to the present invention supplements and nourishes the microbiome of the lower gastro-intestinal tract of a person by orally ingesting the multi-chamber dosage form of the present invention. In accordance with this embodiment, the multi-chamber dosage form is advantageously enteric coated to protect the probiotic bacteria from the strong acids of the upper digestive tract. The product may be administered orally with a frequency and quantity typical for a probiotic treatment regimen, i.e. as done with conventional probiotic products taken orally on a daily basis the current multi-chamber probiotic delivery system may also be administered daily. (see also claims 16-18 in Lynch).
Thus, the Examiner disagrees with applicant’s argument that Lynch is primarily directed to a dosage form that is administered via rectal, vaginal or urethral routes.
Applicant next argue that although Lynch teaches ([0079]) that when the dosage form is in capsule form it “may optionally be coated with an enteric coating formulated to dissolve at a predetermined gastrointestinal location,” such teaching alone fails to teach or provide a proper motivation to form the delivery system with an inner capsule that is acid resistant (as required in instant claim 1), let alone in combination with an outer capsule that is acid resistant (as required in instant claim 7) as Lynch’s such teaching is limited to a conventional, single-layer protective strategy. Applicant further argue that Lynch provides no motivation to modify its system to include an acid-resistant inner capsule, let alone in combination with an acid-resistant outer capsule and argue that Lynch's reliance on a melting matrix indicates that protection and release are
achieved through contact with mucosal tissue, not resistance to gastric conditions and one skilled in the art would therefore have no reason to replace or supplement the matrix-based release mechanism with an acid-resistant inner capsule. Applicant argue that such a modification (to have the inner capsule acid-resistant) would only be apparent with impermissible hindsight in view of Applicant's disclosure. The Examiner disagrees. In [0079], Lynch first teaches that when its multi-chamber dosage form is in a capsule form, “they may optionally be coated with an enteric coating to dissolve at a predetermined gastrointestinal location. Since Lynch’s multi-chamber dosage form comprises both an inner chamber containing probiotic bacteria and an outer chamber containing prebiotic nutrient (see [0041]-[0043]), it is the Examiner’s position that Lynch is teaching or suggesting that both inner chamber and outer chamber may optionally be enteric-coated. The Examiner’s such position is also supported by Lynch’s own express teachings: Lynch expressly teaches ([0079]) that the outer wall forming the outer chamber may be formed from an enteric coating formulated to dissolve at a predetermined gastrointestinal location and also expressly teaches ([0070]) that the delayed release of the probiotic bacteria (relative to the prebiotic nutrients) can be effected by numerous techniques, such as enteric coating the probiotic bacteria (which is contained in the inner chamber of the inner capsule) to slow their release in the subject’s gastrointestinal tract). Based on Lynch’s teaching, it would be obvious to one skilled in the art to enterically coat both chambers (both instant outer and inner capsules) of its multi-chamber dosage form with a reasonable expectation of protecting the probiotic bacteria from the strong acids of the upper digestive tract and delivering probiotic bacteria at a predetermined gastrointestinal location. Thus, Lynch teaches instant limitation “said inner capsule being acid resistant” as recited in claim 1 as well as instant limitation “the outer capsule is an acid resistant capsule” as recited in claim 7.
Applicant further argue that even assuming, arguendo, that Lynch could be modified in the manner proposed by the Office Action, the experimental evidence in the
present application demonstrates that the claimed configuration yields unexpected and
superior results. Applicant argue that the Examples of the present disclosure show that
capsule-in-capsule systems as claimed provide significantly improved performance relative to conventional single capsule systems: applicant first argue that the experimental data show that capsule-in-capsule configurations exhibit substantially enhanced resistance to gastric conditions, with minimal release of the active compound during simulated stomach phases under both fed and fasted conditions (Example 1, FIG. 5 and FIG. 6), whereas single capsule systems exhibit rapid and premature release in the stomach, leading to early exposure of the active substance to harsh gastric environments (Example 1, FIGS. 5 and 6, Comparative Sample C3). Applicant further argue that the claimed configurations provide controlled and delayed release profiles that extend well beyond those achievable with single capsules: certain capsule-in-capsule systems (Sample C) demonstrated delayed release into later regions of the small intestine and even the colon, whereas single capsule systems consistently released their contents in the stomach or proximal intestine (Examples 1, Fig.5 and Fig.7). Applicant additionally argue that the data show that probiotic viability is significantly improved when delivered via capsule-in-capsule systems with higher survival rates observed throughout gastrointestinal transit and into the colonic environment (Example 1, Fig.7 and Fig.8) whereas single capsule systems result in reduced viability due to premature release and degradation (Example 1, Fig.7 and Fig.8). The improved delivery profile results in enhanced functional outcomes, including increased production of beneficial metabolites such as butyrate and improved modulation of the gut microbiome (Example 1, FIG. 9). Applicant argue that these downstream effects further underscore that the claimed configuration provides more than a predictable improvement. The Examiner disagrees. As already explained above, Lynch teaches or renders obvious enterically coating both inner and outer chambers (i.e., both inner and outer capsules) of its multi-chamber dosage form in order to protect the probiotic bacteria from the strong acids of the upper digestive tract (thus providing enhanced resistance to gastric conditions and giving minimum release of the probiotic bacteria in the stomach) and deliver probiotic bacteria at a predetermined gastrointestinal location (i.e., the probiotic bacteria will be released at the predetermined gastrointestinal location in a controlled and delayed manner). Lynch teaches ([0074]) that the probiotic bacteria are enteric coated to thereby protect the viability of the probiotic bacteria until they reach the intestine of the subject (thus enhancing the probiotic viability with higher survival rates for the probiotic bacteria). Such improved delivery profile (obtained by enteric coating the inner and outer capsules of Lynch’s multi-chamber dosage form) in Lynch will naturally improve the health of the microbiome in a human gastrointestinal system (see the title of the reference) because probiotic bacterial are beneficial to the human microbiome ([0081]). Since those beneficial results (of the claimed invention) listed above by applicant are already taught by Lynch, the Examiner disagrees with applicant’s argument of unexpectedly superior results of the claimed invention.
Applicant finally argue that Example 2 of the present disclosure demonstrates that capsule-in-capsule configurations comprising acid-resistant inner and outer capsules exhibit disintegration times that exceed the sum of the individual capsule components. Applicant argue that this non-additive behavior reflects a synergistic interaction between the nested capsule structures, which would not have been predicted by one skilled in the art and that such results further confirm that the claimed configuration provides more than a predictable use of known elements. The Examiner disagrees. Grimm et al (“Characterization of the gastrointestinal transit and disintegration behavior of floating and sinking acid-resistant capsules using a novel MRI labeling technique”, European Journal of Pharmaceutical Sciences, vol.129 (2019), pg.163-172) investigated (see pg.164, right hand-column, section 2.1) Cap-in-Cap capsule formulations where both the inner and outer capsules are acid-resistant, and for such investigation, floating and sinking Cap-in-Cap systems of commercially available DRcapsTM (which is also taught by applicant – see [0057] and [0062] of present specification) were used: a size 0 DRcapsTM capsule was filled inside a DRcapsTM capsule of size 00, where both of the DRcapsTR are acid-resistant. Grimm reported (see abstract) that the mean disintegration time for the floating DRcapsTM Cap-in-Cap was 139 ± 35 min and the mean disintegration time for the sinking DRcapsTM was 163 ± 55 min. These disintegration times are comparable to the disintegration time 123 ± 25 min (see Table 6 in [00158] of present specification) obtained by applicant for Study Arm X (both outer and inner capsules being acid resistant HPMC capsules). Thus, it is the Examiner’s position that the longer disintegration time (123 ± 25 min) for the claimed invention (capsule-in-capsule formulation with both the inner and outer capsules being acid-resistant) was predictable and thus not unexpected. Besides, although applicant argue that Example 2 of present specification demonstrates that capsule-in-capsule configurations comprising acid-resistant inner and outer capsules exhibit disintegration times that exceed the sum of the individual capsule components (and thus showing synergism), the Examiner disagrees because in order to show a synergistic interaction between the nested capsule structure in Study Arm X, applicant have to show the individual disintegration time for both the inner capsule and the outer capsule, but in Table 2, only the disintegration time for the outer capsule is shown (through Study Arm VII).
For these reasons, instant 103 rejections over Lynch still stand.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SIN J. LEE whose telephone number is (571)272-1333. The examiner can normally be reached on M-F 9 am-5:30pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Brian Kwon can be reached on 571-272-0581. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SIN J LEE/
Primary Examiner, Art Unit 1613
August 11, 2026
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