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 .
Claim Status
Claims 1-14 and 50-52 are withdrawn.
Claims 15-17, 20, 22-23, 26-36, 38, 40-49, 53, and 56 are rejected.
No claims are allowed.
Modified Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
The factual inquiries 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.
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.
1. Claims 15-17, 22-23, 27, 29, 30, 31, 33, 36, 38, 40, 41, 43-46, 48, and 56 are rejected under 35 U.S.C. 103 as being unpatentable over Cheng (US 2021/0128479 A1, May 06, 2021) (cited by Examiner on Form 892 01/03/2025) (hereinafter Cheng) in view of Brewer (US 2004/0009237 A1, Jan. 15, 2004) (hereinafter Brewer) and Santos da Silva et al. (Inhibition of NF-κB activation by diethylcarbamazine prevents alcohol-induced liver injury in C57BL/6 mice, November 2014) (cited by Examiner on Form 892 01/03/2025) (hereinafter Santos da Silva).
Cheng discloses drug dosage forms that are capable of controlling the release rates and release time under different gastrointestinal tract environment, thus allowing the drugs to be released and absorbed at specific gastrointestinal sites and increase the bioavailability of the drugs ([0006]). The controlled release dosage form comprises a shell defining a first and second compartment with a first and second active pharmaceutical ingredient (API) loaded respectively, which can be the same or different API (Abstract) and may include a third API and third, fourth, and fifth compartments ([0020]). Pharmaceutically acceptable carriers such as cocoa butter and polyethylene glycol are disclosed ([0065]). The API may be drugs for treating liver diseases ([0023]). A suitable API can include tetrathiomolybdate (TTM) ([0069]) in an oral dosage form ([0051]) and can be delayed release or sustained release (i.e., extended release) ([0076-0077]) with an enteric coating ([0057]). The amount of an API in a drug dosage form may be greater than about 60 mg ([0071]). An additional API can include sulforaphane (i.e., at least one other active) ([0069]). Cheng teaches a variety of materials can be used for the 3D printing process that determines the shape and size of the substrate and compartment of the composition and includes thermoplastic materials disclosed as well as pastes and colloidal suspensions, silicones and other semisolids ([0106]). The overall resolution of the 3D printed structure created is a function of the powder particle size, the fluid droplet size, the print parameters, and the material properties ([0107]). The first compartment is formed by a first material and the second compartment is formed by a second material ([0011]). Materials include thermoplastic materials such as lactose, microcrystalline cellulose, hydroxypropyl methylcellulose, and combinations thereof ([0012]). The composition can be formed in a multi-layer structure ([0098 – 0099]) and the 3D printing process is what forms the layer-by-layer design ([0133]). FIG. 2 discloses a drug dosage form 200 including a shell 201, a first API 212, a second API 222 and a third API 232. The shell 201 includes a stomach soluble material 211, a small intestine soluble material 221, and a colon soluble material 231. The stomach soluble material 211 forms a first compartment 210 (i.e., claimed larger second capsule), the small intestine soluble material 221 forms a second compartment 220 (i.e., claimed filler), and the colon soluble material 231 forms a third compartment 230 (i.e., claimed first capsule). The first API 212 is located in the first compartment 210, the second API 222 is located in the second compartment 220, and the third API 232 is located in the third compartment 230 ([0114]). The third API may be wrapped in a coat ([0094]). The drug dosage forms can further be coated, such as embedded, encased, or attached thereto, to protect the components of the drug dosage form from light, moisture, and/or air or to control the release of the components of the drug dosage form and the coating may be enteric ([0057]) Magnesium carbonate is another example of a suitable API ([0069]). Cheng discloses that multiple APIs can be loaded into multiple compartments that are soluble at different and specific gastrointestinal sites ([0020]), the gastrointestinal site refers to any site in the gastrointestinal tract, including stomach, small intestine (including duodenum, jejunum and ileum) and large intestine (including cecum, colon and rectum) ([0050]). Dosage forms also include capsule shaped tablets ([0088]). The drug dosage form may be coated, such as embedded, encased, or attached thereto, with a gelatin layer ([0057]). Cheng discloses that where a particular feature is disclosed in the context of a particular aspect or embodiment of the invention, that feature can also be used in combination with and/or in the context of other particular aspects and embodiments of the invention, and in the invention generally ([0040]).
Cheng differs from the instant claims insofar as not teaching wherein the composition comprises ammonium tetrathiomolybdate (ATTM).
However, Brewer discloses a method of treating inflammatory or fibrotic disease in a patient, comprising administering to the patient having an inflammatory or fibrotic disease a biologically effective amount of at least a first agent that binds or complexes copper, such as, a thiomolybdate. The thiomolybdate may be tetrathiomolybdate and is administered in amount between about 20 mg and about 200 mg (i.e., therapeutically effective amount) ([0008]). The inflammatory or fibrotic disease can be liver disease including liver cirrhosis and hepatitis C ([0010]). The method further comprises administering to the patient a therapeutically effective amount of at least a second agent, where the second agent is chosen from anti-inflammatory agents and anti-fibrotic agents ([0011]). Examples of thiomolybdates also include trithiomolybdate ([0046]). Tetrathiomolybdate (TM) or any thiomolybdate may be utilized as one or several of different salts ([0102]), such as ammonium (i.e., ammonium tetrathiomolybdate (ATTM)) ([0103]). Pharmaceutical compositions will generally comprise an effective amount of an agent dissolved or dispersed in a pharmaceutically acceptable carrier ([0117]). TM is administered orally in tablets or other solids, time release capsules ([0119]). Supplementary active ingredients can also be incorporated into the compositions ([0050]). Pharmaceutical compositions will generally comprise an effective amount of an agent for use in the invention ([0117]).
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. Cheng discloses wherein the composition comprises tetrathiomolybdate. Accordingly, it would have been obvious to one of ordinary skill in the art to have incorporated ammonium tetrathiomolybdate (ATTM) in amount between about 20 mg and about 200 mg (i.e., therapeutically effective amount) into the composition of Cheng since it is a known and effective tetrathiomolybdate salt and amount used to treat liver disease as taught by Brewer.
The combined teachings of Cheng and Brewer do not teach wherein the composition comprises diethylcarbamazine (DEC).
However, Santos da Silva teaches that induction of NF-κB-mediated gene expression has been identified in the pathogenesis of alcoholic liver disease (ALD). Diethylcarbamazine (DEC) is a piperazine derivative drug with anti-inflammatory properties and DEC alleviates alcoholic liver injury, in part by the inhibiting activation of NF-κB and by suppressing the induction of NF-κB-dependent genes (Abstract). NF-kB is a transcription factor involved in inflammation and immune response and is activated by oxidants and cytokines such as interleukin 1 (IL-1) and cytokine tumor necrosis factor-alpha (TNF-), which play important roles in inflammation (Introduction, page 363, second column). DEC treatment at 50 mg/kg inhibits hepatic injury and decreases inflammatory infiltration induced by ethanol consumption (i.e., therapeutically effective amount) (Discussion, page 366). DEC not only inhibits the hepatic local inflammatory response, but also attenuates the positive feedback loop between oxidative stress and inflammation (last paragraph, page 370).
As discussed above, the composition of Cheng may comprise multiple APIs used to treat liver disease. Further, Brewer discloses wherein the composition further comprises anti-inflammatory agents and treats liver disease. Accordingly, it would have been obvious to one of ordinary skill in the art to have incorporated diethylcarbamazine (DEC) at an amount of 50 mg/kg (i.e., therapeutically effective amount) into the composition of Cheng in view of Brewer since anti-inflammatory agents may be used in combination with ATTM to treat liver disease as taught by Brewer and DEC is a known and effective anti-inflammatory agent and amount for inflammation associated with liver disease as taught by Santos da Silva.
Regarding claim 16, as discussed above, the composition of Cheng may comprise multiple APIs. Further, Brewer teaches administering at least a first agent that binds or complexes copper, such as, a thiomolybdate and that examples of thiomolybdates include trithiomolybdate and tetrathiomolybdate, which may be used in the ammonium salt form. Accordingly, it would have been obvious to one of ordinary skill in the art to have further incorporated ammonium trithiomolybdate into the composition of Cheng in view of Brewer since ammonium trithiomolybdate is a known and effective API as taught by Brewer.
Regarding claims 22 and 33, Cheng discloses wherein it is desirable to have different APIs in different compartments (i.e., dosage forms) in a sustained release composition and the composition of the prior art comprises ATTM and DEC. Accordingly, it would have been obvious to one of ordinary skill in the art to have formulated ATTM and DEC to be in different compartments, such as ATTM in the third compartment 230 (i.e., claimed first capsule) and DEC in the first compartment 210 (i.e., claimed larger second capsule).
Regarding the limitation of claim 27 reciting wherein the second capsule comprises an enteric coating on an outer surface, as discussed above, Cheng teaches that the drug dosage form can further be coated, such as encased, and the coating may be enteric. Accordingly, because Cheng teaches that the drug dosage form is encased in an enteric coating, it would have been obvious that the first compartment 210 (i.e., claimed larger second capsule), which is the outermost compartment, would have an enteric coating on its surface.
Regarding claims 29-30, as discussed above, Cheng teaches that magnesium carbonate is an example of a suitable API and drug dosage forms can have a protective and enteric coating. Accordingly, it would have been obvious to one of ordinary skill in the art to have incorporated magnesium carbonate into the second compartment 220 of FIG. 2 because Cheng teaches that the second compartment 220 comprises an API 222 and magnesium carbonate is a suitable API. Thus, by magnesium carbonate being in the second compartment 220 and ATTM being in the third compartment 230, as discussed above, ATTM is encapsulated by magnesium carbonate.
Regarding the limitation of claim 29 reciting a protective coating, because magnesium carbonate is in the second compartment encapsulating the ATTM in the third compartment, magnesium carbonate is further distancing ATTM from the external environment, thus making it a protective coating.
Regarding claims 36 and 38, as discussed above, Cheng teaches that sulforaphane (i.e., at least one other active) is a suitable APIs and multiple APIs may be loaded into multiple compartments. Accordingly, it would have been obvious to one of ordinary skill in the art to have formulated the composition of Cheng in view of Brewer and Santos da Silva wherein ATTM is combined with sulforaphane (i.e., at least one other active) in the third compartment, such that magnesium carbonate (i.e., claimed protective coating) in the second compartment is encapsulating them, and the enteric coating on the surface of the third compartment is encapsulating the magnesium carbonate, as discussed above.
Regarding claims 43-45, as discussed above, Cheng teaches that the overall resolution of the 3D printed structure created is a function of the powder particle size. Accordingly, one of ordinary skill in the art would have arrived at the claimed percentage and particle size through routine experimentation to achieve the desired overall resolution, as taught by Cheng. Where 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. See MPEP 2144.05(II)(A).
Regarding claim 56, as discussed above, Cheng teaches a drug dosage form 200 including a shell 201 and a third API 232. The shell 201 includes a colon soluble material 231 and the colon soluble material 231 forms a third compartment 230 (i.e., claimed first capsule). The third API 232 is located in the third compartment 230 (i.e., claimed first capsule) and the third API may be wrapped in a coat. Suitable coatings include gelatin. Thus, it would have been obvious to one of ordinary skill in the art to have formulated the composition of Cheng such that the third compartment 230 (i.e., claimed first capsule) comprises gelatin since the third compartment 230 (i.e., claimed first capsule) comprises the third API and the third API may be coated in gelatin. Further, as discussed above, Cheng teaches that the drug dosage form can further be coated, such as embedded, and the coating may be enteric. Accordingly, because Cheng teaches that the drug dosage form is embedded in an enteric coating, it would have been obvious that the first compartment 210 (i.e., claimed larger second capsule), which is the outermost compartment, would comprise an enteric coating.
2. Claims 20, 28, 32, 34, 35, 42, 47, and 49 are rejected under 35 U.S.C. 103 as being unpatentable over Cheng (US 2021/0128479 A1, May 06, 2021) (cited by Examiner on Form 892 01/03/2025) (hereinafter Cheng) in view of Brewer (US 2004/0009237 A1, Jan. 15, 2004) (hereinafter Brewer) and Santos da Silva et al. (Inhibition of NF-κB activation by diethylcarbamazine prevents alcohol-induced liver injury in C57BL/6 mice, November 2014) (cited by Examiner on Form 892 01/03/2025) (hereinafter Santos da Silva) and further in view of Kim et al., (Astaxanthin inhibits inflammation and fibrosis in the liver and adipose tissue of mouse models of diet-induced obesity and nonalcoholic steatohepatitis, Jan. 21, 2016) (hereinafter Kim).
As discussed above, Cheng, Brewer, and Santos da Silva make obvious the limitations of claim 15 but do not teach wherein the composition further comprises astaxanthin (ATX).
However, Kim teaches that astaxanthin (ASTX) is a xanthophyll carotenoid that inhibits inflammation and fibrosis in the liver and adipose tissue (Abstract). Obese individuals have a high risk of developing nonalcoholic fatty liver disease (NAFLD), specifically, nonalcoholic steatohepatitis (NASH), which is characterized by inflammation and fibrosis (Introduction, page 27). ASTX prevents fibrosis and inflammation through decreased expression of COL6A1, COL6A3 and LOXL2 (page 33, first paragraph). ASTX also significantly decreases the expression of fibrogenic genes, including TGFβ1, LUM, TNC, COL1A1, COL6A1 and COL6A3 in the liver (page 33, second paragraph). The effect of ASTX on inflammation and fibrosis was noted with 0.03% ASTX (w/w) supplementation (page 30, Fig. 1).
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. Cheng discloses wherein the API may be drugs for treating liver diseases. Accordingly, it would have been obvious to one of ordinary skill in the art to have incorporated astaxanthin (ASTX) into the composition of Cheng since it is a known and effective agent that inhibits inflammation and fibrosis in the liver as taught by Kim.
Regarding claim 32, as discussed above, Cheng teaches that multiple APIs may be loaded into multiple compartments. Accordingly, it would have been obvious to one of ordinary skill in the art to have incorporated ATX in the second compartment, such that ATX in the second compartment is encapsulating ATX.
Regarding claim 34, as discussed above, ATTM, DEC, and ATX are suitable APIs. Cheng discloses wherein each compartment in Fig. 2 may be include an API. Accordingly, it would have been obvious to one of ordinary skill in the art to have incorporated ATTM in the third compartment 230, DEC in the second compartment 220, and ATX in the first compartment 210.
Regarding claim 35, as discussed above, ATTM, DEC, magnesium carbonate, and ATX are suitable APIs and Cheng teaches that multiple APIs may be loaded into multiple compartments. Accordingly, it would have been obvious to one of ordinary skill in the art to have incorporated ATTM, DEC, and ATX in the third compartment 230 and magnesium carbonate in the second compartment 220. When magnesium carbonate is in the second compartment 220, it encapsulates ATTM, DEC, and ATX.
3. Claim 26 is rejected under 35 U.S.C. 103 as being unpatentable over Cheng (US 2021/0128479 A1, May 06, 2021) (cited by Examiner on Form 892 01/03/2025) (hereinafter Cheng) in view of Brewer (US 2004/0009237 A1, Jan. 15, 2004) (hereinafter Brewer) and Santos da Silva et al. (Inhibition of NF-κB activation by diethylcarbamazine prevents alcohol-induced liver injury in C57BL/6 mice, November 2014) (cited by Examiner on Form 892 01/03/2025) (hereinafter Santos da Silva) and further in view of Wang et al., (Moisture adsorption and desorption properties of colloidal silicon dioxide and its impact on layer adhesion of a bilayer tablet formulation, 2014) (cited by Examiner on Form 892 01/03/2025) (hereinafter Wang).
As discussed above, Cheng, Brewer, and Santos da Silva make obvious the limitations of claim 15 but do not teach wherein the filler comprises mesoporous dicalcium phosphate, colloidal silicon dioxide, or a combination thereof.
However, Wang discloses a filler comprising colloidal silicon dioxide with a surface area of 200 m2/g called Aerosil 200®, used in the construction of bilayer tablets. It adsorbs relatively smaller amounts of moisture but it retains moisture due to its larger pore sizes, compared with a similar filler of larger surface area. The moisture, if not retained, can interact with excipients, such as, microcrystalline cellulose and can generate significant shear stress at the layer interface triggering the delamination (Abstract). Wang discloses a multilayer composition of Drug Y containing microcrystalline cellulose and lactose with Drug Z hydroxypropylmethyl cellulose and colloidal silicon dioxide as a moisture scavenger. The bilayer tablets did not show any delamination with Aerosil® 200 was used as the colloidal silicon dioxide (page 22, second column).
As discussed above, Cheng teaches that the second compartment 220 (i.e., claimed filler) is formed by a thermoplastic material such as lactose, microcrystalline cellulose, hydroxypropyl methylcellulose, and combinations thereof. Accordingly, it would have been prima facie obvious to one of ordinary skill to have the thermoplastic materials forming the second compartment 220 (i.e., claimed filler) of Cheng further comprise Aerosil 200® (i.e., colloidal silicon dioxide) motivated by the desire to retain moisture and prevent delamination of bilayer or multilayer drug designs as taught by Wang.
4. Claim 53 is rejected under 35 U.S.C. 103 as being unpatentable over Cheng (US 2021/0128479 A1, May 06, 2021) (cited by Examiner on Form 892 01/03/2025) (hereinafter Cheng) in view of Brewer (US 2004/0009237 A1, Jan. 15, 2004) (hereinafter Brewer) and Santos da Silva et al. (Inhibition of NF-κB activation by diethylcarbamazine prevents alcohol-induced liver injury in C57BL/6 mice, November 2014) (cited by Examiner on Form 892 01/03/2025) (hereinafter Santos da Silva) and further in view of and further in view of Schor et al., (US 4,389,393 A, June 21, 1983) (cited by Examiner on Form 892 01/03/2025) (hereinafter Schor).
As discussed above, Cheng, Brewer, and Santos da Silva make obvious the limitations of claim 15 but do not teach a water content of 2% to 3.5%.
However, Schor teaches a solid unit dosage form having a carrier base material being hydroxypropyl methylcellulose (Abstract). The dosage form may be capsule shaped tablets as disclosed in Examples 1-2 (col 6, lines 59-60). The moisture content (i.e., water content) of the carrier used in the preparation of the sustained release tablets may be in the 0.1-10% range, the lower end of the range being preferable when moisture sensitive medicaments are used (col 5, lines 51-54). The hydroxypropyl methylcellulose used in Examples 3-4 was dried in an oven at 210 F. to a moisture content of 2.3% (col 8, lines2-3).
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 discussed above, Cheng discloses wherein hydroxypropyl methylcellulose is a material that may be used to form the compartments of the dosage form. Accordingly, it would have been obvious to one of ordinary skill in the art to have incorporated hydroxypropyl methylcellulose (HPMC) having a water content of 2% to 3.5% into the third compartment 230 (i.e., first capsule) of Cheng since it is a known and effective HPMC with moisture protection property as taught by Schor.
Response to Applicant’s Arguments
Applicant argues that a person of ordinary skill in the art would have had the well-known view that ATTM is too unstable for routine use in an oral formulation, as evidenced by the Declaration under 37 CFR § 1.132 of Charles Magolske, filed April 16, 2025, that states that the instability of ATTM is well documented in the literature and the FDA has refused to file new drug applications (NDA) for the use of ATTM due to such instability.
Applicant’s argument has been fully considered but found not to be persuasive. As discussed above, Cheng teaches that tetrathiomolybdate (TTM) is a suitable active pharmaceutical ingredient (API) for the capsular oral dosage form and Brewer teaches that ammonium tetrathiomolybdate (ATTM) is a suitable salt form for oral delivery. Further, Brewer teaches that the ammonium salt of TM has one undesirable property, that of mild air instability. Thus, the bulk drug should be stored in the absence of oxygen, or the oxygen will gradually exchange with the sulfur, rendering the drug ineffective over time. The bulk drug is therefore stored under argon. Stability assays indicate that this drug is stable for several years under argon. Capsules can be filled by hand, and the drug is stable in capsules for several months at room temperature ([0104]). Thus, one of ordinary skill in the art would have recognized that the reported instability of ATTM when stored under oxygenated air is mild and may be overcome by storage in argon and that when ATTM is filled into a capsule, it becomes stable for several months at room temperature. Accordingly, one of ordinary skill in the art would have considered ATTM to be a suitable API for use in the capsular oral dosage form of Cheng since its instability is easily overcome.
Applicant argues that the pill within a pill design capsule according to the present claims provides a dramatic improvement to the storage stability and superior properties of ATTM, which is an unexpected result as evidenced by the April 16, 2025 Declaration.
Applicant’s argument has been fully considered but found not to be persuasive. The results do not appear to be unexpected to one of ordinary skill in the art. A stability study was provided on page 2 of the April 16, 2025 Declaration which demonstrated that an enteric coated capsule comprising ATTM showed degradation of ATTM to about 33% after 26 months compared to a pill within a pill capsule of the instant invention which showed degradation of ATTM to about 90% after 18 months and about 83.7% after 26 months. However, as evidenced by Kathpolia et al., (Recent trends in Hard Gelatin capsule delivery System, June 2014) (hereinafter Kathpolia), Duo Cap Technology is a single, oral-dosage unit that comprises a capsule-in-capsule and offers broad therapeutic applications wherein the capsules may contain different actives for use with combination therapies or actives that are incompatible in a single capsule and the inner capsule may contain liquid, semi-solid, powder or pellet formulations and the outer capsule contains liquid or semi-solid formulations (page 169, D. Capsule) Additionally, Micro-FloraGuard™ is presented in a unique DuoCap - capsule in a capsule. The design enhances product stability by protecting the probiotic inner capsule in an HPMC capsule. This creates an effective barrier to moisture, which helps the probiotic remain inactive until it is consumed (page 170, first paragraph). Thus, a pill within a pill capsule design was known in the art previous to the filing date of the instant invention and further, such a design was known to protect the inner active ingredient within a capsule to provide enhanced stability. As such, the showing provided by the Declaration wherein the pill within a pill capsule of the instant invention demonstrates less degradation of ATTM compared to an enteric coated capsule over 26 months would not be unexpected to one of ordinary skill in the art.
Applicant argues that the pill within a pill design capsule according to the present claims protects the ATTM from moisture for an extended period of time directly resulting from the physical isolation of the inner capsule from the outer enteric shell by a filler spacer, which is an unexpected result as evidenced by the April 16, 2025 Declaration.
Applicant’s argument has been fully considered but found not to be persuasive. The results do not appear to be unexpected to one of ordinary skill in the art. A moisture protection study was provided on pages 5-6 of the April 16, 2025 Declaration which demonstrated that in Experiments 1-5, ATTM was placed within a single enteric capsule both with and without filler, and became wet in a simulated stomach environment within 60-90 minutes. Experiment 6 showed that ATTM stayed dry for up to 120 minutes when placed within an inner capsule that was placed within a larger enteric coated capsule with filler. However, in the location where the inner capsule contacted the outer enteric capsule there was evidence that the inner capsule became wet in a simulated stomach environment. Further, in Experiments 7 and 8, no evidence of wetness of the inner capsule was noted when the same drug formulation used in Experiment 6 was subjected to light vibration to isolate the inner capsule from the outer enteric capsule. Regarding the Applicant’s showing that ATTM remained dry for up to 120 minutes when formulated as the pill within a pill capsule of the instant invention, as evidenced by the teachings of Kathpolia discussed above, the DuoCap capsule in capsule design enhances product stability by protecting the probiotic inner capsule in an HPMC capsule, which creates an effective barrier to moisture and helps the probiotic remain inactive until it is consumed. Thus, the Applicant’s showing of moisture protection of the inner capsule would not be unexpected to one of ordinary skill in the art. Regarding the Applicant’s assertion that the unexpected result of improved moisture protection is due to the claimed configuration wherein the filler isolates the inner capsule from the outer capsule, in Experiment 6, no vibration was provided to the formulation comprising an inner and outer capsule with a filler and moisture was noted where the inner capsule contacted the outer capsule. However, because the capsules of Experiments 7 and 8 require light vibration to achieve total isolation of the inner capsule from the outer capsule and comprise a filler, it is unclear if the demonstrated moisture protection of the inner capsule is due to the filler or the light vibration provided that achieved the total isolation.
Applicant argues that a person of ordinary skill in the art reading Brewer would conclude that ATTM is pharmacologically interesting but formulation- limited, and that Brewer's recognition of ATTM's rapid degradation and the field's move to the more stable bis-choline TTM thus teaches away from routine oral ATTM formulations, undermining any reasonable expectation of success in combining Brewer with Cheng.
Applicant’s argument has been fully considered but found not to be persuasive. “Disclosed examples and preferred embodiments do not constitute a teaching away from the broader disclosure or non-preferred embodiment.” See MPEP 2123. As discussed above, Brewer teaches that ammonium tetrathiomolybdate (ATTM) is a suitable salt form of TTM for oral delivery, and that stability assays indicate that this drug is stable for several years under argon. Capsules can be filled by hand, and the drug is stable in capsules for several months at room temperature. Brewer further discloses that TM, which is generally synthesized as the ammonium salt, may be more stable under air as a different salt and in some embodiments the salt choline TM has suitable desirable properties ([0105]). Thus, one of ordinary skill in the art would have recognized that the disclosure of Brewer does not teach away from the use of ATTM in oral formulations but instead teaches that the reported instability of ATTM may be overcome with argon storage and that when ATTM is filled into a capsule, it becomes stable for several months at room temperature and that the choline salt has suitable desirable properties in other embodiments in air environments. The teachings of Brewer do not suggest that ATTM be replaced with the bis-choline TTM salt but instead discloses that they are both suitable salt forms of TTM. Accordingly, one of ordinary skill in the art would have had a reasonable expectation of success when selecting ATTM as a suitable API for use in the capsular oral dosage form of Cheng.
Applicant argues that the improved stability over extended storage leads to improved safety and efficacy when treating a patient, which is an unexpected result as evidenced by the April 16, 2025 Declaration.
Applicant’s argument has been fully considered but found not to be persuasive. The results do not appear to be unexpected to one of ordinary skill in the art, as discussed above. As the improved safety and efficacy of the ATTM formulation of the instant invention is directly attributed to the improved stability of ATTM as indicated on page 2, first paragraph of the Declaration dated April 16, 2025, and reiterated on page 2 of the February 09, 2026 Declaration, these results are not unexpected for reasons regarding the expected enhanced stability of a capsule in capsule formulation evidenced by Kathpalia above.
Applicant argues that Cheng fails to teach or suggest dosage forms for improving the chemical or storage stability of an API as it is directed to controlled release dosage forms as opposed to the instantly claimed invention that is directed to moisture isolation of the ATTM, which are compared in instant Appendix A.
Applicant’s argument has been fully considered but found not to be persuasive. The claims as presently recited do not require the use of the composition for improving the chemical or storage stability of an API. Further, the comparison box on page 43 of instant Appendix A concludes that the instantly claimed dosage formulation provides unexpected long-term stability of ATTM, which would not be unexpected as discussed above.
Applicant argues that in view of Brewer and Cheng, a person of ordinary skill would not have considered combining ATTM with Cheng's delivery systems with any expectation of success of achieving a shelf-stable and orally reliable product since Cheng is silent as to chemical stability and fails to offer any solution to moisture-triggered degradation, while Brewer affirmatively teaches that ammonium TTM is too unstable for routine oral use.
Applicant’s argument has been fully considered but found not to be persuasive for reasons discussed above.
Applicant argues that laundry list disclosures in the cited references do not teach or suggest a combination of ATTM and DEC since Cheng discloses the use of TTM but not ATTM and Dec is an antifilarial agent but Cheng does not provide preference for antifilarial agents.
Applicant’s argument has been fully considered but found not to be persuasive. A reference that “discloses a multitude of effective combinations does not render any particular formulation less obvious.” Merck & Co., Inc. v. Biocraft Labs., Inc., 874 F.2d 804, 807 (Fed. Cir. 1989). Further, a reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art. See MPEP 2123. Therefore, as discussed above, one of ordinary skill in the art would have considered ATTM to be a suitable API for inclusion in the capsular drug dosage form of Cheng in view of the teachings of Cheng and Brewer. Further, as discussed above, the composition of Cheng may comprise multiple APIs used to treat liver disease and Brewer discloses wherein the composition further comprises anti-inflammatory agents and treats liver disease. Accordingly, it would have been obvious to one of ordinary skill in the art to have incorporated diethylcarbamazine (DEC) into the composition of Cheng in view of Brewer since anti-inflammatory agents may be used in combination with ATTM to treat liver disease as taught by Brewer and DEC is a known and effective anti-inflammatory agent for inflammation associated with liver disease as taught by Santos da Silva. Also, having to select from various lists and locations in a reference does not mean the claimed invention is nonobvious since combining prior art elements supports a conclusion of obviousness. See MPEP 2143(I)(A). As such, Applicant’s argument is unpersuasive.
Applicant argues that the teachings of Santos da Silva cannot be incorporated into the presently claimed composition because the DEC of Santos da Silva was administered directly to the stomach of mice at a dose 16-40 times higher than the presently claimed delayed release oral form composition.
Applicant’s argument has been fully considered but found not to be persuasive. A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art. See MPEP 2123. Santos teaches that mice received a solution of DEC administered orally (page 364, 2.3 Experimental groups). Thus, one of ordinary skill in the art would have considered DEC suitable for oral administration. Further, where 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. See MPEP 2144.05(II)(A). As discussed above, Santos da Silva teaches that DEC is a known and effective anti-inflammatory agent for inflammation associated with liver disease and that DEC treatment at 50 mg/kg inhibits hepatic injury and decreases inflammatory infiltration induced by ethanol consumption. Thus, one of ordinary skill in the art would have arrived at the claimed amount of DEC through routine experimentation depending on the amount necessary to effectively inhibit hepatic injury and decrease inflammatory infiltration.
Applicant argues that the Office's position fails to consider the claimed invention as a whole and relies on impermissible hindsight reasoning.
Applicant’s argument has been fully considered but found not to be persuasive. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Applicant argues that the superior and synergistic results from the combination of ATTM and Dec in a first capsule within a second capsule oral form, as evidenced in the instant specification, would not have been obvious to one of ordinary skill in the art.
Applicant’s argument has been fully considered but found not to be persuasive. The studies provided in the Declaration of April 16, 2025 are discussed above. An affidavit or declaration under 37 CFR 1.132 must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. See MPEP 716.02(e). The data provided from the Applicant in all forms, including Declarations and the instant specification, do not provide comparative results of formulations comprising combination of ATTM and Dec in a first capsule within a second capsule oral form. Although the instant specification discloses that diethylcarbamazine (DEC) greatly enhances the efficacy of TTM in paragraph [0010], Applicant has not provided any objective evidence supporting Applicant’s assertion. Mere conclusory statements in the specification, unsupported by objective evidence, are entitled to little weight when the PTO questions the efficacy of those statements. In re Greenfield, 571 F.2d 1185, 197 U.S.P.Q. 227, 229 (C.C.P.A. 1978). Therefore, since Applicant’s argument is merely speculative, Applicant’s argument is unpersuasive.
Applicant argues that claims to a pharmaceutical composition comprising the combination of TTM and DEC have been allowed in an issued patent that includes broader subject matter, therefore the instant claims are allowable.
Applicant’s argument has been fully considered but found not to be persuasive. The Examiner submits that in view of the maintained prior art rejections discussed above, the instant claims are not allowable.
Applicant argues that Kim, Wang, and Schor fail to remedy the deficiencies of Cheng, Brewer, and Santos da Silva.
Applicant’s argument has been fully considered but found not to be persuasive. The Examiner submits that Applicant’s argument with regards to Koopaei is addressed above and is unpersuasive. Therefore, these rejections are maintained.
Response to Affidavit/Declaration
The arguments of the Affidavit/Declarant filed 02/09/2026 have been fully considered and are addressed above.
Conclusion
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.
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/S.J.K./ Examiner, Art Unit 1614
/TRACY LIU/ Primary Examiner, Art Unit 1614