87632
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 .
Election/Restrictions
Applicant’s election of Group II, claims 24-30, drawn to a method for treating a disorder, and the following species: a formulation comprising domperidone, polyethylene oxide 303, and polyethylene glycol has a MW of about 400 as the pharmaceutical formulation species, and insufficient lactation as the disorder species is maintained.
Please note the elected “polyethylene oxide 303” is construed in light of page 10, paragraph [0039] of the instant specification that discloses: “[i]n yet other embodiments, the nonionic poly (ethylene oxide) is polyethylene oxide 303”; and therefore, the Examiner has determined that the elected polyethylene oxide 303 is a species of nonionic poly (ethylene oxide) polymer.
Claims 20-21 and 43 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
Expansion of Election of Species Requirement
A reasonable and comprehensive search of the elected species conducted by the Examiner
discover a prior art by Hughey et al. (US 9,943,513 B1; cited in the previous Office Action) that renders obvious the claimed formulation (see rejection below), wherein the prior art teaches also teaches other species of nonionic poly (ethylene oxide) polymer, including polyethylene oxide 301. In light of this discovery, the search is expanded to the subject matter of the formulation to include polyethylene oxide 301 in addition to the elected species of nonionic poly (ethylene oxide) polymer (i.e., polyethylene oxide 303), such that it does not encompass the full scope of the claim.
Status of Claims
Acknowledgement is made of the receipt and entry of the amendment to the claims filed on December 19, 2025, wherein claims 1-16, 18, 22, 28-38, 40-42 and 44 are cancelled; claims 17, 19-21, 25-27 and 43 are unchanged; and claims 23-24 and 39 are amended; claims 45-46 are newly added.
Claims 17-21, 23-27, 39, 43 and 45-46 are pending.
Claims 20-21 and 43 remain withdrawn.
Claims 17, 19, 23-27, 39, and 45-46 are under examination in accordance with the elected species.
Priority
The instant application 17/287,632 filed on April 22, 2021 is a 371 of PCT/US2019/058037 filed
on October 15, 2019, which claims priority to, and the benefits of U.S. Provisional Application No.
62/750,480 filed on October 25, 2018.
Action Summary
Applicant’s amendment to the claims overcome each and every objection previously sets
forth in the Non-Final Office Action mailed on December 18, 2025.
Claims 16-19, 23-27, 39, 41 and 44 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement are withdrawn in light of the claim amendments.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 45 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention (newly applied as necessitated by amendment).
Regarding the newly added claim 45, the claim recites the limitation of “wherein the formulation comprises 75% (w/w), based on the weight of the formulation, of the nonionic polyethylene glycol”, and there is insufficient written basis for the nonionic polyethylene glycol to have 75% weight-by-weight percentage in the formulation.
Applicant has failed to discloses “75% (w/w), based on the weight of the formulation, of the nonionic polyethylene glycol”, aside from a recitation in the newly added claim that such weight-by-weight percentage are contemplated for use in the invention. It is noted that the specification only describes the nonionic polyethylene glycol at the weight by weight percentage shown below:
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, and that does not include “75% (w/w)”. Therefore, it is not apparent that applicant was actually in the possession of “wherein the formulation comprises 75% (w/w), based on the weight of the formulation, of the nonionic polyethylene glycol”.
This is a new matter rejection.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 24 and 46 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention (newly applied as necessitated by amendment).
Regarding claim 24, the term “about” in the phrase of “about 400,000 to about 8,000,000” renders the claims indefinite. While the specification describes the term “about” in paragraph [0014] of the specification shown below:
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, it does not provide a standard for ascertaining the requisite degree of the term “about”. When the term “about” is used in the context of numerical range, it suggests an approximation or estimate that does not have a precise or exact boundary for the numerical range. Therefore, one of ordinary skill in the art would not be reasonably apprised of the scope of the term “about".
Regarding claim 46, the recitation of “(ii) 15% (w/w)… of a nonionic poly(ethylene oxide) polymer, and (iii) 75% (w/w)… of a polyethylene glycol” renders the claim indefinite, because “polyethylene glycol” can be considered a nonionic poly(ethylene oxide) polymer; and therefore, it is not clear if the “nonionic poly(ethylene oxide) polymer” and the “polyethylene glycol” are both referring to the same polymer. Please note the term “poly (ethylene oxide)” and the term “polyethylene glycol” are chemically synonymous and used interchangeably to refer to polymers composed of repeating subunits of identical structure called monomers, as evidenced by Kabanov (Adv Drug Deliv Rev, 2006. Vol. 58(15): 1597–1621; cited in the previous Non-Final Office Action mailed on December 18, 2025) (see page 4, footer) and polyethylene glycol encyclopedia (Chemeurope. [Online]. Published online one June 5, 2016; cited in the previous Non-Final Office Action mailed on December 18, 2025) (see e.g., first paragraph).
In order to advance prosecution, the Examiner is examining claim 46 to the extent that the “nonionic poly (ethylene oxide) polymer” recites therein is referring to a nonionic poly (ethylene oxide) polymer with a molecular weight of 400,000 to 8,000,000; and “polyethylene glycol” recites therein is referring to a nonionic poly(ethylene oxide) polymer/polyethylene glycol with a molecular weight of 300 to 1000.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 45 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends (newly applied as necessitated by amendment).
Regarding claim 45, the recitation of “the formulation comprises 75% (w/w), based on the weight of the formulation, of the nonionic polyethylene glycol” fails to further limit the nonionic polyethylene glycol of claim 24, which it depends. It is noted that claim 24 recites “a formulation comprising…10 to 15% (w/w), based on the weight of the formulation, of a nonionic poly(ethylene oxide) polymer having a molecular weight (Mw) of about 400,000 to about 8,000,000”; and therefore 75% (w/w) exceed the upper limit of 15% (w/w).
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 non-obviousness.
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.
Claims 17, 19 and 23-27 remain rejected and claims 39 and 45 are rejected under 35 U.S.C. 103 as being unpatentable over Asztalos et al. (Journal of Human Lactation., 2017. Vol. 33(1): 181-187), in view of Hughey et al. (US 9,943,513 B1) and Soldano et al. (US 2017098046 A1; cited under “U.S. Patent Application Publication”, cited no. 2 in IDS filed on April 24, 2021) (partially newly applied as necessitated by amendments).
Asztalos et al. teaches mothers of preterm infants often are at risk of expressing an inadequate amount of milk for their infants and the use of galactogogues is often considered (see e.g., p. 181, “Background”). Asztalos et al. further teaches the EMPOWER study enrolled mothers of preterm infants with milk volume reduction, in which the reduction of milk volume was confirmed by lactation support personnel at the center (see e.g., p. 182, left column, “Sample” section). Asztalos et al. further teaches the studies demonstrates the proportion of mothers who achieve a 50% increase in expressed milk volume on day 14 was significantly higher in Group A (intervention group: domperidone 10 mg orally three time daily for 28 days) compared with Group B (comparison group: placebo 10 mg orally three times daily for 14 days followed by domperidone 10 mg orally three times daily for 14 days) (see e.g., p. 184, right column, line 6-11 under Table 2; p. 183, first paragraph under “Setting”; Table 2). Asztalos et al. further teaches mother who had started domperidone 2 weeks later were still able to produce milk at similar volume to mother who had started 2 weeks earlier (see e.g., p. 185, right column under “Discussion”). Asztalos et al. further teaches over the 3 years of the study, there were four warnings issued regarding the risk of Q-Tc prolongation, cardiac arrhythmias and sudden death (see e.g., p. 186, right column, 3rd paragraph).
Aszralos et al. does not teach the claimed formulation (5 to 10% (w/w) of domperidone, 10 to 15 % (w/w) of nonionic poly (ethylene oxide) polymer, and 70 to 75% (w/w) of polyethylene glycol). Aszralos et al. also does not teach the elected nonionic poly (ethylene oxide) polymer (polyethylene oxide 303), and the elected polyethylene glycol (polyethylene glycol 400 with a Mw of 400).
Hughey et al. teaches a tamper resistant oral controlled release matrix composition shown below:
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(see e.g., Table 7); and these are exemplary compositions comprising: (a) one or more flowability enhancer; (b) one or more release modifier; and (c) one or more active pharmaceutical ingredients (see e.g., Col. 8, line 7-12). Hughey et al. further teaches in one embodiment, the composition comprises: (a) about 35% to about 70% of one or more flowability enhancer; (b) about 20% to about 50% by mass of one or more release modifier; and (c) about 1% to about 30% by mass of one or more active pharmaceutical ingredients (see e.g., Col. 3, line 44-49). Hughey et al. further teaches suitable flowability enhancer have surfactant like properties, and the exemplary and non-limiting flowability enhancer may comprise, inter alia, polyethylene glycol (molecular weight of about 200 or greater) (see e.g., Col. 20, line 32-36). Hughey et al. further teaches the release modifier may comprise a high molecular weight polyethylene oxide having a molecular weight of about 7,000,000 (see e.g., Col. 22, line 22-24), and the polyethylene oxide polymer is POLYOXTM WSR-303 (molecular weight ≈ 7,000,000) (see e.g., Col. 23, line 2-4). Hughey et al. further teaches the addition of one or more flowability enhancers increases the flowability of the one or more release modifier (e.g., high molecular weight polyethylene oxide), and thus, provide for a flowable matrix suitable for encapsulation in soft or hard capsule shells (see e.g., Col. 25, line 61-67). Hughey et al. further teaches the controlled release pharmaceutical composition releases one or more active pharmaceutical ingredients over a period of about 12 hours (see e.g., Col. 19, line 1-4). Hughey et al. further teaches administration of a therapeutically effective amount of one or more pharmaceutical compositions is useful for treating, retarding the progression of, prophylaxis of, delaying the onset of, ameliorating, or reducing the symptoms of, inter alia, gastroparesis (see e.g., Col. 63, line 46-67). Hughey et al. further teaches the process of heating and colling the matrices comprising polyethylene oxide and a suitable flow ability enhance further allow for reduced levels of polyethylene oxide to be used, while exhibiting effective abuse deterrent and controlled release properties (see e.g., Col. 26, line 40-45). Hughey et al. further teaches in another aspect, the one or more release modifier comprises, inter alia, about 20%, or about 50% of the matrix fill mass (see e.g., col. 24, line 21-24). Hughey et al. further teaches the release modifier may comprise a high molecular weight polyethylene oxide having a molecular weight of about 4,000,000 (see e.g., Col. 22, line 17-19); and in one aspect, the polyethylene oxide polymer is POLYOXTM WSR-301 (molecular weight ≈ 4,000,000) (see e.g., Col. 23, line 4-6).
Soldano et al. further teaches the safety of domperidone is dependent upon its metabolism, and a decreased metabolism renders a drug to have a longer residence time in the body (see e.g., [0033]). Soldano et al. further teaches an extended dosage form, including controlled release, releases active at a predetermine rate over time in order to maintain a constant drug concentration for a specific period of time with minimum side effects (see e.g., [0130]). Soldano et al. further teaches the dosage form can be a liquid filled soft gel capsule that may contain formulation for controlled release (see e.g., [0243]). Soldano et al. further teaches the composition can also be formulated into a dosage form, and can exhibit extended-release profiles, releasing active for a period of a few hours up to 12 hours after ingestion (see e.g., [0229]).
In the present case, Asztalos et al. teaches significantly greater proportion of mothers with reduced milk volume achieves a 50% increase in expressed milk after oral administration of domperidone for 2 weeks; and that is a method for treating insufficient lactation in a patient. The difference between the method of Asztalos et al. and the claimed method is that the prior art does not expressly teach the formulation of oral domperidone whereas the claimed method uses the formulation comprising 5 to 10% (w/w) of domperidone or a pharmaceutically acceptable salt thereof, 10 to 15% (w/w) of a nonionic poly (ethylene oxide) polymer, and 70 to 75% (w/w) of a polyethylene glycol. It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to arrive at the claimed invention by modifying the oral domperidone administered in the method of Asztalos et al. into the tamper resistant oral controlled release matrix composition F6 of Hughey et al. by incorporating 9% of the active pharmaceutical ingredient, 10.7% of polyethene oxide (WSR 303), 60% of polyethylene glycol 600, and 8% polyethylene glycol 1000; and then optimizing the weight-by-weight percentage of the polyethylene glycol. One would have been motivated to do so, because Hughey et al. teaches the oral controlled release matrix composition (comprising about 35% to about 70% of one or more flowability enhancer [polyethylene glycol 600 and polyethylene glycol 1000]; about 20% to about 50% by mass of one or more release modifier [polyethene oxide WSR 303 with a molecular weight ≈ 7,000,000]; and about 1% to about 30% by mass of one or more active pharmaceutical ingredients) provides a flowable matrix suitable for encapsulation in soft or hard capsule shell that can releases one or more active pharmaceutical ingredients over a period of about 12 hours; and teaches the flowability enhancer have surfactant like properties and increases the flowability of the one or more release modifier; and Soldano et al. teaches the domperidone in an extended-release form, including controlled release, can maintain a constant drug concentration for a specific period of time with minimum side effects. One would have a reasonable expectation of success to arrive at the claimed invention through routine optimization, because one would have reasonably expected that by formulating the oral domperidone used in the method of Asztalos et al. into the controlled release matrix composition F6 of Hughey et al., which contains 9% of the active ingredient (domperidone), 68% of polyethylene glycol (60% of polyethylene glycol 600 and 8% of polyethylene glycol 1000), and 10.7% of polyethylene oxide [WSR 303]) will successfully increase milk expression by releasing domperidone at a predetermine rate over time with minimum side effects; and therefore, by increasing the weight-by-weight percentage of one or more polyethylene glycol as the flowability enhancer to 70% will successfully increases the flowability of the polyethene oxide WSR 303 as the release modifier when incorporating into a soft or hard capsule shell; and that renders obvious the limitation of “70 to 75% (w/w), based on the weight of the formulation, of a polyethylene glycol having Mw of 300 to 1000” in claim 24. Please note the polyethene oxide WSR 303 is a nonionic poly (ethylene oxide) polymer with a molecular weight ≈ 7,000,000, and that renders obvious the limitation of “nonionic poly (ethylene oxide) polymer…having a molecular weight (Mw) of about 4000,000 to about 8,000,000” in claim 24, and the limitation of “wherein the nonionic poly (ethylene oxide) polymer has a Mw of 7,000,000” in claim 17.
Regarding the limitation of “wherein the polyethylene glycol has a Mw of 400” in claim 19, each of these limitations is drawn to the molecular weight of the polyethylene glycol in the formulation. It would have been prima facie obvious to one of ordinary skill in the art to further modify the oral domperidone composition set forth in the method above to selectively choose to incorporate polyethylene glycol with a molecular weight of 400 as the polyethylene glycol with a molecular weight of about 200 or greater, as taught by Hughey et al. One would have been motivated to do so, because Hughey et al. teaches polyethylene glycol can have a molecular weight of about 200 or greater in the controlled release matrix composition; and specifically exemplify polyethylene glycol 600 and polyethylene glycol 1000 in the working example. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the oral domperidone composition with 70% of polyethylene glycol with a molecular weight of 400, which can be reasonably selected from the teaching of PEG-200, PEG-600, and PEG-1000 as taught by Hughey et al., can successfully increase the flowability of the release modifier as well as exhibits control release properties for treating reduced milk production.
Regarding the limitation of “wherein the formulation comprises 1 to 50 mg of the domperidone” in claim 23, said limitation is drawn to the amount of domperidone in the formulation. It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to incorporate 10 mg of domperidone into the controlled release matrix composition in the method set forth above. One would have been motivated to do so, because Asztalos et al. teaches 10 mg of oral domperidone can increase milk production in mothers with reduced milk volume. One would have reasonably expected that the 10 mg of domperidone taught in the method of Asztalos et al. when formulate into the controlled release composition using the weight percentage of active pharmaceutical ingredients taught by Hughey et al. would successfully minimize side effects and exerts the control release properties.
Regarding the limitation of “wherein the formulation is in the form of…capsule” in claim 27, it would have been prima facie obvious to one of ordinary skill in the art to further modify the oral domperidone composition set forth in the method above to selectively choose to incorporate said composition in to a capsule as taught by Hughey et al. One would have been motivated to do so, because Hughey et al. teaches the matrix composition is suitable for encapsulation in soft or hard capsule shell. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the oral domperidone composition can successfully incorporate into a soft or hard capsule shell for oral administration.
Regarding the limitation of “wherein the formulation comprises 15% (w/w), based on the weight of the formulation, of the nonionic poly (ethylene oxide) polymer” in claim 39, said limitation is drawn to the weight-by-weight percentage of the nonionic poly (ethylene oxide) polymer in the formulation. It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to further modified the method set forth above by optimizing the weight-by-weight percentage of the polyethene oxide WSR 303 in the oral domperidone composition through routine experimentation. One would have been motivated to do so, because Hughey et al. teaches high molecular weight polyethylene oxides, including polyethene oxide WSR 303, are release modifier used for the oral controlled release matrix composition to releases one or more active pharmaceutical ingredients over a period of about 12 hours; and further teaches in some embodiments, the release modifier can be about 20%; and Soldano et al. teaches the domperidone composition with extended release profiles can releasing active for a period of a few hours up to 12 hours after ingestion. One would have a reasonable expectation of success to arrive at the claimed invention including the claimed weight-by-weight percentage through routine optimization, because one would have reasonably expected that by increasing the weight-by-weight percentage of polyethene oxide WSR 303, starting from 10.7%, would successfully adjust the release profile of the oral controlled release matrix composition.
Regarding the limitation of “wherein the formulation comprises 75% (w/w), based on the weight of the formulation, of the nonionic polyethylene glycol” in claim 45, said limitation is drawn to the weight-by-weight percentage of the nonionic polyethylene glycol in the formulation. It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to arrive at the claimed invention by modifying the oral domperidone administered in the method of Asztalos et al. into the tamper resistant oral controlled release matrix composition F4 of Hughey et al. by incorporating 9% of the active pharmaceutical ingredient, 10.7% of polyethene oxide (WSR 303), 10.7 % of polyethylene oxide (WSR 301), 60% of polyethylene glycol 600, and 8% polyethylene glycol 1000; and then optimizing the weight-by-weight percentage of the polyethylene glycol and the weight-by-weight percentage of the polyethene oxide. One would have been motivated to do so, because Hughey et al. teaches the oral controlled release matrix composition (comprising about 35% to about 70% of one or more flowability enhancer [polyethylene glycol 600 and polyethylene glycol 1000]; about 20% to about 50% by mass of one or more release modifier [polyethene oxide WSR 301 with a molecular weight ≈ 4,000,000 and polyethene oxide WSR 303 with a molecular weight ≈ 7,000,000]; and about 1% to about 30% by mass of one or more active pharmaceutical ingredients) provides a flowable matrix suitable for encapsulation in soft or hard capsule shell that can releases one or more active pharmaceutical ingredients over a period of about 12 hours; and teaches the flowability enhancer have surfactant like properties and increases the flowability of the one or more release modifier; and Soldano et al. teaches the domperidone in an extended-release form, including controlled release, can maintain a constant drug concentration for a specific period of time with minimum side effects. One would have a reasonable expectation of success to arrive at the claimed invention including the claimed weight-by-weight percentage through routine optimization, because one would have reasonably expected that by formulating the oral domperidone used in the method of Asztalos et al. into the controlled release matrix composition F4 of Hughey et al., which contains 9% of the active ingredient (domperidone), 68% of polyethylene glycol (60% of polyethylene glycol 600 and 8% of polyethylene glycol 1000), 21.4% of polyethylene oxide (10.7% of polyethene oxide WSR 303 and 10.7% of polyethene oxide WSR 301] will successfully increase milk expression by releasing domperidone at a predetermine rate over time with minimum side effects; and therefore, by increasing the weight-by-weight percentage of one or more polyethylene glycol as the flowability enhancer to 70% will successfully increases the flowability of the polyethene oxide as the release modifier when incorporating into a soft or hard capsule shell; and by increasing the weight-by-weight percentage of one or more polyethylene oxide, including polyethene oxide WSR 301 and polyethene oxide WSR 303, starting from 10.7% to about 50% would successfully adjust the release profile of the oral controlled release matrix composition. 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). In this case, increasing the weight-by-weight percentage of one or more polyethylene glycol (polyethylene glycol 600 and polyethylene glycol 1000) as the flowability enhancer starting from 60% for polyethylene glycol 600, or starting from 8% of polyethylene glycol 1000 to 70% renders obvious the limitation of “70 to 75% (w/w), based on the weight of the formulation, of an polyethylene glycol having a Mw of 300 to 1000”; and increasing the weight-by-weight percentage of one or more polyethylene oxide, including polyethene oxide WSR 301 and polyethene oxide WSR 303, from 10.7% to about 50% renders obvious the limitation of “70 to 75% (w/w), based on the weight of the formulation, of the nonionic polyethylene glycol”.
Therefore, the claimed invention is prima facie obvious to one of ordinary skill in the art, absent factual evidence to the contrary.
Claim 46 is rejected under 35 U.S.C. 103 as being unpatentable over Asztalos et al. (Journal of Human Lactation., 2017. Vol. 33(1): 181-187), in view of Hughey et al. (US 9,943,513 B1) and Soldano et al. (US 2017098046 A1; cited under “U.S. Patent Application Publication”, cited no. 2 in IDS filed on April 24, 2021) (newly applied as necessitated by amendments).
Asztalos et al. teaches mothers of preterm infants often are at risk of expressing an inadequate amount of milk for their infants and the use of galactogogues is often considered (see e.g., p. 181, “Background”). Asztalos et al. further teaches the EMPOWER study enrolled mothers of preterm infants with milk volume reduction, in which the reduction of milk volume was confirmed by lactation support personnel at the center (see e.g., p. 182, left column, “Sample” section). Asztalos et al. further teaches the studies demonstrates the proportion of mothers who achieve a 50% increase in expressed milk volume on day 14 was significantly higher in Group A (intervention group: domperidone 10 mg orally three time daily for 28 days) compared with Group B (comparison group: placebo 10 mg orally three times daily for 14 days followed by domperidone 10 mg orally three times daily for 14 days) (see e.g., p. 184, right column, line 6-11 under Table 2; p. 183, first paragraph under “Setting”; Table 2). Asztalos et al. further teaches mother who had started domperidone 2 weeks later were still able to produce milk at similar volume to mother who had started 2 weeks earlier (see e.g., p. 185, right column under “Discussion”). Asztalos et al. further teaches over the 3 years of the study, there were four warnings issued regarding the risk of Q-Tc prolongation, cardiac arrhythmias and sudden death (see e.g., p. 186, right column, 3rd paragraph).
Aszralos et al. does not teach the claimed formulation (5 to 10% (w/w) of domperidone, 10 to 15 % (w/w) of nonionic poly (ethylene oxide) polymer, and 70 to 75% (w/w) of polyethylene glycol). Aszralos et al. also does not teach the elected nonionic poly (ethylene oxide) polymer (polyethylene oxide 303), and the elected polyethylene glycol (polyethylene glycol 400 with a Mw of 400).
Hughey et al. teaches a tamper resistant oral controlled release matrix composition shown below:
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(see e.g., Table 7 and 15), and these are exemplary compositions comprising: (a) one or more flowability enhancer; (b) one or more release modifier; and (c) one or more active pharmaceutical ingredients (see e.g., Col. 8, line 7-12). Hughey et al. further teaches in one embodiment, the composition comprises: (a) about 35% to about 70% of one or more flowability enhancer; (b) about 20% to about 50% by mass of one or more release modifier; and (c) about 1% to about 30% by mass of one or more active pharmaceutical ingredients (see e.g., Col. 3, line 44-49). Hughey et al. further teaches suitable flowability enhancer have surfactant-like properties, and the exemplary and non-limiting flowability enhancer may comprise, inter alia, monoglycerides, diglycerides, polyethylene glycol (molecular weight of about 200 or greater) (see e.g., Col. 20, line 32-36). Hughey et al. further teaches the release modifier may comprise a high molecular weight polyethylene oxide having a molecular weight of about 7,000,000 (see e.g., Col. 22, line 22-24), and the polyethylene oxide polymer is POLYOXTM WSR-303 (molecular weight ≈ 7,000,000) (see e.g., Col. 23, line 2-4). Hughey et al. further teaches the addition of one or more flowability enhancers increases the flowability of the one or more release modifier (e.g., high molecular weight polyethylene oxide), and thus, provide for a flowable matrix suitable for encapsulation in soft or hard capsule shells (see e.g., Col. 25, line 61-67). Hughey et al. further teaches the controlled release pharmaceutical composition releases one or more active pharmaceutical ingredients over a period of about 12 hours (see e.g., Col. 19, line 1-4). Hughey et al. further teaches administration of a therapeutically effective amount of one or more pharmaceutical compositions is useful for treating, retarding the progression of, prophylaxis of, delaying the onset of, ameliorating, or reducing the symptoms of, inter alia, gastroparesis (see e.g., Col. 63, line 46-67). Hughey et al. further teaches the process of heating and colling the matrices comprising polyethylene oxide and a suitable flow ability enhance further allow for reduced levels of polyethylene oxide to be used, while exhibiting effective abuse deterrent and controlled release properties (see e.g., Col. 26, line 40-45). Hughey et al. further teaches in another aspect, the one or more release modifier comprises, inter alia, about 20%, or about 50% of the matrix fill mass (see e.g., col. 24, line 21-24). Hughey et al. further teaches the release modifier may comprise a high molecular weight polyethylene oxide having a molecular weight of about 4,000,000 (see e.g., Col. 22, line 17-19); and in one aspect, the polyethylene oxide polymer is POLYOXTM WSR-301 (molecular weight ≈ 4,000,000) (see e.g., Col. 23, line 4-6).
Soldano et al. further teaches the safety of domperidone is dependent upon its metabolism, and a decreased metabolism renders a drug to have a longer residence time in the body (see e.g., [0033]). Soldano et al. further teaches an extended dosage form, including controlled release, releases active at a predetermine rate over time in order to maintain a constant drug concentration for a specific period of time with minimum side effects (see e.g., [0130]). Soldano et al. further teaches the dosage form can be a liquid filled soft gel capsule that may contain formulation for controlled release (see e.g., [0243]). Soldano et al. further teaches the composition can also be formulated into a dosage form, and can exhibit extended-release profiles, releasing active for a period of a few hours up to 12 hours after ingestion (see e.g., [0229]).
In the present case, Asztalos et al. teaches significantly greater proportion of mothers with reduced milk volume achieves a 50% increase in expressed milk after oral administration of domperidone for 2 weeks; and that is a method for treating insufficient lactation in a patient. The difference between the method of Asztalos et al. and the claimed method is that the prior art does not expressly teach the formulation of oral domperidone whereas the claimed method uses the formulation comprising 10% (w/w) of domperidone or a pharmaceutically acceptable salt thereof, 15% (w/w) of a nonionic poly (ethylene oxide) polymer, and 75% (w/w) of a polyethylene glycol. It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to arrive at the claimed invention by modifying the oral domperidone administered in the method of Asztalos et al. into the tamper resistant oral controlled release matrix composition F6 of Hughey et al. by incorporating 9% of the active pharmaceutical ingredient, 10.7% of polyethene oxide (WSR 303), 60% of polyethylene glycol 600, and 8% polyethylene glycol 1000; and then optimizing the weight-by-weight percentage of the active pharmaceutical ingredient, the polyethene oxide, and the polyethylene glycol. One would have been motivated to do so, because Hughey et al. exemplified another oral controlled release matrix composition Ex 8 comprising 10% of active pharmaceutical ingredient, 70% of flowability enhancer, 15% of release modifier (e.g., polyethene oxide); and further teaches the oral controlled release matrix composition comprising about 35% to about 70% of one or more flowability enhancer [polyethylene glycol 600 and polyethylene glycol 1000 can provide a flowable matrix suitable for encapsulation in soft or hard capsule shell that can releases one or more active pharmaceutical ingredients over a period of about 12 hours; and teaches the flowability enhancer have surfactant like properties and increases the flowability of the one or more release modifier; and Soldano et al. teaches the domperidone in an extended-release form, including controlled release, can maintain a constant drug concentration for a specific period of time with minimum side effects. One would have a reasonable expectation of success to arrive at the claimed invention through routine optimization, because one would have reasonably expected that by formulating the oral domperidone used in the method of Asztalos et al. into the controlled release matrix composition F6 of Hughey et al., which contains 9% of the active pharmaceutical ingredient (domperidone), 68% of polyethylene glycol (60% of polyethylene glycol 600 and 8% of polyethylene glycol 1000), and 10.7% of polyethylene oxide [WSR 303]) will successfully increase milk expression by releasing domperidone at a predetermine rate over time with minimum side effects; and therefore, by increasing the weight-by-weight percentage of the active pharmaceutical ingredient (domperidone) from 9% to 10%, increasing the weight-by-weight percentage of the polyethene oxide (WSR 303) as the release modifier from 10.7% to 15%, and one or more polyethylene glycol as the flowability enhancer (60% of polyethylene glycol 600 and/or 8% of polyethylene glycol 1000) to 70% will reasonably expected to exert the same or substantially similar control release property as the oral controlled release matrix composition Ex 8, and will reasonably expect to increases the flowability of the polyethene oxide WSR 303 as the release modifier when incorporating into a soft or hard capsule shell.
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). In this case, increasing the weight-by-weight percentage of one or more polyethylene glycol (polyethylene glycol 600 and polyethylene glycol 1000) as the flowability enhancer starting from 60% for polyethylene glycol 600, or starting from 8% of polyethylene glycol 1000 to 70% renders obvious the limitation of “70 to 75% (w/w), based on the weight of the formulation, of a polyethylene glycol”.
Therefore, the claimed invention is prima facie obvious to one of ordinary skill in the art, absent factual evidence to the contrary.
Response to Arguments
Applicant's arguments filed on December 19, 2025 with respect to the rejection of claims 15-19, 23-27, 39, 41 and 44 under 35 U.S.C. 103 as being unpatentable over Asztalos et al. (Journal of Human Lactation., 2017. Vol. 33(1): 181-187), in view of Hughey et al. (US 9,943,513 B1) and Soldano et al. (US 2017098046 A1; cited under “U.S. Patent Application Publication”, cited no. 2 in IDS filed on April 24, 2021) have been fully considered but they are not persuasive.
Applicant amends claim 24 from the recitation of “1 to 20 %(w/w)...of domperidone…10 to 15% (w/w)...a nonionic poly(ethylene oxide) polymer having a molecular weight (Mw) of about 400,000 to about 8,000,000… 70 to 75% (w/w)…of a polyethylene glycol having a Mw of 300 to 1000” to the recitation of “5 to 10 %(w/w)...of domperidone…10 to 15% (w/w)...a nonionic poly(ethylene oxide) polymer having a molecular weight (Mw) of about 400,000 to about 8,000,000… 70 to 75% (w/w)…of a polyethylene glycol having a Mw of 300 to 1000”, which narrows the weight-by-weight percentage of the domperidone, the nonionic poly(ethylene oxide) polymer, and the polyethylene glycol in the formulation. Applicant further amends claim 39 from the recitation of “wherein the formulation comprises 12 to 25% (w/w), based on the weight of the formulation, of the nonionic poly(ethylene oxide) polymer” to the recitation of “wherein the formulation comprises 15% (w/w), based on the weight of the formulation, of the nonionic poly(ethylene oxide) polymer”, such that the nonionic poly(ethylene oxide) polymer is now in a fixed weight-by-weight percentage rather than a range of “12 to 25% (w/w)”. Each of these findings demonstrate that the claim amendment changes the scope of the claims; and therefore, the rejection on the record has been revisit and modified in light of the claim amendments.
In Summary, applicant argues the teachings of Asztalos et al. concludes that domperidone’s risks outweighed its lactation benefits for new mothers by directing attention to the “conclusion” section in page 187 shown below:
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. Based upon said teaching, Applicant argues cardiac safety concerns outweigh the modest increase in lactation, and nothing in Asztalos et al. teaches or suggest cardiac concerns can be addressed simply by reformulation or otherwise. Applicant further argues the dosage form taught by Hughey et al. is directed to preparing tamper-resistant opioid containing dosage forms, not "controlled release" dosage forms (see page 6 of the remark). Applicant argues the obviousness-type rejection requires reasonable chance of being successful in a method of safely treating insufficient lactation, and further argues the teachings of Soldano et al. does not provide reasonable expectation of success lacking prove that a tamper-resistant domperidone formulation would be safer.
In response, applicant’s argument is not found persuasive for the reasons set forth below:
First, it may well be true Asztalos et al. teaches there were cardiac concerns associated with domperidone use; However, just because the prior art teaches domperidone has cardiac risk and suggest careful risk-benefit assessment, that does not mean the domperidone taught by Asztalos et al. cannot support mother to increase their milk volume postdelivery. Solely to rebut applicant’s argument, all medicines have side effects, as evidenced by Allegaert et al. (Arch Dis Child October, 2016. Vol. 101, 10). In other words, there mere fact that domperidone has side effects does not neglect the fact Asztalos et al. teaches significantly greater proportion of mothers with reduced milk volume achieves a 50% increase in expressed milk after oral administration of domperidone (10 mg) for 2 weeks (see e.g., Table 2 of Asztalos et al.). It is also worth noting that Allegaert et al. has indicated “no serious adverse events were reported…there was no evidence of prolongation of Q-Tc interval with any mother participating in the trial” (see e.g., p. 185, left column, last paragraph). Therefore, the suggestion of performing careful risk–benefit assessment does not constitute a teaching away that domperidone is incapable of increasing milk volume in a subject.
Furthermore, the rejection on the record is form on the basis that one would have found it obvious to modify the oral domperidone (10 mg) in the method of Allegaert et al. in light of the fact that Hughey et al. teaches oral controlled release matrix composition suitable for encapsulation in soft or hard capsule shell that can releases one or more active pharmaceutical ingredients over a period of about 12 hours; and the fact that Soldano et al. teaches the domperidone in an extended-release form, including controlled release, can maintain a constant drug concentration for a specific period of time with minimum side effects. In other words, one would have reasonably expected that the oral domperidone formulated in controlled release form can minimize side effects by releasing the active pharmaceutical ingredients over a period of time (about 12 hours). Therefore, applicant’s argument that Asztalos et al. fails to teach the incorporation of controlled release for minimizing side effects is 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).
In response to applicant's argument that Hughey et al. fail to teach “controlled release" dosage forms, this appears to be mere argument without supporting evidence. The exemplary composition(s) cited in the rejection is clearly a controlled release as indicated in the title of the table shown below (see shaded):
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(see e.g., Table 7 and Table 15). Hughey et al. also clearly teaches the controlled release pharmaceutical composition releases one or more active pharmaceutical ingredients over a period of about 12 hours (see e.g., Col. 19, line 1-4). Therefore, applicant’s argument with respect to “controlled release” is not found persuasive.
In response to Applicant’s assertion that the obviousness-type rejection requires reasonable chance of being successful in a method of safely treating insufficient lactation is not found persuasive, it is noted that the feature upon which applicant relies (i.e., “safely treating insufficient lactation”) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). In other words, to the extent that “safely” which applicant relies is referring to have no cardiac side effects, such feature is not in the claim. Given that applicant does not provide any evidence of unexpected results demonstrating the claimed invention has superior benefit (i.e., safety) compared to the prior art(s), these arguments presented by the applicant are not found persuasive for the reasons set forth herein.
In addition, in response to Applicant’s argument that there is no reasonable expectation of success to arrive at the claimed compound because Soldano et al. fails to provide evidence showing that a tamper-resistant domperidone formulation would be safer. In the present case, Soldano et al. clearly teaches the safety of domperidone is dependent upon its metabolism, and further teaches an extended dosage form, including controlled release, can releases active at a predetermine rate over time in order to maintain a constant drug concentration for a specific period of time with minimum side effects shown below (see e.g., [0033;] and [0130]). Therefore, based on the teachings of Soldano et al., one would have reasonably expected that by formulating the oral domperidone used in the method of Asztalos et al. into the controlled release matrix composition taught by Hughey et al. (see rejection(s) set forth above) would successfully increase milk expression by releasing domperidone at a predetermine rate over time with minimum side effects, as taught by Soldano et al., absent factual evidence to the contrary.
Therefore, the rejection has been maintained, but revisited and modified in light of the claim amendments for the reasons set forth herein.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, 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 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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/CHIHYI LEE/Examiner, Art Unit 1628 /JEAN P CORNET/Primary Examiner, Art Unit 1628