DETAILED ACTION
Status of the Claims
Claims 1-19 are pending in the instant application. Claims 11-12 and 14-16 have been withdrawn based upon Restriction/Election. Claims 1-10, 13 and 17-19 are being examined on the merits in the instant application.
Request for Continued Examination
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 03/09/2026 has been entered.
Advisory Notice
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
All rejections and/or objections not explicitly maintained in the instant office action have been withdrawn per Applicants’ claim amendments and/or persuasive arguments.
Priority
The U.S. effective filing date has been determined to be 03/14/2019, the filing date of the PCT/FR2019/050557. Applicant's claim for a priority date of, 03/23/2018, the filing date of document FR-1870330, is acknowledged, however no English translation this document has been provided such that the examiner can find proper written description support therein.
Claim Objections
Claim 4 has the word “is” in line two underlined, which it should not be as this is a marking used to indicated amendments. Applicant should remove the underline from the word “is” in line two of claim 4.
Claims 2-7 and 9-16 are objected to because of the following informalities: The term “Claim” is capitalized in the middle of the sentences. Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
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.
Claims 1-10, 13 and 17-19 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. This is a New Matter rejection.
Scope of the Claimed Invention:
Applicant claims a formulation of at least one digestive enzyme, the formulation comprising: (a) solid lipid particles, the solid lipid particles being strictly hydrophobic so that solid lipid particles are free of water, of organic solvent, of surfactant compound and of polymer, the solid particles have a size comprised between 50 µm and 1200 µm in size,
wherein the solid lipid particle comprising at least one digestive enzyme selected from pancrelipase, pancreatic enzymes, or analogues thereof and a waxy matrix comprising triglycerides that are strictly hydrophobic and non-hydroscopic,
wherein said at least one digestive enzyme represents between 0.1% and 90% of the mass of the formulation and has homogenous distribution in each solid lipid particle of the formulation, said at least one digestive enzyme is distributed without a distribution gradient towards the interior of the waxy matrix so that said at least one digestive enzyme is dispersed into the waxy matrix, even at the surface of said particles, wherein the formulation having a melting point of between 20 °C and 65 ° C, such that combination of said triglycerides present in the waxy matrix, combined with either pancrelipase, pancreatic enzymes, or analogues thereof that are in the solid lipid particles, in the intestinal pH conditions, results in hydrolysis activity of said at least one digestive enzyme of at least 42 mmol of fatty acids of said triglycerides being released within 60 minutes (instant claim 1).
Applicant further claims similar formulations in new claims 18 and 19, each claim reciting “wherein said formulation is configured for re-establishing exocrine pancreatic insufficiency” (lines 14-15 & 15-16, respectively).
Disclosure of the Instant Application:
Applicant has inserted the specific result of Example 4 “such that combination of said triglycerides present in the waxy matrix, combined with either pancrelipase, pancreatic enzymes, or analogues thereof that are in the solid lipid particles, in the intestinal pH conditions, results in hydrolysis activity of said at least one digestive enzyme of at least 42 mmol of fatty acids of said triglycerides being released within 60 minutes” of the instant Specification into a generic claim. The specific result is not specific structure of Example 4.
Applicant points to paragraphs [0027] and [0063] for support of the limitation “wherein said formulation is configured for re-establishing exocrine pancreatic insufficiency”. Paragraph [0027] disclosing: “The invention relates to a formulation in the form of solid, strictly hydrophobic lipid particles, containing one or more enzymes for re-establishing exocrine pancreatic enzymatic function in the intestine.” And paragraph [0063] reciting: “Thus, one subject of the invention is a formulation of digestive enzymes in a waxy matrix in the form of solid lipid particles, for re-establishing the exocrine pancreatic enzymatic function in the intestine.”
Discussion:
Applicant has inserted the result of Example 4 from the instant Specification - “such that combination of said triglycerides present in the waxy matrix, combined with either pancrelipase, pancreatic enzymes, or analogues thereof that are in the solid lipid particles, in the intestinal pH conditions, results in hydrolysis activity of said at least one digestive enzyme of at least 42 mmol of fatty acids of said triglycerides being released within 60 minutes” - into a generic claim which is not limited to structure of Example 4. Example 4 is insufficient to support the broadly generic claim because it is a single example within the scope of the broadly recited formulation. Therefore it is considered new matter as lacking a necessary structure (i.e. structure of Example 4) with a result (result of Example 4). The instant Specification simply dose not disclose the broader scope of “wherein said formulation is configured for re-establishing exocrine pancreatic insufficiency” which is not disclosed in the as-filed Application. Claims 2-10, 13 and 17 are rejected as depending from and inheriting the limitation of the parent claim(s).
Claim Rejections - 35 USC § 112(d)
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 13 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.
Claim 1 recites “at least one digestive enzyme selected from pancrelipase, pancreatic enzyme, or analogues thereof” (claim 1, lines 5-6). Claim 13 recites “wherein the at least one digestive enzyme is a lipase” which is broader than the limited digestive enzymes of the base claim 1.
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
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-10, 13 and 17-19 are rejected under 35 U.S.C. 103 as being unpatentable over RAYNAL (US 2010/0086595; published April 8, 2010) in view of FALLON (US 2010/0260857; published October, 2010); CUCA (US 5,494,681; published February, 1996), TOMOHIRA (US 2009/0047357; published February, 2009); DIORIO (US 2017/0354599; published December, 2017) and Rosiaux et al. (“Solid Lipid Excipients as Matrix Agents for Sustained Drug Delivery,” 2015, pp. 237-271).
Applicants Claims
Applicant claims a formulation of at least one digestive enzyme, the formulation comprising: (a) solid lipid particles, the solid lipid particles being strictly hydrophobic so that solid lipid particles are free of water, of organic solvent, of surfactant compound and of polymer, the solid particles have a size comprised between 50 µm and 1200 µm in size,
wherein the solid lipid particle comprising at least one digestive enzyme selected from pancrelipase, pancreatic enzymes, or analogues thereof and a waxy matrix comprising triglycerides that are strictly hydrophobic and non-hydroscopic,
wherein said at least one digestive enzyme represents between 0.1% and 90% of the mass of the formulation and has homogenous distribution in each solid lipid particle of the formulation, said at least one digestive enzyme is distributed without a distribution gradient towards the interior of the waxy matrix so that said at least one digestive enzyme is dispersed into the waxy matrix, even at the surface of said particles, wherein the formulation having a melting point of between 20 °C and 65 ° C, such that combination of said triglycerides present in the waxy matrix, combined with either pancrelipase, pancreatic enzymes, or analogues thereof that are in the solid lipid particles, in the intestinal pH conditions, results in hydrolysis activity of said at least one digestive enzyme of at least 42 mmol of fatty acids of said triglycerides being released within 60 minutes (instant claim 1).
Applicant further claims the solid lipid particles have a size between 150 µm and 800 µm (claim 2) or 250 µm and 550 µm (claim 17).
Applicants have elected the following species in the reply filed 09/05/2023: (a)(i) at least one digestive enzyme is lipase, (a)(ii) a material (or combination thereof) of the non-hygroscopic waxy matrix is triglycerides, and (a)(iii) a form of the galenical preparation is a powder.
Claim interpretation: The examiner is interpreting the claim “only one species of digestive enzyme” as a chemically distinct single enzyme such as pancreatin consistent with Applicants Examples. The examiner is interpreting “forming a mixture of digestive enzyme” (claim 7, lines 3-4) as being a mixture of the “only one species of digestive enzyme”.
Determination of the scope
and content of the prior art (MPEP 2141.01)
RAYNAL teaches lipid particles with no surfactants or emulsifiers, comprising a lipid hydrophobic matrix that is non-ionizable at physiological pH in which the active ingredient(s) are dispersed, the lipid particles suitable for administration via the oral route (see whole document, particularly the abstract). RAYNAL teaches their "invention also concerns a process to mask the taste of active ingredients and/or to protect the active ingredients against degradation reactions and/or to modulate the rate of release of the active ingredients, characterized in that lipid particles are prepared without any surfactants or emulsifiers and comprise a lipid, hydrophobic matrix non-ionizable at physiological pH in which the active ingredient( s) are dispersed." [emphasis added]([0009]). RAYNAL teaches that: "The matrix may advantageously be called "strictly hydrophobic" insofar as it does not contain detectable traces of water." [emphasis added]([0010])(instant claim 19 – “solid lipid particles being strictly hydrophobic so that solid lipid particles are insoluble in water, free of water, […], such that the solid lipid particles are unable to make hydrolysis or oxidation reactions”). RAYNAL teaches that: "The lipid, hydrophobic matrix is advantageously chosen from among natural or synthetic oils or waxes that cannot be ionized at physiological pH, and their mixtures and in particular triglycerides and derivatives, palm oil, Carnauba wax, Candelilla wax, Alfa wax, cocoa butter, vegetable waxes, rice wax, hydrogenated jojoba wax or florali absolute waxes, beeswaxes and modified beeswaxes, fatty alcohols, esters of fatty acids and of alcohols with high molecular weight, sterols such as cholesterol and its esters, vegetable oils such as olive oil, groundnut oil, oils of hydrophobic silicones, cyclomethicones, vaseline, paraffin oil, paraffin, linear alkanes and their mixtures." ([0012]). RAYNAL teaches that: "The composition is more particularly devoid of any traces of water or organic solvents. It is strictly hydrophobic." ([0013]).
RAYNAL teaches that: "The active ingredient or ingredients are dispersed in the lipid matrix, and are essentially distributed with constant concentration in said matrix." ([0014 ]). And that: "The particles advantageously have an active ingredient filling ratio of between 0.10 and 2 grams/gram of hydrophobic lipid matrix [ ... ]." ([0015]). And that: "They preferably have a melting point of between 15 and 85° C., more preferably between 30 and 45° C." ([0016])(instant claims 1 & 3, “the melting point”). And that: "Their size advantageously lies between 0.5 and 1500 μm, [ ... ]." ([0018])(instant claims 1, 2, 17).
RAYNAL teaches that: “The active ingredient or ingredients are dispersed in the lipid matrix, and are essentially distributed with constant concentration in said matrix.” ([0014])(instant claim 1, “in which said at least one digestive enzyme has [a] homogenous distribution in each solid lipid particle”).
RAYNAL teaches that: “The filling ratio of the particles may extend from 0.02% to 75% relative to the weight of the particles. The person skilled in the art knows that when these components are incorporated in the particles […].” ([0043])(instant claim 1, “in which said at least one digestive enzyme has [is] represents between 0.1% and 90% of the mass of the formulation”; instant claim 9).
RAYNAL teaches that: “The lipid particles of the invention can therefore be directly formulated as powders, compressed powders […].” ([0048])(instant 10). RYNAL teaches the inclusion of lubricating agents such as talc, starches, silica ([0049])(instant claim 8).
RAYNAL teaches the inclusion of enzymes as active ingredients ([0043] & claim 9), however, RAYNAL does not teach inclusion of the digestive enzyme species lipase.
Ascertainment of the difference between
the prior art and the claims (MPEP 2141.02)
The difference between the rejected claims and the teachings of RAYNAL is that RAYNAL does not expressly teach the biological extract includes digestive enzymes, and particularly a lipase; and RAYNAL teaches that: “Since the lipid particles are devoid of active ingredient on their surface, it is not necessary to have recourse to coating the particles to mask the taste of the active ingredients and/or to protect the active ingredients against degradation reactions and/or to modulate the rate of release of the active ingredients.”
Rosiaux et al. teaches Solid Lipid Excipients as Matrix Agents for Sustained Drug Delivery (title), and teaches “The melt & mix method is very similar to molding. The lipid SR agent is melted and the active substance (and/or additional ingredients) dispersed within the melt. Unlike the molding process, the drug-lipid mass is not directly cast into a mold but cooled down and ground into granules or powder, which can then be filled into capsules or compressed into tablets.” (p. 246, §9.2.1.5, Melt & Mix Methods). RAYNAL teaches that “Finally, the particles can be used in conventional galenic formulations of the type hard capsules, soft capsules, granules, oral powders, dispersible powders, tablets, water dispersible and oral-dispersible tablets.” ([0049]). In the embodiment where the powders are filled into a capsule or compressed into tablets one of ordinary skill in the art would have clearly recognized that “Elimination of active ingredient on the surface is obtained, for example, by washing the particles or by any other suitable method.” would be unnecessary as the lipid particles would not contact the taste sensory organs of the mouth. This is also the case where the lipid particles are subsequently coated, for example an enteric coating to protect the lipid particles from degradation in stomach acid. Therefore, one of ordinary skill in the art would have been motivated to save time and money by skipping the step of washing the surface of the particles in formulations where it is not required for taste masking such as with capsules/tablets/enteric coated lipid particles.
FALLON teaches a coated digestive enzyme preparation and enzyme delivery system and pharmaceutical compositions containing the same for treating persons having ADD, ADHD, autism, cystic fibrosis and other behavioral and neurological disorders (see whole document, particularly the abstract).
FALLON teaches that “The present invention relates generally to coated
digestive/pancreatic enzyme preparations, and pharmaceutical compositions and enzyme delivery systems comprising the preparations, as well as methods for their preparation, use, and controlled delivery in treating individuals with neurological or behavioral diseases or conditions susceptible to treatment with enzymes.” ([0001]).
And that: “Digestive enzymes have been administered to mammals to treat enzyme deficiencies caused by conditions affecting the pancreas, such as pancreatitis and pancreatic enzyme deficiency.” ([0003]). And that: “In one aspect, this invention relates to the use of a lipid encapsulation method to make a coated digestive enzyme preparation for specific delivery times within the human gastrointestinal (GI) tract targeted for use in the treatment of a specific disease or condition. This disease or condition may be caused by or characterized by a digestive deficit that can be treated by the administration of digestive enzymes to the appropriate region of the GI tract.” ([0085]), and teaches “pancreatic insufficiency” ([0216])(instant claims 18 & 19 – “wherein said formulation is configured for re-establishing exocrine pancreatic insufficiency.”).
FALLON teaches that: "the enzyme present in an amount of from about 5% to 90% by weight of the particles" ([0009]). FALLON further teaches that: "In some aspects, the encapsulated pancreatic/digestive enzyme preparations are prepared to obtain specific delivery times or specific regions within the human gastrointestinal (GI) tract." ([0013 ]). And further that: "In addition, the invention relates to the delivery to humans of pancreatic/digestive enzyme composites, preparations, enzyme delivery compositions or systems comprising no or fewer excipients, carriers, additives and/or extenders, and/or requiring the use of no or fewer solvents' in the enzyme preparations. [ ... ] The invention further relates to the delivery of pancreatic and/or digestive enzymes with improved safety of administration." [emphasis added]([0018])(instant claims 1, 18 and 19, “pancreatic enzymes”).
Regarding the limitation “such that combination of said triglycerides present in the waxy matrix, combined with either pancrelipase, pancreatic enzymes, or analogues thereof that are in the solid lipid particles, in the intestinal pH conditions, results in hydrolysis activity of said at least one digestive enzyme of at least 42 mmol of fatty acids of said triglycerides being released within 60 minutes”, the compositions of FALLON are clearly directed at treating enzyme insufficiency, and particularly pancreatic enzyme insufficiency, such that it would have been within the ordinary level of skill to formulate a wax-matrix-particle consistent with the teachings of RAYNAL and FALLON having the desired release profile for treating the same. Therefore the limitation would have been obvious to one of ordinary skill utilizing pancreatic enzymes for the treatment of pancreatic enzyme insufficiency.
FALLON teaches that: "Delivery of digestive enzymes can also be challenging due to the rapid degradation and denaturing of enzymes at ambient room temperature, as well as the enhanced degradation and denaturing that can occur with high temperature, pressure, humidity and/or exposure to light. Moisture and heat together can quickly destabilize enzymes, reducing their effectiveness, and shortening shelf life, leading to inaccurate dosing. Denaturization or destabilization of the enzymes can reduce their effectiveness by reducing the dose of active enzymes to less than the amount needed for effective treatment. Alternatively, attempting to compensate for the denaturization or destabilization by increasing the dose to ensure an effective level of active enzyme, could risk an overdose or overfilling a capsule or other dosage form. To protect and stabilize the pancreatic/digestive enzyme from unfavorable conditions, such a penetration, decomposition, the pancreatic/ digestive enzyme (core) may be coated or encapsulated in a continuous coating containing an emulsifiable lipid. In another aspect, this invention provides new coated enzyme preparations with improved shelf life." ([0043 ]).
FALLON teaches that: “Digestive enzyme, can include, for example, one or more enzymes from more or more sources mixed together. This includes, for example, the addition of single digestive enzymes […]. The digestive enzyme may be, for example a pancreatin/pancrelipase composition.” ([0059]), and teaches lipases ([0067], Table 6, “Lipase (USP)”)(instant claim 1, digestive enzyme; instant claim 1, pancrelipase; instant claims 6-7 “only one digestive enzyme”).
CUCA teaches tasteless pharmaceutical materials comprising an active material, and a waxy matrix material (title, abstract, see whole document), and particularly that:
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(col. 6, lines 31-46). DIORIO teaches a similar lipid particulate composition made by feeding a melt composition onto a spinning disc (toroidal ring) to form droplets (Figure 1), the active agents including biological actives such as proteins ([0020]). DIORIO teaches their process includes forming a molten mixture (“the mixture of an active agent and matrix materials are sufficiently mixed and heated to fluidize the mixture sufficiently to allow it to be atomized into droplets.”), which is then delivered to an atomizer that breaks the molten mixture into small droplets, which are then contacted with a gas at a temperature below the solidification temperature of the molten mixture ([0051] through [0054]). TOMOHIRA teaches methods of producing drug-containing wax matrix particles, “Drug-containing wax matrix granules having at least one wax and at least one drug are produced by the following steps (i) and (ii): (i) supplying the at least one drug and the at least one wax to an extruder in which the temperature of a barrel and the temperature of a die are adjusted to be higher than the melting point of the at least one wax; and (ii) while melting and kneading the at least one drug and the at least one wax in the extruder to give a molten kneaded drug and wax, spraying the molten kneaded drug and wax into an atmosphere having a temperature lower than the melting point of the wax from a spray nozzle directly mounted onto a die provided at a top end of the barrel of the extruder, thereby forming the mixture into granules.” (see whole document, particularly title, abstract, and Figures 1-2).
Finding of prima facie obviousness
Rationale and Motivation (MPEP 2142-2143)
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to include the pancreatic/digestive enzymes of FALLON in the waxy matrix formulation of RANYAL for controlled and sustained delivery of the pancreatic/digestive enzymes to treat enzyme deficiencies caused by conditions affecting the pancreas, such as pancreatitis and pancreatic enzyme deficiency.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention because methods of making solid lipid particles using a spinning disc atomizer, spray atomizer, were known to those having technical knowledge in the art to which the invention pertains as evidenced by CUCA, TOMOHIRA, and DIORIO. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103(a).
Response to Arguments:
Applicant's arguments filed 03/09/2026 have been fully considered but they are not persuasive.
Applicant argues that: “Raynal teaches using lipid particles devoid of active ingredients on their surface (§0046-47). Thereby, active ingredients are contained at the center of the lipid particles. Raynal discloses through paragraphs [0044] and [0045] a general list of active ingredients that does not contain pancrelipase. The examples recited by Raynal also do not contain pancrelipase […] In matter of active ingredient, Raynal's teaching is a general disclosure that does not disclose the integration of pancrelipase in a waxy matrix.”) (p. 9, paragraphs 2-3).
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicant further argues that: “The method for producing lipid particles taught by Raynal's disclosure necessary provides spherical lipid particles into which active principle is concentrated in a core because of the washing step ([Last sentence]). The spherical form of Raynal particles is obtained during the step of adding, into an aqueous gel, the mixture of lipid phase and active principle, namely, the ibuprofen. Indeed, the one skilled knows that when a lipid phase is immersed into an aqueous medium, namely the aqueous gel "aqueous gel of Carbopol Ultrez 10 neutralized to pH 6.2 with sodium hydroxide" (see, §60), the hydrophobic interactions with aqueous medium manage the lipid phase to form lipid particles with a perfect spherical shape.”
In response the examiner argues that the main purpose of RAYNAL is to formulate active ingredients in a waxy matrix for sustained delivery - “The present invention concerns a novel hydrophobic galenic system allowing improved masking of the taste of the active ingredients it contains, the stability of said active ingredients and, when applicable, their sustained release. The galenic system of the invention is suitable for the preparation of pharmaceutical or veterinary preparations, in particular for administration via oral route or via injection.” ([0001]). RAYNAL claims: “A process to mask the taste of active ingredients and/or to protect active ingredients against degradation reactions and/or to modulate the rate of release of active ingredients, wherein lipid particles are prepared without any surfactants or emulsifiers comprising a lipid hydrophobic matrix that is non-ionizable at physiological pH, in which the active ingredient(s) are dispersed such that the surface of the lipid particles is devoid of active ingredient.” [emphasis added](claim 1). Where “mask the taste of active ingredients” is claimed in the alternative unambiguously making clear to one of ordinary skill in the art that this is but one embodiment of the claimed invention. This is also make clear in US 2007/0116728 in paragraph [0086]: “According to one particular embodiment of the process according to the invention, when the active constituent has to be completely eliminated from the surface of lipidic particles, the invention includes a step to wash the said particles obtained with a washing mix including ethanol. In this case, the presence of ethanol in the washing mix is essential to the process since ethanol enables complete washing of any active constituent residues that may be present on the surface of the lipidic particles that could create an unpleasant taste.” RAYNAL teaching that: “Preferably, the lipid particles of the invention are devoid of active ingredient on their surface. Elimination of active ingredient on the surface is obtained, for example, by washing the particles or by any other suitable method.” ([0046]). MPEP §2123 – “Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments.”
Certainly “improved masking of the taste” is one objective but clearly not applicable to all embodiments such as “via injection” and in oral formulations where taste masking is not an issue such as capsules/tablets for swallowing. RAYNAL teaches: “Finally, the particles can be used in conventional galenic formulations of the type hard capsules, soft capsules, granules, oral powders, dispersible powders, tablets, water dispersible and oral-dispersible tablets.” [0049]. Clearly encompassing such formulations which one of ordinary skill in the art would appreciate would be swallowed without need for taste masking of active ingredients. It would have been prima facie obvious to not wash the surface of the particles to remove active ingredient(s), an extra step not necessary where taste masking is not applicable.
Applicant argues that: “Rosiaux discloses some drugs such as granules of Tramadol HCL and glyceryl behenate as lipid binder (2.1.3 Melt granulation/melt pelletization), Etoricoxib in tablet made of glyceryl monostearate and Glyceryl Behenate (ratio 1: 1) ("2.1.1 Direct compression) etc. However, Rosiaux et al. does not disclose a formulation that comprises lipid particles including pancrelipase in a waxy matrix as claimed.” And that: “Applicants note that glyceryl behenate and glyceryl monostearate have at least two free hydroxyl groups. Those hydroxyl groups are available for making hydrolysis or oxidation reaction. In consequence, it cannot be considered as “hydrophobic” as defined by the Applicant in the present specification of mentioned application.” (p. 9 last two paragraphs through p. 10, line 2).
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicant argues that: “’The waxy matrix of the solid lipid particles of a formulation according to the invention consists of a hydrophobic compound or of a mixture of hydrophobic compounds which is (are) insoluble in water, solid at room temperature and totally free of surfactant compounds, solvent residues and water. Thus, any hydrolysis or oxidation reaction is avoided." (page 9, lines 1-5).’”
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., “The waxy matrix […] consists of”) 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).
Applicant argues that: “Rosiaux states that pancreatic lipase increases the kinetic release of drug (See 4.1, in vitro dissolution testing). However, as explained in page 1 of the specification, the subject matter of claim 1 is intended for treating exocrine pancreatic insufficiency. Patients with this disease have pancreatic dysfunction including absence of production of exocrine digestive enzymes. Thus, Rosiaux' s statement cannot be applied to assess the present arrangement as claimed.” (p. 10, 3rd paragraph).
In response the examiner argues that Applicant’s argument is directed at an intended use of a composition claim and therefore not convincing. Indeed FALLON clearly suggest pancreatic insufficiency as a condition to be treated, as discussed above. Rosiaux et al. is directed at Solid Lipid Excipients as Matrix Agents for Sustained Drug Delivery (title) and therefore applicable to RAYNAL clearly teaching high melting-point lipids for their strictly hydrophobic matrix ([0012]-[0020]).
Applicant argues that: “As explained in Applicant's prior remarks in the previous Amendment, Fallon teaches a drug delivery complex wherein the enzyme is gathered in a core which is encapsulated by an emulsifiable lipid coating. More particularly, Fallon specifies that the emulsifiable lipid which has the property to emulsify when exposed to a solvent (Fallon, §57). Please note that the behavior of Fallon's drug delivery complex is the exact opposite of the behavior of the waxy matrix as claimed, where the waxy matrix is inert in solvent precisely for passing through the gastric tract without being degraded.” (p. 10, 4th paragraph). And that: “Fallon teaches that the emulsifiable lipid can be a mixture of lipids comprises vegetal or animal derived lipid, mono, diglyceride or triglyceride (Fallon, §058). One of ordinary skill in the art knows that triglycerides are non-emulsifiable, thereby to be emulsifiable, triglycerides must melt with other emulsifiable lipids. Besides, through example 2, Fallon provides few examples of coating system: Hydrogenated Soy oil, Hydrogenated Castor wax, Carnauba wax, Hydrogenated Monoglyceride, and a blend of Soy and Monoglyceride. No example discloses a composition comprising lipid particles that comprise pancrelipase homogeneously distributed through a strictly hydrophobic waxy matrix containing triglycerides.” (p. 10, 5th paragraph).
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicant then points to Example 4 of FALLON arguing “Example 4 discloses a formulation comprising a core of pancreatic enzyme encapsulated in soy oil. […] One of ordinary skill in the art would understand that Fallon's emulsifiable lipid complex does not protect digestive enzymes from the gastric tract, which is characterized by acidic conditions.” (paragraph bridging pp. 10-11).
In response the examiner argues that: “Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments.” And that this is a clear piecemeal analysis ignoring the primary reference RANYAL. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to include the pancreatic/digestive enzymes of FALLON in the waxy matrix formulation of RANYAL for controlled and sustained delivery of the pancreatic/digestive enzymes to treat enzyme deficiencies caused by conditions affecting the pancreas, such as pancreatitis and pancreatic enzyme deficiency.
Applicants arguments over CUCA’s Disclosure, DIORO disclosure, and TOMOHIRA Disclosure (p. 11-12), are acknowledged.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicant further argues that: “None of the cited documents disclose or suggest such effect either alone or combined in any manner. Furthermore, Applicants have demonstrated in the notes above, that none of the cited prior art teaches to combine pancrelipase homogeneously distributed with strictly hydrophobic matrix.” (p. 13, bottom).
RAYNAL teaches that: “The active ingredient or ingredients are dispersed in the lipid matrix, and are essentially distributed with constant concentration in said matrix.” ([0014])(instant claim 1, “in which said at least one digestive enzyme has [a] homogenous distribution in each solid lipid particle”). And FALLON teaches that: “The digestive enzyme may be, for example a pancreatin/pancrelipase composition.” ([0059]).
Applicant argues that: “Most of the cited prior art wrongly considers that surfactants (mono, di glyceride, or ester comprising hydrophilic free chemical group) or polymers also comprising hydrophilic free chemical group (such as cellulose derivatives) provide efficient protection of the active ingredient against acidic conditions. It is definitively wrong. Those kinds of compounds create hydrophilic pores or breach into the lipid protection that permits penetration of water and acidic compounds into the lipid particle. Thus the cited references teach the opposite of the present arrangement as claimed.” And “Thereby, any cited prior art combining strictly hydrophobic compounds such as triglycerides with surfactant compounds or with compounds bearing free hydrophilic functions cannot provide effective protection of the active ingredient under acidic conditions. In any case, Fallon is probably the best example for illustrating that point. This disclosure teaches an emulsifiable lipid coating that comprises surfactants such as Monoglyceride. Release test of active ingredients in acidic conditions is presented and shows a quick release in acidic condition. Such a disclosure cannot be used for delivering pancrelipase in intestinal tract, because it will degrade into the gastric tract. And Fallon is the only cited prior art that uses pancrelipase as active ingredient. However, pancrelipase compounds form a core that is protected by the emulsifiable lipid coating.” (p. 13 last line through p. 14, 2nd paragraph).
In response the examiner argues that RAYNAL teaches their "invention also concerns a process to mask the taste of active ingredients and/or to protect the active ingredients against degradation reactions and/or to modulate the rate of release of the active ingredients, characterized in that lipid particles are prepared without any surfactants or emulsifiers and comprise a lipid, hydrophobic matrix non-ionizable at physiological pH in which the active ingredient( s) are dispersed." [emphasis added]([0009]). RAYNAL teaches that: "The matrix may advantageously be called "strictly hydrophobic" insofar as it does not contain detectable traces of water." [emphasis added]([0010]). RAYNAL teaches the inclusion of enzymes as active ingredients ([0043] & claim 9), therefore it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to include the pancreatic/digestive enzymes of FALLON in the waxy matrix formulation of RANYAL for controlled and sustained delivery of the pancreatic/digestive enzymes to treat enzyme deficiencies caused by conditions affecting the pancreas, such as pancreatitis and pancreatic enzyme deficiency.
Applicant argues that: “Besides, the fact that repartition of pancrelipase is not disclosed by any cited prior art. It is also not possible to combine Raynal's disclosure with Fallon disclosure for the following reasons.” “Firstly, Raynal's disclosure teaches to wash the lipid particles in order to devoid the surface of active ingredients. That treatment modifies the repartition of active ingredients and creates a surface coat devoid of active ingredients. Thereby, the surface coat devoid of active ingredients must be degraded in first place before releasing active ingredients. Therefor the release of the active ingredients is delayed in comparison with the now claimed formulation.” “Secondly, as Applicant has mentioned in the prior Amendment, Raynal teaches to disperse the active ingredient, e.g, Ibuprofen in the lipid phase and then to add homogeneous mixture to an aqueous gel of Carbopol in acidic condition (pH=6,2) (see, paragraph 0046, 0060). Yet, it is impossible to produce Lipid particles containing pancrelipases taught by Fallon, because in the conditions of aqueous gel, pancrelipases would be activated and would degrade the lipid matrix. Instead of lipid particles loaded with pancrelipases, such a process would manage to an emulsion.” (p. 14, last three paragraphs through p. 15, 1st paragraph).
In response to Applicant’s first point, the examiner argues that RAYNAL teaches that “Finally, the particles can be used in conventional galenic formulations of the type hard capsules, soft capsules, granules, oral powders, dispersible powders, tablets, water dispersible and oral-dispersible tablets.” ([0049]). In the embodiment where the powders are filled into a capsule or compressed into tablets one of ordinary skill in the art would have clearly recognized that “Elimination of active ingredient on the surface is obtained, for example, by washing the particles or by any other suitable method.” would be unnecessary as the lipid particles would not contact the taste sensory organs of the mouth. This is also the case where the lipid particles are subsequently coated, for example an enteric coating to protect the lipid particles from degradation in stomach acid. Therefore, one of ordinary skill in the art would have been motivated to save time and money by skipping the step of washing the surface of the particles in formulations where it is not required for taste masking such as with capsules/tablets/enteric coated lipid particles.
In response to Applicant’s second point, the examiner argues that: (1) “Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments.” (MPEP §2123); and (2) RAYNAL clearly teaches their "invention also concerns a process to mask the taste of active ingredients and/or to protect the active ingredients against degradation reactions and/or to modulate the rate of release of the active ingredients, characterized in that lipid particles are prepared without any surfactants or emulsifiers and comprise a lipid, hydrophobic matrix non-ionizable at physiological pH in which the active ingredient( s) are dispersed." [emphasis added]([0009]). RAYNAL teaches that: "The matrix may advantageously be called "strictly hydrophobic" insofar as it does not contain detectable traces of water." [emphasis added]([0010]). RAYNAL teaches the inclusion of enzymes as active ingredients ([0043] & claim 9), therefore it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to include the pancreatic/digestive enzymes of FALLON in the waxy matrix formulation of RANYAL for controlled and sustained delivery of the pancreatic/digestive enzymes to treat enzyme deficiencies caused by conditions affecting the pancreas, such as pancreatitis and pancreatic enzyme deficiency.
Conclusion
Claims 1-10, 13 and 17-19 are pending and have been examined on the merits. Claim 4 is objected to. Claims 1-10, 13 and 17-19 rejected under 35 U.S.C. 112(a)(New Matter); claim 13 is rejected under 35 U.S.C. 112(d); and claims 1-10, 13 and 17-19 are rejected under 35 U.S.C. 103. No claims allowed at this time.
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/IVAN A GREENE/Examiner, Art Unit 1619
/TIGABU KASSA/Primary Examiner, Art Unit 1619
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