DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after 16 March 2013, is being examined under the first inventor to file provisions of the AIA .
Claims Status
Claims 1-6, 8, 10, 14, 15, 17-20, 22, 24, 28-31 are pending and under current examination in this application. The claim amendments filed 06 March 2024, are acknowledge. Claims 1, 3, 4, 8, 10, 14, 15, 17-19, 22, 24, 30 and 31 have been amended and are supported by the originally-filed disclosure. Claims 7, 9, 11-13, 16, 21, 23, 25-27, and 32-34 have been cancelled and no new claims have been added.
Claim Rejections - 35 USC § 112(b)
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 Applicant regards as his invention.
Claims 1-3, 18, 28, 29 and 31 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, regards as the invention.
In claims 1 and 31, the phrase, "one or more of the particle according to claim 4" is ambiguous. It does not distinctly claim whether every particle must be "according to claim 4" or if the collective is "according to claim 4" (e.g., are the one or more particles of the oral dosage form or pharmaceutical composition identical to the particle defined in claim 4, a mixture of different particles that each individually satisfy claim 4, or one or more particles that collectively contain the required 200 mg or more of lactoferrin but where individual particles may not satisfy claim 4) and it is ambiguous whether the recited “200 mg or more of lactoferrin” refers to the total amount of lactoferrin across all particles, to the amount within each particle, or to another component of the oral dosage form or pharmaceutical composition, thus the terminology does not provide reasonable certainty as to the structure of the claimed oral dosage form or pharmaceutical composition. This ambiguity fails to inform the public of the metes and bounds of the claimed invention with reasonable certainty (see Nautilus, Inc. v. Biosig Instruments, Inc., 572 U.S. 898 (2014)). Dependent claim 2 is included in this rejection because it does not cure the defect noted above. Claim 31 also recites, "The pharmaceutical composition” which lacks antecedent basis in claim 4, the claim from which it depends, thereby creating ambiguity in scope of the claim.
Further, claim 3 recites, “which comprises from about 400 mg to about 600 mg of said particles”, while claim 1 recites “200 mg or more of lactoferrin.” The "said particles" is indefinite as it lacks a clear antecedent basis. In addition, the specification discloses that "products can be provided which contain 200 mg or more of lactoferrin in a single dose" (¶[0008]). However, claim 3 attempts to define the dosage form by the mass of the particles themselves, not the mass of the lactoferrin. This introduces ambiguity. The claim does not specify whether the recited mass of 400-600 mg refers to the total weight of the oral dosage form, the total fill weight of the capsule, the collective weight of the claimed particles within the dosage form, the total amount of lactoferrin present in the dosage form, the amount of lactoferrin per particle. Furthermore, the weight range of the particles is not necessarily predictive of the lactoferrin dose without knowing the particle's lactoferrin content. The lack of a clear measurement reference renders the metes and bounds of the claimed subject matter ambiguous. The Applicant is advised to clarify the claim by specifying what the claimed mass represents (e.g., "a total mass of said particles," "a fill mass," etc.) and/or by linking it directly to the lactoferrin content.
To overcome these rejections, the Applicant may cancel the claims, amend the claims to clearly and unambiguously define the invention, or amend the specification to provide adequate written description support for an oral dosage form or pharmaceutical composition characterized by containing both (a) the specific particles of claim 4 and (b) a total lactoferrin content of 200 mg or more. Such amendment must not introduce new matter (see 35 U.S.C. 132(a)).
Claim 18 recites, “an anionic (meth)acrylate copolymer composed of ethyl acrylate and methyl methacrylate (e.g., EUDRAGIT® NM)”, however EUDRAGIT® NM is a neutral, non-ionic not anionic copolymer composed of ethyl acrylate and methyl methacrylate. Therefore, while the monomers are correct, characterizing EUDRAGIT® NM as anionic is inaccurate as it is a neutral, pH-independent polymer. The lack of clarity creates ambiguity in the scope of the claims and appropriate correction is required.
Claim 28, which depends from claim 4, suffers from several formal defects under 35 U.S.C. § 112(b), primarily relating to antecedent basis and unnecessary redundancy. Instead of using "wherein" clauses to modify the elements of claim 4, claim 28 restates the entire claim using "comprising" creating a confusing parallel structure that does not properly refer back to its parent. These issues create ambiguity and make the claim difficult to construe with reasonable certainty. Claim 28 also needlessly repeats the entire three-layer structural framework of the particle already established in claim 4 but uses the open-ended transitional phrase "comprising" for each layer. This creates direct conflicts and ambiguities with the limitations already introduced by claim 4. Ambiguity is also created transitioning from optional components in claim 4 to mandatory components in claim 28 without making such clear.
Claim 4 defines the core as, "comprising an inert core-forming material selected from cellulose polymer, sugar, sugar alcohol, starch and carnauba wax", then claim 28 states the core comprises "microcrystalline cellulose", wherein microcrystalline cellulose is a species of "cellulose polymer" from the genus in claim 4. The claim 28 language "a core comprising microcrystalline cellulose" does not properly refer back to the core of claim 4. It reads as a new, independent definition. This limitation would be more properly stated as, "wherein the inert core-forming material is microcrystalline cellulose" or "wherein the cellulose polymer is microcrystalline cellulose", which directly modifies the antecedent term from claim 4.
Claim 4 also defines the first layer as "comprising b-1) lactoferrin, b-2) a pharmaceutically acceptable binder which is a non-polyvinylpyrrolidone (PVP) binder and optionally b-3) one or more other suitable excipients. Claim 28 restates it as "comprising b-1) lactoferrin, b-2) hydroxypropylmethylcellulose and b-3) polyethylene glycol". Claim 28 specifies "hydroxypropylmethylcellulose", which is a proper narrowing of the "non-PVP binder" from claim 4, but again, it is incorrectly presented as a new element. The Applicant is advised to amend the claim to state, for example, "wherein the pharmaceutically acceptable binder is hydroxypropylmethylcellulose”.
Claim 28 lists "polyethylene glycol" as component b-3). In claim 4, b-3) is defined as “optionally... one or more other suitable excipients". By explicitly including polyethylene glycol, claim 28 is exercising the option present in claim 4, however, claim 28 presents b-3) as a mandatory element, "comprising... b-3) polyethylene glycol", without acknowledging its optional origin and moreover, there is no antecedent basis for polyethylene glycol in claim 4. Therefore, polyethylene glycol appears as a new, undefined component.
Claim 4 defines the second layer as "comprising c-1) an enteric coating material, and optionally c-2) one or more suitable excipients". Claim 28 restates it as "comprising c-1) an anionic (meth)acrylate copolymer, c-2) triethyl citrate (TEC), c-3) glycerol monostearate, and c-4) polyoxyethylene (20) sorbitan monooleate". The “anionic (meth)acrylate copolymer" narrows "an enteric coating material" of claim 4 but lacks proper antecedent reference and should be introduced as, "wherein the enteric coating material is an anionic (meth)acrylate copolymer”.
Claim 4 only provides for "optionally... c-2) one or more suitable excipients". Claim 28 makes this optional component mandatory and lists three specific excipients. None of these three excipients (i.e., TEC, glycerol monostearate, and polysorbate 80) have any antecedent basis in claim 4. They are introduced as new, positive limitations. In addition, the list of three excipients in the second layer, c-2) triethyl citrate (TEC), c-3) glycerol monostearate, and c-4) polyoxyethylene (20) sorbitan monooleate, could be ambiguously read (e.g., does it require the presence of all three, or is it a Markush-style listing of alternatives?). The use of "and" followed by a series separated by commas strongly implies all three are required, which is likely the intent. However, given the other drafting flaws, this ambiguity further clouds the meaning of the claim.
Claim 28 also needlessly recites the entire architecture of the particle. This is redundant because claim 4 already provides that architecture. The purpose of a dependent claim is to add a narrowing limitation to the independent claim and does not need to restate it.
To overcome this rejection, the Applicant may cancel the claim or amend the claim claims to clearly and unambiguously define the invention (e.g., “The particle according to claim 4, wherein the inert core-forming material is microcrystalline cellulose, wherein the pharmaceutically acceptable binder is hydroxypropylmethylcellulose, wherein the first coating layer further comprises polyethylene glycol, wherein the enteric coating material is an anionic (meth)acrylate copolymer, and wherein the second coating layer further comprises triethyl citrate, glycerol monostearate, and polyoxyethylene (20) sorbitan monooleate.”).
Likewise, claim 29, which depends from claim 4, suffers from similar defects in antecedent basis issues and unnecessary redundancy, rendering the claim ambiguous. Claim 29 improperly re-states the entire three-layer particle structure from claim 4 using the open-ended transitional phrase "comprising." This creates direct conflicts and a lack of clear connection to the limitations established in the parent claim. Like claim 28, claim 29 needlessly recapitulates the entire particle structure from claim 4. This is redundant. The specific excipients in claim 29, polyethylene glycol, triethyl citrate (TEC), and talc, are not mentioned in claim 4 and therefore lack antecedent basis. Claim 29 also implicitly changes the status of optional components from claim 4 (b-3 and c-2) into mandatory lists of specific components without a clear transitional phrase.
To overcome this rejection, the Applicant may cancel the claim or amend the claim claims to clearly and unambiguously define the invention (e.g., “The particle according to claim 4, wherein the inert core-forming material is microcrystalline cellulose, wherein the pharmaceutically acceptable binder is hydroxypropylmethylcellulose, wherein the first coating layer further comprises polyethylene glycol, wherein the enteric coating material is an anionic (meth)acrylate copolymer, and wherein the second coating layer further comprises triethyl citrate and talc.”).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. § 102 and 103 (or as subject to pre-AIA 35 U.S.C. § 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. § 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. § 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. § 102(b)(2)(C) for any potential 35 U.S.C. § 102(a)(2) prior art against the later invention.
Claims 1-6, 8, 10, 14, 15, 17-20, 22, 24, 28-31 are rejected under 35 U.S.C. § 103 as being unpatentable over Terruzzi et al. (US-20160206707-A1; published 21 July 2016, hereinafter referred to as “Terruzzi”) in view of Yang et al. (US-20160317454-A1; published 03 November 2016, hereinafter referred to as “Yang”).
Terruzzi teaches an enteric-coated, lactoferrin-containing oral dosage form. Terruzzi explicitly teaches oral formulations with lactoferrin (¶[0024]) and an outer coating or gastroresistant coating for site-specific release in the gastrointestinal tract (¶[0028]), specifying suitable coating materials to include polymethacrylates and cellulose acetophtalate (¶[0029]). Further describing in Examples 4 and 5 the preparation of tablets film coated with polymethacrylates and plasticizers to ensure gastric resistance (¶[0117]) or coated with shellac to create an enteric film coated tablet (¶[0123]; i.e., a second enteric coating layer on a lactoferrin-containing core).
Terruzzi teaches multiple methods for formulating the lactoferrin-containing core/first layer, specifically disclosing preparation of "a core containing pharmaceutical multi particulate or monolithic lactoferrin... by loading lactoferrin on inert excipients" (¶[0047]). This "loading" of an active onto an inert carrier is a standard pharmaceutical technique (e.g., drug-layering) that makes a first coating layer comprising lactoferrin on an inert core obvious.
Furthermore, the Terruzzi teaches the inclusion of binders and excipients in the lactoferrin layer as core-forming materials, including diluents, gliding agents, lubricants (¶[0047]) and wherein the matrix in which the lactoferrin is dissolved and/or dispersed and/or embedded in includes hydrophilic substances (¶[0024]), including microcrystalline cellulose, corn starch and lactose (¶[0031]), which correspond to the claimed cellulose polymer and sugar. Example 3 explicitly uses microgranules made of microcrystalline cellulose and corn starch as a substrate for lactoferrin loading (¶[0109]), and Example 4 uses microcrystalline cellulose and corn starch in the granulation (¶[0113] and ¶[0113]).
Terruzzi also lists hydroxypropylmethylcellulose as a preferred hydrophilic matrix substance (¶[0031]) and uses it extensively in examples (e.g., Example 1, ¶[0098] and ¶[0101]; Example 2, ¶[0107]; Example 5, ¶[0119]; Example 6, ¶[0125] and ¶[0129]; Example 8, ¶[0139] and ¶[0142]; Example 9, ¶[0147]). While Example 1 uses polyvinylpyrrolidone (PVP) as a binder (¶[0097]), Terruzzi’s broad disclosure of matrix/formulation components provides a person of skill in the art a finite list of known alternative non-PVP binders. Preferred substances in lactoferrin matrices/cores, incorporated to increase in volume, include cellulose polymers hydroxyalkylcelluloses and carboxyalkylcelluloses such as hydroxypropylmethylcellulose, carboxymethycellulose, and hydroypropylcellulose and microcrystalline cellulose as well as the polysaccharide, alginate, pectin, starch, gums, etc. as binders (¶[0031]), which are all standard pharmaceutical excipients in which selecting one well-known binder over another from these common binders would not be anticipated to produce an unexpected result. Similarly, Terruzzi teaches the use of plasticizers (e.g., glycerine; ¶[0123]), anti-tacking agents (e.g., talc; ¶[0099], ¶[0129], and ¶[0140]), and non-ionic emulsifiers (e.g., lecithin in claim 6, ¶[0032], ¶[0121], ¶[0127], ¶[0133]; and polysorbates in ¶[0032]) as optional pharmaceutically acceptable excipients, making their inclusion in a coating layer obvious.
The matrix may also comprise amphiphilic substances in addition to the hydrophilic matrix substance (¶[0024]), including lecithin, phosphatidylcholine, phosphatidylethanolamine, glycol alkyl ethers (e.g., diethylene glycol monomethyl ether), macrogolglyceride polyethylene glycol derivatives (e.g., Gelucire® 44/14, Labrafil®M2130Cs, Gelucire® 50/13), polyethylene glycol 1500 esters and polyethylene glycol hydroxystearates, waxes, hydrogenated coconut oil, and hydrogenated palm oil, polysorbates, anionic surfactants (i.e., sodium laurylsulfate, sodium dodecylsulfate, sodium sulphosuccinate, and sodium laurylsarcosinate), and poloxamers which are structurally similar to polyethylene glycol in their function in formulations (¶[0032]), in which the amphiphilic plasticizer polyethylene glycol may function as an alternative to and is often used in conjunction with the listed substances as a complementary ingredient in a formulation to achieve the desired physical properties (e.g., flexibility, viscosity, miscibility). However, Terruzzi does not explicitly teach the use of polyethylene glycol in the composition as a plasticizer or wherein the polyethylene glycol has an average molecular weight of 6000 g/mol. Terruzzi does not explicitly teach the use of triethyl citrate in the composition as a plasticizer either.
Terruzzi teaches specific enteric coating materials and additives, such as polymethacrylates as gastroresistant agents (claim 8 and ¶[0029]; see also use in Example 4 film coating, ¶[0117]), encompassing anionic (meth)acrylate copolymers composed of methacrylic acid and ethyl methacrylate, such as Eudragit® L, and neutral (meth)acrylate copolymers composed of ethyl acrylate and methyl methacrylate such as, EUDRAGIT® NM. Selecting a specific known species of polymethacrylate from the polymethacrylate genus, wherein there is a finite, well-defined list of commercially available polymethacrylates used for enteric coating in pharmaceuticals (i.e., primarily Evonik Eudragit® and BASF Kollicoat®) is obvious. The inclusion of plasticizers like glycerine with these coatings
Terruzzi teaches administration amounts of lactoferrin between 50-250 mg per day (claim 9 and 13; ¶ [0020]), wherein, “…those of ordinary skill would be capable of adjusting the dosage amounts and schedule by observation of the effectiveness of treatment. Accordingly, it is contemplated that the range in dosage for the application could be several logs higher or lower than the optimum above. While the preferred route of administration is oral administration…” (¶[0021]). A person of skill in the art seeking a robust, high-dose formulation would thus be motivated to formulate a single unit containing 200 mg or more lactoferrin by increasing the payload through routine experimental scaling activity optimization.
Terruzzi describes its formulations as tablets (Example 1, ¶[0100]- [0102]; Example 2, ¶[0106]- [0108]; Example 4, ¶[0116]- [0118]; Example 5, ¶[0122]- [0124]; Example 6, ¶[0128]- [0130]; Example 7, ¶[0134]- [0136]; Example 8, ¶[0141]- [0143]; Example 9, ¶[0146]- [0148]) and size 0 capsules (Example 3, ¶[0111]), wherein a standard two-piece shell (body and cap) size 0 pharmaceutical capsule is considered a hard capsule.
In the tablet or capsule oral dosage examples provided by Terruzzi, Examples 1 and 7 teach a 470 mg total particle/core tablet weight containing 200 mg lactoferrin (¶[0096]-[0102] and ¶[0131]-[0136]), providing 42.6% lactoferrin relative to the total weight of the particle/core and Examples 5 and 6 teach a 510 mg total particle/core tablet weight before the final shellac enteric coat containing 200 mg lactoferrin (¶[0119]-[0130]), providing 39.2% lactoferrin relative to the total weight of the particle/core, encompassing the limitations of instant claims 1, 3, 30 and 31. Further, arriving at the he instant claimed particle weight ranges and lactoferrin load as a percentage of particle weight are the result of routine optimization of the taught process (¶[0047]).
Terruzzi teaches the individual components of the specific embodiments in instant claims 28 and 29: a core of microcrystalline cellulose (¶[0109], ¶[0113], and ¶[0119]); a first layer with lactoferrin and hydroxypropylmethylcellulose (a binder taught in ¶[0031] and used in nearly every Example); polyethylene glycol hydroxystearates and macrogolglycerides ¶[0032] as a potential excipient/plasticizer, in which the simpler polyethylene glycol would be an obvious alternative; an anionic (meth)acrylate enteric coating as polymethacrylates in claim 8, ¶[0029] and ¶[0117]); glycerine taught in ¶[0123] as a plasticizer that can commonly be substituted with triethyl citrate; and excipients talc (¶[0099]) and non-ionic emulsifiers lecithin (claim 6, ¶[0032], ¶[0121], ¶[0127], ¶[0133]), akin to glycerol monostearate, and polysorbates (¶[0032]), which would include the specific species polyoxyethylene (20) sorbitan monooleate. Combining these known elements explicitly taught from Terruzzi or standard alternatives and natural implementations of its broad teachings to create a specific particle formulation with slight modifications to arrive at the instant claimed invention would be obvious to one of skill in the art.
However, Terruzzi does not explicitly teach the use of polyethylene glycol or triethyl citrate as an excipient/plasticizer, the non-ionic emulsifier glycerol monostearate, the specific choice of the anionic (meth)acrylate species from the polymethacrylate genus and polyoxyethylene (20) sorbitan monooleate as the species from the polysorbate genus.
Yang explicitly discloses the use of the plasticizers polyethylene glycol (claim 10; ¶[0019]) and triethyl citrate (claim 10; ¶[0019]; Embodiment 2-7, ¶[0034]-[0044]), glycerol [glyceryl] monostearate as a lubricant (claim 5, ¶[0016]), also serving to function as an emulsifier, and the use of a copolymer of ethyl acrylate and methyl methacrylate (Eudragit NE30D) and a copolymer of methylpropenoic acid and ethyl acrylate (Eudragit L30D-55) (¶[0030]; Embodiments 2-7 ¶[0034]-[0044]), wherein Eudragit L30D-55 is an anionic (meth)acrylate polymethacrylate.
Yang also discloses the use of polysorbate in embodiments of the invention (Embodiment 4, ¶[0037]; Embodiment 6, ¶[00342]; Embodiment 7, ¶[0044]), however Yang does not explicitly specify that the polysorbate species is specifically polyoxyethylene (20) sorbitan monooleate. Although, a person of ordinary skill in the art would immediately consider the use of polysorbate 80 (polyoxyethylene (20) sorbitan monooleate) as a primary candidate as a polysorbate (amongst polysorbate 20, 40, 60, and 80) due to its extensive use in the pharmaceutical industry for oral formulations as an excipient, as polysorbate 80 is arguably the most commonly used, next to polysorbate 20, but is often preferred for providing superior increases in solubility because of its high hydrophilic-lipophilic balance value. Selecting the most commonly used and effective species from the group of polysorbates (polysorbate 80) to achieve a desired solubility result is considered routine optimization. Because polysorbate 80 is so frequently used as a surfactant and solubilizer in oral pharmaceutical formulations, a person of ordinary skill in the art would have a high expectation of success in using it to stabilize or solubilize an active ingredient, making the choice obvious to try. Unless the use of polysorbate 80 provides a surprising or unexpected result that distinguishes it significantly from other polysorbates, it is considered an obvious choice for the broad polysorbate taught by Yang.
Terruzzi also does not explicitly teach a particle with a specific three-layer structure: an inert core, a discrete lactoferrin/binder layer covering the core, and a discrete enteric coating layer covering the lactoferrin layer. Terruzzi’s disclosure is more generic, describing matrices, loaded cores, and outer coatings. It does not mandate the specific layered architecture of instant claims, however the Applicant has not demonstrated that this specific structural arrangement, as a whole, yields unexpected or superior results compared to the formulations taught by Terruzzi. For example, evidence showing that the claimed layered particle provides surprisingly improved lactoferrin stability, more precise or reproducible enteric release profiles, or enhanced bioavailability compared to the monolithic matrix tablets or simply coated granules described in Terruzzi's examples. Mere optimization of known parameters (e.g., coating weight, binder choice) is not sufficient if the results are predictable.
Nonetheless, Yang discloses a controlled-release pharmaceutical composition with the exact multi-layer particle structural limitations of the instant claimed enteric-coated particle having an inert core, an active ingredient layer (first coating), and a controlled release coating (second enteric coating).
Yang expressly teaches a particle with an inert core, an active ingredient layer covering the core, and a controlled-release coating layer covering the drug core (¶[0010], ¶[0013], ¶[0029], and FIG.1). This three-layer structure corresponds directly to the core, first coating layer, and second coating layer structure of instant claim 4. The inert core is taught to be made of materials such as sugar or microcrystalline cellulose (claim 3, ¶[0015]), teaching the limitations of instant claims 5 and 6, wherein Yang’s embodiment examples (¶[0030]-[0040]) specifically use the microcrystalline cellulose core and teach the overall structure of the embodiments of instant claims 28 and 29.
The active ingredient layer in Yang contains the drug and a first pharmaceutical acceptable polymer, applied via coating (¶[0013]), teaching the first coating layer of instant claim 4. The outer controlled release coating layer (¶[0011]) teaches the second coating layer of instant claim 4. Yang also teaches the excipients in the coating layers. Yang teaches that the first pharmaceutical acceptable polymer in the active layer includes hydroxypropyl methylcellulose (claim 6, ¶[0017]), a non-PVP binder. Yang’s examples consistently use hydroxypropyl methylcellulose in the drug core (Embodiments 1-7, ¶[0032]-[0044]), thus teaching the first coating layer binder limitations of instant claims 4 and 8. Yang teaches the active ingredient layer may further comprise standard excipients like binders and lubricants (¶[0016]), which a person of skill in the art would understand to include plasticizers for film formation, as the first coating layer excipients of instant claim 10.
Yang teaches the second controlled-release coating layer comprises specific polymers, including a copolymer of ethyl acrylate and methyl methacrylate (e.g., Eudragit® NE) and a copolymer of methylpropenoic acid (methacrylic acid) and ethyl acrylate (e.g., Eudragit® L) (¶[0018]; see ¶[0030] and Embodiments 2-7, ¶[0034]-[0044]). This directly teaches the enteric coating material of instant claim 4, the anionic (meth)acrylate copolymers (e.g., Eudragit® L) of instant claims 14, 15, and 17, and the specific polymer combination of instant claim 18 (Eudragit Eudragit® L and Eudragit® NM/NE; see specific Embodiment 3 (¶[0036]) and Embodiment 5, ¶[0040]).
Yang also teaches the second coating layer excipients. Yang teaches the controlled-release coating layer may further comprise a plasticizer such as triethyl citrate (claim 10; ¶[0019]; Embodiments 2-7, ¶[0034]-[0044]), teaching instant claims 19 and 20. Yang teaches that the coating may include a slip agent (¶[0019]) and the talc anti-tacking agent (claim 5, ¶[0016]; Embodiments 1-7, ¶[0032]-[0044]) of instant claim 22 and the emulsifier (claim 5 as glyceryl monostearate and metallic stearates or polysorbate in the drug core exemplified in Embodiment 4, ¶[0037]; Embodiment 6, ¶[00342]; Embodiment 7, ¶[0044], which includes arguably the most obvious choice as polysorbate 80 (polyoxyethylene (20) sorbitan monooleate)) of instant claim 24. Embodiment 4 explicitly includes mannitol in the coating (¶[0038]), teaching the use of general excipients. The specific combinations in instant claims 28 and 29 (microcrystalline cellulose core; hydroxypropyl methylcellulose and polyethylene glycol first layer; anionic (meth)acrylate copolymer, triethyl citrate, and talc/glycerol monostearate/polysorbate second layer) are assembled from individual components all taught by Yang.
While Yang teaches a person of ordinary skill in the art how to make a particle with the precise three-layer structure including an inert core, active ingredient and binder layer, and functional polymer coating for controlled intestinal release of an active ingredient, Yang does not teach the use of lactoferrin as the active ingredient (rather uses a different drug, carvedilol).
It would have been prima facie obvious to one of ordinary skill in the art prior to the instant effective filing date to a person of skill in the art, aware from the teachings of Terruzzi that lactoferrin is a known bioactive protein that is acid-sensitive and benefits from enteric protection to ensure delivery to the intestines (¶[0003]), to use the known controlled-release particle structure of Yang with another active ingredient known to require enteric delivery, such as lactoferrin, to achieve the same purpose of protecting the drug and targeting intestinal release.
Arriving at the claimed lactoferrin amount of 30-50% of particle weight of instant claim 30 and dosage forms containing 200 mg or more (instant claims 1, 31) and an overall particle weight of 400-600 mg (instant claim 3) in the particle structure of Yang using this different acid-sensitive active ingredient involves routine optimization of adjusting the ratio of lactoferrin to core to achieve a desired payload, in which Terruzzi supplies exact guidance for lactoferrin, meeting the limitations of the instant claims.
Formulating the resulting particles into an oral dosage form, such as filling them into a hard capsule, as in instant claim 2, is a standard and obvious final step, as Yang itself notes its particles can be formulated into a capsule or a tablet (¶[0028]) and Terruzzi does so precisely in Example 3 (¶[0111] and ¶[0112]). Determining that a therapeutic dose requires 400-600 mg of particles, as in instant claim 3, to deliver 200 mg or more of lactoferrin, as in instant claim 1, is a matter of routine dosage calculation based on the known particle drug load and the known required dose of lactoferrin and is directly taught by Terruzzi for lactoferrin (50-250 mg lactoferrin (claim 9 and 13; ¶[0020]; see also rationale for adjustments for payloads >250 mg lactoferrin in ¶[0021]); total particle weight and 42.6% and 39.2% lactoferrin to total particle weight ratios of (Examples 1 and 7, ¶[0096]-[0102] and ¶[0131]-[0136]; Examples 5 and 6 (¶[0119]-[0130])).
Terruzzi provides the core invention of an oral, enteric-coated lactoferrin formulation for intestinal release. The claimed particle architecture is merely one of several known pharmaceutical delivery formats (e.g., drug-layered pellets) that a person of skill in the art would conventionally employ to achieve Terruzzi’s stated goals of modified release, site specific release, and homogeneous release (¶[0023] and ¶[0048]). The motivation to use a multi-particulate, coated particle system for uniform gastrointestinal distribution and reliable enteric protection is longstanding in pharmaceutical science. Yang discloses a controlled-release pharmaceutical composition that provides the exact structural template. A person of ordinary skill in the art seeking to improve Terruzzi’s formulations for targeted intestinal release of lactoferrin, lacking the explicit specific structural outline of the most effective embodiments of the invention, would have been motivated to employ a known and effective controlled-release particle architecture as taught by Yang expressly, describing the specific layered particle architecture. Yang provides precisely such an architecture, designed for the pH-dependent, extended release of an active ingredient. A person of ordinary skill in the art would have been motivated to combine its teachings to arrive at the claimed subject matter with a reasonable expectation of success.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to REBECCA L. SCOTLAND whose telephone number is (571) 272-2979. The examiner can normally be reached M-F 9:00 am to 5:00 pm EST.
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/RL Scotland/
Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615