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 .
Status of the Claims
Amendments to the Claims and Arguments/Remarks filed 05 May 2026, in response to the Office Correspondence dated 05 February 2026, are acknowledged.
The listing of Claims filed 05 May 2026, have been examined. Claims 1-6, 8, 10, 14-15, 17-20, 22, 24, and 28-31 are pending. Claims 1, 3, 18, 28, 29, and 31 are amended, claims 7, 9, 11-13, 16, 21, 23, 25-27, and 32-34 are canceled, and no new claims have been added.
Response to Amendment
The claim amendments have been entered. The applicant has amended claims 1, 3, 28, 29, and 31 substantially in accordance with the suggestions provided in the prior Office Correspondence.
Claim 1 now recites, "An oral dosage form comprising one or more particle[s] according to claim 4, wherein said oral dosage form comprises 200 mg or more of lactoferrin." Claim 31 has likewise been amended to clarify that the pharmaceutical composition comprises 200 mg or more of lactoferrin and to provide proper antecedent basis. Claims 28 and 29 have been rewritten as proper dependent claims using "wherein" clauses that directly modify limitations recited in claim 4. Claim 18 has been amended to remove the improper labeling EUDRAGIT® NM as anionic. Accordingly, the prior rejections of claims 1, 3, 18, 28, 29, and 31 under 35 U.S.C. §112(b) are withdrawn.
The applicant’s amendments to the claims and Arguments/Remarks have been fully considered, however, claims 1-6, 8, 10, 14, 15, 17-20, 22, 24, and 28-31 remain rejected under 35 U.S.C. §103 over Terruzzi in view of Yang. General knowledge of Eudragit® coating systems were known prior to the instant effective filing date.
Maintained Rejections
The following rejections are maintained from the previous Office Correspondence dated 05 February 2026, since the art which was previously cited continues to read on the amended/newly cited limitations.
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, and 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.
Response to Arguments
The applicant’s Arguments/Remarks of the reply, filed 05 May 2026, have been fully considered. The applicant argues that Terruzzi does not disclose a three-layer structure comprising inert core, lactoferrin-containing coating layer, and enteric coating layer; a dosage form containing 200 mg or more lactoferrin; rapid intestinal release; and the specific combination of polymers recited in claim 18. The arguments have been considered but are not persuasive.
The applicant contends that Terruzzi teaches only matrix systems and does not teach an inert core coated with a lactoferrin-containing layer which is subsequently coated with an enteric coating layer. This argument is not persuasive. Terruzzi expressly teaches loading lactoferrin on inert excipients by techniques known in the art (¶[0047]; e.g., by loading lactoferrin on inert excipients or by granulating lactoferrin optionally together with suitable excipients and further teaches enteric or gastro-resistant coatings applied over the resulting lactoferrin-containing structures; ¶[0028]-[0029], ¶[0117], and ¶[0123]). Loading lactoferrin on inert excipients is a standard pharmaceutical technique known as drug layering, which produces a particle with an inert core and an active ingredient-containing coating layer (i.e., the core and first coating layer of instant claim 4). Loading an active pharmaceutical ingredient onto an inert substrate constitutes a conventional drug-layering process that inherently produces a coated inert core.
Further, Example 3 of Terruzzi further teaches microgranules are prepared with microcrystalline cellulose 28.9% and corn starch 11.6%, wherein the microgranules are then coated with a composition containing lactoferrin, and after that, the microgranules are inserted into hard gelatine capsules (¶[0109]-[0111]). The microcrystalline cellulose/corn starch mixture forms an inert core, the lactoferrin composition forms a first coating layer, and the capsule itself is not the enteric coating. However, Terruzzi’s other examples (e.g., Example 4, ¶[0117]) explicitly teach a film coating with polymethacrylates to render the formulation gastroresistant. One of ordinary skill in the art would readily understand that the microgranules of Example 3 could be enteric-coated before encapsulation, which is a routine modification. Thus, Terruzzi provides explicit or implicit teaching of all three structural layers.
Yang expressly discloses the precise layered pellet architecture consisting of inert core, active-containing intermediate layer, and outer functional coating layer (FIG. 1; ¶[0010]-[0013], and ¶[0029]). The rejection is not predicated on Terruzzi alone. Rather, Yang provides the explicit structural architecture while Terruzzi provides the lactoferrin-specific enteric delivery system. A reference need not expressly teach the claimed structure if the structure would have been obvious from the combined teachings of the references (see KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398 (2007)). Accordingly, the argument is not persuasive.
The applicant argues that Yang's formulations are prolonged-release formulations rather than enteric formulations. The argument is not persuasive. Yang expressly teaches use of Eudragit® L30D-55, Eudragit® NE30D, methacrylic acid copolymers, and pH-dependent polymer systems (¶[0018], ¶[0030], ¶[0036], and ¶[0040]). Eudragit® L polymers are well-known enteric polymers that remain substantially intact in gastric conditions and dissolve at elevated intestinal pH (see evidentiary reference Evonik, Oral Drug Delivery, Functional Polymers EUDRAGIT® functional film coating polymers). Although Yang's overall formulation may additionally provide controlled-release properties, this does not negate its teaching of enteric polymer systems. The obviousness rejection relies on Yang for teaching the particle architecture and specific coating materials, not for the therapeutic indication or release profile of carvedilol. A reference may be relied upon for all that it reasonably teaches to one of ordinary skill in the art and is not limited to its preferred purpose. Accordingly, the argument is not persuasive.
The test is whether a person of ordinary skill, knowing that lactoferrin requires enteric protection, as taught by Terruzzi, would have been motivated to use a known controlled-release particle architecture, as taught by Yang, to deliver lactoferrin. Yang teaches a versatile multi-particulate system with an inert core, drug layer, and functional coating that can be tailored for pH-dependent release using anionic methacrylate copolymers (e.g., Eudragit® L). The fact that Yang’s specific embodiment uses carvedilol and aims for prolonged release does not negate the structural and functional similarity. A person of skill in the art would understand that the Yang platform can be adapted for enteric (delayed) release by selecting appropriate coating polymers, exactly the polymers Terruzzi already teaches for enteric protection. The combination is therefore straightforward.
Yang explicitly teaches the use of “a copolymer of methylpropenoic acid (methacrylic acid) and ethyl acrylate” (¶[0018]; e.g., Eudragit® L), which is a standard anionic enteric polymer that is insoluble at low pH and soluble at pH above 5.5. Yang’s coating is therefore enteric, not merely prolonged release, and thus using a Eudragit® L embodiment would not be semipermeable at acidic pH and would hence protect lactoferrin.
The applicant argues that Terruzzi's capsule Example 3 contains only 100 mg lactoferrin and that Yang provides no suggestion that higher amounts of lactoferrin could be achieved. This argument is not persuasive. Terruzzi expressly teaches daily doses of 50-250 mg lactoferrin (claims 9 and 13; ¶[0020]) and further teaches that dosage amounts may be adjusted higher or lower depending upon treatment requirements to achieve a therapeutically effective amount (¶[0021]). A person of skill seeking a 200 mg dose would simply scale up the formulation by increasing particle size, number of particles, or lactoferrin concentration. This is routine optimization, not invention. Moreover, multiple Terruzzi examples disclose formulations containing 200 mg lactoferrin. Examples 1, 5, 6, and 7 disclose formulations containing 200 mg lactoferrin. Thus, Terruzzi expressly teaches the claimed dosage amount. Selecting a known therapeutic dose from a disclosed range constitutes routine optimization absent evidence of criticality or unexpected results (see In re Peterson, 315 F.3d 1325 (Fed. Cir. 2003)). The applicant has not provided evidence that 200 mg constitutes a critical threshold. Accordingly, the argument is not persuasive.
The applicant argues that the claimed formulation releases lactoferrin more rapidly in the intestine and thereby improves therapeutic performance and that Terruzzi and Yang are inferior because they provide inconsistent and unreliable pharmacokinetics. The argument is not persuasive because attorney argument cannot substitute for objective evidence (see In re De Blauwe, 736 F.2d 699 (Fed. Cir. 1984)).
No comparative experimental data have been submitted comparing Terruzzi formulations, Yang formulations, and the presently claimed formulations (e.g., a side-by-side dissolution study of the claimed particle vs. Terruzzi’s Example 3 microgranules vs. Yang’s Example 3 particle). No declaration under 37 CFR 1.132 has been submitted. No evidence establishes unexpectedly faster release, improved bioavailability, improved stability, improved therapeutic efficacy, or improved safety. Mere statements in argument are not evidence. Without such comparative data, the examiner cannot credit assertions of unexpected results. Moreover, even if the claimed invention provides faster release, the applicant has not explained why a person of skill would have expected slow release from the combination of Terruzzi and Yang. Yang’s coating is enteric, designed to delay release until the intestine, but not necessarily prolonged beyond that point. Faster release from an enteric formulation is often a design goal, not an unexpected result.
Claim 18 now specifically recites EUDRAGIT® L-type polymer combined with EUDRAGIT® NM-type polymer in the enteric coating. Yang teaches combinations of methacrylic acid copolymers (Eudragit® L), ethyl acrylate/methyl methacrylate copolymers (Eudragit® NE) for coating multiparticulate dosage forms (¶[0030], ¶[0036], and ¶[0040]). EUDRAGIT® NM and EUDRAGIT® NE are closely related neutral ethyl acrylate/methyl methacrylate copolymers used interchangeably in pharmaceutical coating technology to modify film flexibility and permeability. A person of ordinary skill in the art would have found it obvious to substitute one known neutral ethyl acrylate/methyl methacrylate copolymer for another to achieve predictable coating characteristics. Such substitution merely involves selection among recognized equivalents and constitutes routine formulation optimization.
The amended claims 28 and 29 merely recite specific selections from components already disclosed by the applied references. The amendments do not alter the underlying obviousness analysis because microcrystalline cellulose cores are taught by both references, hydroxypropylmethylcellulose binders are taught by both references, polymethacrylate enteric coatings are taught by both references, polyethylene glycol is taught by Yang, triethyl citrate is taught by Yang, talc is taught by Terruzzi and Yang, polysorbates are taught by both references, and glycerol monostearate is taught by Yang. The presently claimed formulations therefore represent no more than the predictable selection and combination of known pharmaceutical excipients performing their known functions. The applicant has not demonstrated any unexpected result associated with the specific combinations. Accordingly, claims 28 and 29 remain obvious.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (87 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.
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.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, Applicant is encouraged to use the USPTO Automated Interview Request (AIR) at: http:/Awww.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’ s supervisor, Robert A. Wax can be reached at (571) 272-0623. The fax phone number for the organization where this application or proceeding is assigned is (571) 273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https:/Awww.uspto.gov/patents/apply/patent- center for more information about Patent Center and https:/Awww.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at (866) 217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call (800) 786-9199 (IN USA OR CANADA) or (571) 272-1000.
/RL Scotland/
Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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