DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 9/30/2025 has been entered.
Claim Status
Claims 1, 3, 5, 9-12, 18-22, 35, and 113 are pending; claims 2, 6-8, 41-42, 49-53, and 108-112 were canceled; claim 113 was newly added; and claims 1, 3, 5, 9-12, and 18-22 were amended in the Reply field 9/30/2025. Claim 22 remains withdrawn. Claims 1, 5, 9, 18-21, 35, and 113 are presently considered.
Election/Restriction
Applicant’s election without traverse of Group I and the species of Example 1 consisting of a single emulsion formulation of zilucoplan (SEQ ID NO: 1) in combination with RESOMER®502H (acid terminated 7-17k MW) with 37% loading as described at ¶¶[0269]-[0272] of the Specification filed 10/21/2021 in the reply filed on 9/23/2024 is acknowledged.
The elected species is understood as follows: The originally elected species is a single emulsion formulation of Zilucoplan in the form of a microsphere particle, wherein the “release modulating matrix” is the PLGA of RESOMER®502H (acid terminated 7-17k MW), and the elected species is understood to consist of a polymer of poly(D,L-lactide-co-glycolide) in a 50:50 ratio. The “zilucoplan-PLGA particles” of unspecified diameter and are not spherical (see, e.g., Spec. filed 10/21/2021 at ¶¶[0271], noting that the particles had a “collapsed or concave sphere structure”, rather than spherical, but no diameter was actually identified for the 37% loaded formulation). “37% loading” is presumed to mean percent w/w between SEQ ID NO: 1 (or PLGA) over the total (e.g., SEQ ID NO: 1 and PLGA). Zilucoplan is understood to correspond to the sodium salt structure of
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631
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(see, e.g., Spec. filed 10/21/2021 at ¶¶[0031], [0270]), which comprises instant SEQ ID NO: 1, and is the prior art element1 of Zilucoplan.
The amended claims are understood to continue reading upon the originally filed disclosure, and the original search has been repeated. Following extensive search and examination, the originally elected species has been deemed anticipated and/or obvious in view of the prior art as applied below. Per MPEP § 803.02(III)(A),
Following election, the Markush claim will be examined fully with respect to the elected species and further to the extent necessary to determine patentability. Note that where a claim reads on multiple species, only one species needs to be taught or suggested by the prior art in order for the claim to be anticipated or rendered obvious...
If the Markush claim is not allowable, the provisional election will be given effect and examination will be limited to the Markush claim and claims to the elected species, with claims drawn to species patentably distinct from the elected species held withdrawn from further consideration.
Accordingly, claims 1, 5, 9, 18-21, and 35 are rejected in view of the originally elected species and claims that do not read upon the originally elected species are withdrawn.
Claim 22 remains withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10/21/2024.
Claims 1, 3, 5, 9-12, 18-21, 35, and 113 are presently considered.
Priority
The priority claim to Pro 62/837,978 (filed 4/24/2019) is acknowledged.
Information Disclosure Statement
No IDS was filed on 9/30/2025 or prior to the completion of the instant Action.
Claim Interpretation
For purposes of examination, the claim scope has been interpreted as set forth below per the guidance set forth at MPEP § 2111. If Applicant disputes any interpretation, Applicant is invited to unambiguously identify any alleged misinterpretations or specialized definitions in the subsequent response to the instant action (see, e.g., MPEP § 2111.01(IV)).
Claim 1 is representative of the pending claim scope. Applicable claim interpretations are set forth below.
“Comprising” is an open-ended transitional term (see, e.g., MPEP § 2111.03(I)), wherein additional steps or components are not excluded. However, “‘[c]omprising’ is a term of art used in claim language which means that the named elements are essential” (see, e.g., id.; see also Genentech, Inc. v. Chiron Corp., 112 F.3d 495, 501, 42 USPQ2d 1608, 1613 (Fed. Cir. 1997)).
Regarding the preamble reciting “a sustained release formulation”, per MPEP § 2111.02, “where a patentee defines a structurally complete invention in the claim body and uses the preamble only to state a purpose or intended use for the invention, the preamble is not a claim limitation”. Here, the body of claim 1 is understood to recite a structurally complete invention, and therefore the preamble is deemed fully satisfied by prior art that satisfies the steps and structures recited in the body of claim 1 (see also MPEP § 2111.04(I), noting that “Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure”).
Amended claim 1 now recites the phrase “a single emulsion of condensed particles in an aqueous continuous phase”. This limitation is understood to require particles (i.e., a discrete phase) to be suspended within water (i.e., an aqueous continuous phase). In view of the originally elected species, it is understood to correspond to a single oil-in-water emulsion (see, e.g., Spec. filed 10/21/2021 at ¶[0271]). Accordingly, the newly recited limitation is understood to require that the particles are suspended in an aqueous solution.
References to “a sustained release formulation” are understood to refer to the claimed invention as a whole, whereas references to “a release modulating matrix” are understood to specifically refer only to that specific subcomponent of the claimed invention. In the originally elected species, the “release modulating matrix” is the PLGA polymer is RESOMER®502H (acid terminated 7-17k MW).
Instant SEQ ID NO: 1 and the description at previously pending claims 13-17 (canceled in Reply filed 3/06/2025) are understood to be fully satisfied by Zilucoplan. “Zilucoplan” has a PubChem CID of 133083018 and corresponds to a CAS No. of 1841136-73-9, and is also referred to RA101495, among other names. The structure of Zilucoplan associated with RA101495 and CAS No. 1841136-73-9 was disclosed in the prior art at least by 5/16/20182. Accordingly, all names associated the prior art structure, including Zilucoplan, RA101495, CAS No. 1841136-73-9, etc. would have been known, searchable, and recognized by artisans as synonyms prior to the instantly filed application.
Claims 1, 5, 12, 18-20, and 113 recite the term “about”, which is not defined on record. Accordingly, the term “about” is given its ordinary meaning in view of the biochemical arts, and is understood to mean “within 20 percent” (see, e.g., US 2009/0028832 A1 at ¶[0111]; see also US 2009/0105341 A1 at ¶[0049]; see also US 2012/0178676, at ¶[0277]). Accordingly, with respect to the instant disclosure and with prior art of record, unless the term “about” is otherwise clearly defined, the term is reasonably inferred to indicate a range either “within 20 percent” of a recited number. For example, the range of “about 50:50” is reasonably inferred to include at least a range of 40:60 to 60:40.
Additional claim interpretations are set forth below.
Revised Rejections as Necessitated by Applicant Amendment
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, 3, 5, 9, and 12 are rejected under 35 U.S.C. 103 as being unpatentable over WO2015/191951A23 (Dec. 17, 2015) and further in view of Mader4.
Claim interpretation: The applicable claim interpretation has been set forth in a preceding section above, and those interpretations are incorporated into the instant rejection. Additional claim interpretations are set forth below.
Regarding instant claim 1, and the structure Zilucoplan (i.e., a lipidated polypeptide of instant SEQ ID NO: 1), WO’951 discloses C5 inhibitors (see, e.g., WO’951 at ¶[00171]), including instant SEQ ID NO: 1 (see, e.g., WO’941 at Tables on 60 and 100, disclosing SEQ ID NO: 194 as “R3193”, having the structure [cyclo(l,6)] Ac-K-V-E-R-F-D-(N-Me)D-Tbg-Y-azaTrp-E-Y-P-Chg-B285,6; see also id. at ¶[00268], reducing to practice R3193 with a lipophilic moiety conjugated to the lysine residue; see also id. at Substance Table on 156 at Substance 194, identifying it as CAS NO. 1841136-73-9). Accordingly, Zilucoplan is a prior art element. Furthermore, R3193 was one of only two lipidated polypeptides (see, e.g., WO’941 at ¶[00268]), and WO’941 identifies that such “Lipidation resulted in an increase in . . . [AUC] by 2.1-fold” to “2.7-fold”, depending upon administration route (see, e.g., WO’941 at ¶[00300]). Accordingly, Zilucoplan is a prior art element, which would be reasonably expected to exhibit a 2.1-2.7-fold increase in AUC relative to non-lipidated compounds. Regarding claim 9 and the presence of an excipient, WO’951 explicitly claims formulations comprising excipients (see, e.g., WO’951 at ¶¶[0017], [00156], claims 1, 17, 20-21, 26).
The prior art of WO’951 differs from the instantly claimed invention as follows: WO’951 does not explicitly reduce to practice R3193 (i.e., Zilucoplan) in a single emulsion of condensed particles in an aqueous continuous phase and sustained release formulation, wherein Zilucoplan is formulated in combination with a PLGA polymer comprising a ratio of poly lactic acid to poly glycolic acid of from about 25:75 to about 75:25 as required by amended claim 1.
Therefore, the relevant issue is whether or not it would have been obvious to combine and formulate a known drug with a known PLGA polymer in a known manner, specifically comprising a ratio of poly lactic acid to poly glycolic acid of from about 25:75 to about 75:25 to yield predictable results.
Regarding instant claims 1, 3, 5, 9, 12, and PLGA, WO’951 provided direct guidance that the disclosed inhibitors could be formulated with PLGA: R3193 is identified as a C5 inhibitor of the invention (see, e.g., WO’951 at ¶[00171]), and WO’951 expressly identifies that such inhibitors may be formulated using emulsions, microemulsions, microspheres, nanoparticles, and time release formulations, etc. (see, e.g., WO’951 at ¶¶[00153]-[00154], [00157], [00236]), including wherein such compounds may be formulated with carriers, such as Poly(L-lactide-co-glycolide) copolymers (see, e.g., WO’951 at ¶[00157]). Accordingly, PLGA was a prior art element, and explicitly taught for use as a carrier agent, for use with R3193 by WO’951, for use in emulsions, microemulsions, microspheres, time release formulations, etc. (see, e.g., WO’951 at ¶¶[00153]-[00154], [00157]). Accordingly, WO’951 directed artisans to PLGA polymers.
RESOMER®502H (50:50 PLGA) was commercially available and taught for use in drug delivery formulations: In view of the express guidance to PLGA polymers by WO’951, it is well-within the ordinary skill in the art to identify commercially available PLGA polymers. Mader identifies that RESOMER®502H was a commercially available PLGA polymer in the prior art circa at least 2011 (see, e.g., Mader at 65 at Table of “RESOMER® Products”), which was taught and disclosed for use in drug delivery systems (see, e.g., Mader at title on 62, 62 at Table 1, 62 at Fig. 2, 63 at col I-II at § Implant Formulation, 63 at Fig. 3). Regarding instant claim 1, claim 5, and a ratio of 50:50 lactide/glycolide in the PLGA, Mader identifies that RESOMER®502H was commercially available as an acid-terminated, 50:50 PLGA, having a Mw of 7-17k (see, e.g., Mader at 65 at Table of “RESOMER® Products”). Regarding claims 1, 3, 12, and microparticles with a diameter range of “about 5 µm to about 200 µm”, Mader identifies that PLGA RESOMER® Products could be utilized to make nanoparticle to microparticles, with diameters ranging from at least 200 nm to 50 µm (see, e.g., Mader at 63 at col I-II at § Implant Formulation, 63 at Fig. 3). Regarding amended claim 1, 3, 5, 9, 12, and the particles formed by “single emulsion of condensed particles in an aqueous continuous phase”, Mader identifies that PLGA may be utilized to “deliver therapeutic agents via microparticle encapsulation”, wherein “loaded microparticles are commonly prepared via . . . emulsification” (see, e.g., Mader at 63 at col II at 1st partial ¶). The usage of water to form an emulsion would be readily apparent to one of skill in the art to facilitate biological capatibility. In summary, the prior art of Mader teaches that the PLGA polymer of RESOMER®502H was well-known in the prior art, commercially available, and art-recognized for suitability in drug delivery systems, including in microparticles circa 2011.
The combination of a prior art drug (Zilucoplan) and a known PLGA 50:50 polymer of RESOMER®502H would yield predictably and expected results: R3193 is identified as a C5 inhibitor of the invention (see, e.g., WO’951 at ¶[00171]), wherein such polypeptides have known applications in the treatment of disorders, conditions, and diseases (see, e.g., WO’951 at ¶[00194]), including the treatment of paroxysmal nocturnal hemoglobinuria (PNH) as well as autoimmune diseases and disorders, neurological diseases and disorders, blood diseases and disorders, and infectious diseases and disorders (see, e.g., WO’951 at ¶¶[00194]-[00195]). In combination with PLGA RESOMER®502H, the drug formulation would be predicted and expected to have the benefits attributable to the drug delivery systems (see, e.g., Mader at title on 62, 62 at Table 1, 62 at Fig. 2, 63 at col I-II at § Implant Formulation, 63 at Fig. 3). Furthermore, as noted above, WO’951 literally directs artisans to utilize PLGA polymers with the disclosed inhibitors in formulations such as emulsions, microemulsions, microspheres, drug depots, time release formulations, etc. (see, e.g., WO’951 at ¶¶[00153]-[00154], [00157], [00236]).
Therefore, it would have been obvious to one of ordinary skill in the art, either before the effective filing date of the claimed invention (AIA ) or otherwise at the time the invention was made (pre-AIA ), to arrive at the instantly claimed invention in view of the prior art for at least the following reason(s): The claimed invention is the obvious combination of prior art elements (i.e., the lipidated structure of R3193, and the PLGA carrier of RESOMER®502H), according to known methods of making pharmaceutical formulations (e.g., time release formulations, microspheres, drug depots, etc.) exactly as explicitly taught and suggested by the primary reference, wherein such a combination would merely yield the predicted and expected results, namely a pharmaceutical formulation comprising R3193 and RESOMER®502H suitable for use in the treatment of conditions requiring a C5 inhibitor, such as PNH or other diseases or conditions, wherein R3193 would reasonably be expected to exhibit increased AUC relative to non-lipidated C5 inhibitors (see, e.g., MPEP §§ 2143(I)(A), (G)). In addition or alternatively, RESOMER®502H was commercially available and were explicitly taught for use in drug formulations; accordingly, the simple selection of a known material (e.g., RESOMER®502H) based on its suitability for its intended purpose of forming a microparticle drug delivery system is obvious because the claims are directed to a combination of prior art elements that merely perform their same art-recognized, expected, and predicted functions when in combination as they do separately (see, e.g., MPEP § 2143(I)(A), MPEP § 2144.077,8).
Furthermore, there would be a reasonable expectation of success because the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)). Furthermore, it is well-within the ordinary skill in the art to combine a prior art therapeutic compound with a commercially available prior art carrier to arrive at a known, prior art pharmaceutical formulation suitable for treating the same, exact conditions and patient populations taught and disclosed by the prior art.
Accordingly, claims 1, 3, 5, 9, and 12 are rejected.
Claims 1, 5, 9-12, 18-21, 35, and 113 are rejected under 35 U.S.C. 103 as being unpatentable over WO2015/191951A2 in view of Mader9 as applied to claims 1, 3, 5, 9, and 12 above, and further in view of Han10 and Acharya11.
Claim interpretation: The applicable claim interpretation has been set forth in a preceding section and/or rejections above, and those interpretations are incorporated into the instant rejection. Additional claim interpretations are set forth below.
The teachings of WO’951 in view of Mader as applied to claims 1, 5, and 9 have been set forth above, and those teachings are incorporated into the instant rejection.
The prior art of WO’951 in view of Mader differs from the instantly claimed invention as follows: WO’951 in view of Mader does not specifically teach a drug loading percentage of 37% with a release profile as set forth in the instant claims, microparticle diameter range, or specific usage of PVA.
However, Han establishes that PLGA-based polymers were well-known in the sustained-release drug formulation arts (see, e.g., Han at title, abs, Table 1 on 3-4). In addition, Han identifies that PLGA delivery systems could have different particle sizes, different drug loading percentages, different drug release profiles, and could be utilized to encapsulate a wide-range of drugs (see, e.g., Han at title, abs, Table 1 on 3-4). Similarly, Acharya identifies a method for making microparticles of 200 nm to >50µm, having a drug loading capacity of 50% or higher with minimal initial burst release (see, e.g., Acharya at title, abs).
Regarding claim 1 and the preamble reciting “a single emulsion of condensed particles in an aqueous phase”, in addition to the discussion set forth in view of WO’951 in view of Mader, above, it is noted that Han identifies that such single emulsions in aqueous phase using PLGA were well-known and common in the prior art (see, e.g., Han at Table 2 at p. 6, showing oil-in-water single emulsion in aqueous phase). Accordingly, such formulations were well-known in the prior art.
Regarding claim 12 and particle size, Han identifies that microparticles have “optimal release profiles” with diameters within the range of “10-200 µm” (see Han at p. 2 at col II at § Particle Size; see also Acharya at abs; see also MPEP § 2144.05(I)).
Regarding amended claims 9-11 and 35 and the emulsion stabilizer of polyvinyl alcohol (PVA), Han identifies that PVA is the “most widely used emulsifier in the preparation of PLGA micro/nanoparticles” (see, e.g., Han at 5 at col I at § Choice of Surfactant). Regarding instant claim 35 and product-by-process language utilizing PVA, instant claim 35 is directed to a product, but recites limitations directed to a product-by-process (see instant claim 35). Per MPEP § 2113(I),
[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985) (citations omitted).
Accordingly, claim 35 is rejected as obvious for the reasons applied to claims 1, 5, and 9, as set forth above (see also Han at 5 at col I at § Choice of Surfactant, noting that PVA is the “most widely used emulsifier in the preparation of PLGA micro/nanoparticles” and is used to “ensure droplet stability”).
Regarding instant claims 18-20, 113, and the percentages of polypeptide and release modulating matrix (PLGA), Han identifies that drug loading varies depending upon drug used, particle size, and method of particle manufacture from at least 1% drug loading to >57% (w/w) drug loading (see, e.g., Han at Table 1(1) and Table 1(3) on p. 3, Table 1(3) and Table 1(4) on p. 4, p. 5 at col II at § Hydrogel Templates, Table 2 at p. 6-7; note that the PLGA content is understood to be the 100% - drug loading percentage (w/w)). Accordingly, the prior art teaches that, circa 2016, artisans knew how to obtain drug loading percentages (w/w) within the ranges of at least 1-57% (see id.; see also Acharya at abs, disclosing drug loading capacity of 50% or higher), which overlaps in scope with the claimed ranges (see, e.g., MPEP § 2144.05(I), "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists).
Regarding claim 21 and uniform distribution, Han identifies multiple methods for making PLGA-based microparticles for use in drug delivery (see Han at Table 2 on 6-7); and Han identifies hydrogel templates that are reasonable understood to have a uniform distribution of drug within the matrix (see id at 7). Similarly, Acharya identifies that such hydrogel templates yields homogenous size distributions (see, e.g., Acharya at abs), and that such microparticles are made by pouring a “solution or a paste of drug/polymer mixture” into a “gelatin mold” (see, e.g., Acharya at 315 at Fig. 1, 315 at col I at 1st full ¶), which is reasonably inferred to yield a uniformly distributed drug within PLGA (see, e.g., Acharya at Fig. 3 on 316, noting uniformly distributed dye). Furthermore, such structures are identified as “homogenous” (see, e.g., Acharya at Fig. 2 on 316), and are therefore understood to be uniform. Accordingly, uniform distribution as claimed is understood to be an obvious result of prior art methods of forming microparticles.
Regarding predicted and expected sustained release formulations with different release kinetics, Mader identifies that it was well-understood that RESOMER® PLGA polymers impacted drug delivery (see, e.g., Mader at 62 at Table 1 and Fig. 2). Mader identifies that
The release profile depends on the size distribution and porosity of the microparticles, the drug characteristics and concentration, and the release conditions. . . . The release profile can be adjusted by appropriate formulation parameters. For example, linear release, pulsed release (e.g., for vaccination with no burst release, and a tunable lag phase release can be achieved”
(see, e.g., Mader at 63 at col II at 1st ¶).
Mader further identifies that, for PLGA, “degradation takes place for approximately three weeks” (see, e.g., Mader at 63 at col II at 4th ¶, Fig. 4), and that the release of peptides “can be [] over days to several weeks” (see, e.g., Mader at 64 at col I at 2nd ¶). In addition, Han exemplifies that microparticle drug delivery systems have wide ranges of achievable and obtainable drug release profiles, which can vary from sustained release over a 550 hr period or 90% release in over 21 days, to no initial burst and sustained release for over 3 months (see, e.g., Han at Table 1(1) and 1(3) on 3, Table 1(4) on 4). Like Mader, Han also identifies that
…the desired release rates can be achieved by adjusting the ratio of lactic acid to glycolic acid and by altering the physiochemical properties [e.g., Mr, end-group (ester or carboxylic) functionality] that influence microparticle morphology.
(see, e.g., Han at Table 1(1) and 1(3) on 3, Table 1(4) on 4).
Accordingly, one of ordinary skill in the art would readily appreciate that the art-recognized and achievable release profiles presently claimed overlap in scope with the release profiles known and generally taught in the microparticle arts (see also MPEP § 2144.05(I)); and that a desired particle size and release profile (including effective concentration, initial release, timing, and sustained release profile) could be achieved via routine optimization of art-recognized variables and formulation parameters as taught by Mader and Han (e.g., size distribution, porosity, drug concentration, ratio of lactic acid to glycolic acid, Mr, end-group chemistry, etc.).
Therefore, it would have been obvious to one of ordinary skill in the art, either before the effective filing date of the claimed invention (AIA ) or otherwise at the time the invention was made (pre-AIA ), to arrive at the instantly claimed invention in view of the prior art for at least the following reason(s): The claimed invention is the combination of prior art elements (i.e., the lipidated structure of R3193, a PLGA carrier, PVA as an emulsion stabilizer) according to known prior art methods of forming PLGA emulsions using routine methodologies in the PLGA emulsion arts, wherein such combination merely produces the predicted and expected results taught and disclosed by the prior art, namely PLGA particle emulsions in an aqueous phase suitable for use in pharmaceutical applications as taught by the primary reference (i.e., applications requiring treatment with a C5 inhibitor), wherein the particle loading and size is within prior art expected ranges taught by the prior art (see, e.g., MPEP §§ 2143(I)(A), (G), MPEP § 2144.05(I)). In addition or alternatively, PLGA was a commercially available therapeutic drug delivery system, explicitly mentioned in the primary reference, and well known in the drug delivery arts as established by Mader, Han and Acharya, wherein the invention is understood to be the simple selection of known materials (e.g., PLGA delivery systems, formulated as an emulsion as known in the PLGA arts as an emulsion, loaded within range taught by PLGA arts, diameter as taught in the PLGA arts) based on the PLGA delivery system’s suitability for its intended purpose of forming a microparticle drug delivery system is obvious because the claims are directed to a combination of prior art elements that merely perform their same art-recognized, expected, and predicted functions when in combination as they do separately (see, e.g., MPEP § 2143(I)(A), MPEP § 2144.0712,13).
The disclosed ranges of instant claims 18-20 and 113 are understood to amount correspond to overlapping ranges taught and disclosed by the prior art (see, e.g., discussion above; see also MPEP § 2144.05(I), "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists); furthermore, it has long been settled to be no more than routine experimentation for one of ordinary skill in the art to discover an optimum value of a result effective variable because "where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation" and "No invention is involved in discovering optimum ranges of a process by routine experimentation" since the "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art" (see, e.g., MPEP § 2144.05(II)); as explained above, art-recognized variables and formulation parameters as taught by Mader and Han (e.g., size distribution, porosity, drug concentration, ratio of lactic acid to glycolic acid, Mr, end-group chemistry, etc.) were understood to control PLGA release profiles and release kinetics. Since Applicant has not disclosed that the specific limitations recited in instant claims 18-20 and 113 are for any particular purpose or solve any stated problem and the prior art teaches that microparticle drug loading and drug release profiles often vary according to the intended application and drug being utilized, and various parameters appear to work equally as well, absent unexpected results, it would have been obvious for one of ordinary skill to discover the optimum workable ranges of the methods disclosed by the prior art by normal optimization procedures known in the PLGA microparticle drug delivery arts.
Furthermore, there would be a reasonable expectation of success because the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)). Furthermore, it is well-within the ordinary skill in the microparticle arts to take a combine a known drug (e.g., zilucoplan) with a known drug delivery system (e.g., PLGA microparticles), according to known methods of making microparticles (e.g., Han, Mader, and Acharya), to predictably obtain drug-loaded PLGA microparticles having the general diameters, drug loading, and release profiles taught and disclosed in the prior art.
Claims 1, 5, 9-12, 18-21, 35, and 113 are rejected.
Response to Arguments
Applicant's arguments filed 9/30/2025 have been fully considered but they are not persuasive as discussed below.
All claim interpretations and holdings not specifically disputed are understood to currently be undisputed on record.
The Examiner’s prior responses of record remain applicable in view of the revised rejections relying upon art already of record. Accordingly, the Examiner’s prior responses are incorporated into the instant action.
It is the Examiner’s understanding that Applicant addresses the revised rejection above at pages 6-12 (see, e.g., Reply filed 9/30/2025 at 6 at § “Response” to page 12 at 3rd ¶). Applicant acknowledges the Examiner’s prior position of record (see, e.g., id. at 7 at 1st ¶), and then raises arguments addressed below.
At pages 7-8, it is the Examiner’s understanding that Applicant alleges that WO’951 in view of Mader fails to teach or suggest a formulation “including a particular single emulsion of condensed particles” as now claimed (see, e.g., Reply filed 9/30/2025 at 7 at final ¶ to 8 at 1st full ¶). This argument is conclusory in nature as Applicant fails to consider the merits of the rejection by specifically addressing the cited portions of each document as set forth in the rejection. Examiner directs Applicant to the rejection, including cited portions of the prior art and applicable patent law. Notably, Applicant fails to identify a single feature not directly taught or otherwise rendered obvious in view of the prior art. The prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)), which includes combinations of a known drug compound (i.e., Zilucoplan) with a known drug delivery system (i.e., PLGA), formulated according to known methods in the PLGA arts.
At pages 8-10, it is the Examiner’s understanding that Applicant alleges that “Mader discourages one of ordinary skill in the art from utilizing PLGA polymers in favor of PEGylated PLGA copolymers (PEG-PLGA polymers) in sustained release formulations (see, e.g., Reply filed 9/30/2025 at 8 at 2nd full ¶ to 10 at 1st full ¶) on the basis that Mader provides a preference for PEG-PLGA polymers (see id). A preference does not rise to the level of a “teaching away” because an Artisan would readily appreciate the expected and predicted results of utilizing PLGA in the absence of PEG as clearly and unmistakably described by Mader at pages 62-63. Furthermore, PLGA without PEG is clearly sold and marketed to users, which would not be reasonable if Mader was “teaching away” from their own commercially available products. In addition, Applicant appears to rely upon unclaimed limitations (e.g., “pH inside PLGA implants”, “acidic microclimate”, etc.), which do not clearly pertain to the invention as it is actually claimed; 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). Accordingly, such arguments alleging a “teaching away” are not credible and do not reflect the prior art of record, or the fact that commercially available compounds have commercially recognized benefits when considered as a whole. Accordingly, this line of reasoning is not persuasive because Mader does not criticize, discredit, or otherwise discourage the solution claimed. Per MPEP § 2145(X)(D)(1),
…the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). See also UCB, Inc. v. Actavis Labs, UT, Inc., 65 F.4th 679, 692, 2023 USPQ2d 448 (Fed. Cir. 2023) ("a reference does not teach away if it merely expresses a general preference for an alternative invention but does not criticize, discredit or otherwise discourage investigation into the invention claimed.
Accordingly, disclosures showing a preference for PEG does not amount to a “teaching away” because it does not criticize, discredit or otherwise discourage the solution claimed, or render the instantly claimed combination less predictable (see previous paragraph).
Allegations suggesting “skepticism of experts”: It is the Examiner’s understanding that Applicant’s statements amount to a suggestion that the Examiner’s position would be met with skepticism of experts (see, e.g., Reply filed 9/30/2025 at 8 at 2nd full ¶ to 10 at 1st full ¶, discussing suitability of PLGA and an alleged “teaching away”). If Applicant means to suggest the existence of skepticism of experts, such evidence should be filed per MPEP § 716.05 as evidence is required to establish skepticism of experts. In the absence of such evidence, such statements are understood to be unsupported conjecture of counsel. The prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)), including “all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments” (see, e.g., MPEP § 2123(I)), and no objective evidence rebutting this presumption has been placed on record to date.
Allegations suggesting “inoperability” or lack of enabling disclosure regarding a prior art reference: It is the Examiner’s understanding that Applicant’s statements amount to a suggestion that the prior art is not fully enabled or operable (see, e.g., Reply filed 9/30/2025 at 8 at 2nd full ¶ to 10 at 1st full ¶, discussing suitability of PLGA and an alleged “teaching away”). If Applicant is attempting to allege that the prior art is not enabling or inoperable Applicant is directed to MPEP § 2121(I), which notes that the prior art is presumed fully enabled for all that it discloses, and the burden is on the Applicant to rebut the presumption of operability (see, e.g., MPEP § 2121(I); MPEP § 716.07). No evidence of inoperability commensurate in scope with the requirements of MPEP § 716.07 have been placed on record at this time; critically, arguments of counsel cannot take the place of evidence in the record (see, e.g., In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965), and evidence is required to rebut the presumption of operability. The Examiner’s position is that the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)), including “all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments” (see, e.g., MPEP § 2123(I)). Accordingly, the Applicant has not satisfied their burden to rebut the presumption of operability of the prior art at this time (see, e.g., MPEP § 2121(I); MPEP § 716.07).
Unexpected Results: It is the Examiner’s understanding that Applicant alleges unexpected results premised upon particle loading (see, e.g., Reply filed 9/30/2025 at 10 at § Unexpected Results to page 11 at 1st full ¶). To establish such unexpected results, the allegations must be timely and supported by objective evidence (see, e.g., 37 C.F.R. 1.132; see MPEP §§ 716.01, 716.01(a), 716.01(c)); to be of probative value the proffered evidence must be related to the claimed invention (see MPEP §§ 716.01(b), discussing nexus requirement and noting that "[w]here the offered secondary consideration actually results from something other than what is both claimed and novel in the claim, there is no nexus to the merits of the claimed invention"); the evidence must establish that the expected results occur to an unexpected extent (see, e.g., MPEP § 716.02(a)(I)), on the basis of statistically and practically significant evidence (see, e.g., MPEP § 716.02(b)(I)), which is fully explained (see, e.g., MPEP § 716.02(b)(II)), commensurate in scope with the claimed invention (see, e.g., MPEP § 716.02(d)), and wherein a comparison of the claimed invention with the closest prior art of record is provided (see, e.g., MPEP § 716.02(e)). Furthermore, even if evidence satisfying MPEP §§ 716.02, 716.02(a), 716.02(b), 716.02(d), and 716.02(e) is set forth on record, such evidence may not be sufficient to rebut prima facie obviousness because the evidence of expected and unexpected results must be weighed (see, e.g., MPEP § 716.02(c)(I)) and the totality of the record considered (see, e.g., MPEP §§ 716.01(d), 716.02(f)), including teachings in the prior art and evidence of expected results which weigh in favor of a determination of obviousness (see, e.g., MPEP § 716.02(c)(II)). Here, the allegation of unexpected results is premised upon the assertion that
The inventors demonstrated that single emulsion formulations with 36-37.5% zilucoplan loading percentage had the highest allowable load before burst values became excessive. Unexpectedly, single emulsion formulations displayed more favorable release properties than comparable double emulsion formulations.
These results are contrary to the teachings of the prior art, as exemplified by Acharya, that the majority of particles for drug delivery applications (e.g., sustained release formulations) prepared by conventional emulsion methods possess "rather low drug loading capacity, usually much less than 10% of the total weight, and often show significant initial burst release of the drug, which can be a half or more of the total loaded drug" (Acharya at 317, column II).
(see, e.g., Reply filed 9/30/2025 at 10 at § Unexpected Results to page 11 at 1st full ¶)
First, the alleged data is not of statistical significance identified on record, and therefore does not satisfy MPEP § 716.02(b). Second, the alleged data is not commensurate in scope with the claimed invention, which is not presently limited to the exact formulation referenced by the Applicant, and therefore does not satisfy MPEP § 716.02(d). Third, zero evidence criticality of range has been placed on record commensurate in scope with MPEP §§ 716.02(a), (b), and (d). Fourth, Applicant misconstrues the disclosure of Acharya, which identifies drug loading may be over 50% (see, e.g., Acharya at abs, Fig. 6 on 318). Accordingly, arguments premised upon piecemeal or incomplete consideration of the prior art as a whole does not lend credibility to the Applicant’s position. Therefore such arguments are not persuasive. Fifth, per MPEP § 716.02(c)(II) evidence of expected results weigh in favor of a determination of obviousness, and here the combination of a known compound with a known drug delivery system yields the predicted and expected results, namely a drug loaded into a drug delivery system suitable for use in the applications explicitly taught and disclosed by the primary reference. In sum, the proffered evidence is insufficient to establish unexpected results commensurate in scope with the requirements of MPEP §§ 716, 716.01, and 716.02, and therefore zero evidence of unexpected results have been placed on record at this time. Furthermore, in view of the evidence showing expected results, the evidence of record weighs in favor of a determination of obviousness per MPEP § 716.02(c)(II).
It is the Examiner’s understanding that Applicant addresses the rejection in view of WO’951, Mader, Han, and Achary at pages 11-12 (see, e.g., Reply filed 9/30/2025 at 11 at § “Response to Rejection” to page 12 at final ¶).
It is the Examiner’s understanding that Applicant alleges that “nowhere does Han or Acharya disclose that such loading percentages are achievable with a single emulsion formulation” (see, e.g., Reply filed 9/30/2025 at 11-12 at bridging ¶). First, single emulsions in aqueous continuous phases are not a point of novelty, and are in fact taught by and rendered obvious in view of the prior art (see revised rejections above; see, e.g., Han at Table 2 at p. 6, showing oil-in-water single emulsion in aqueous phase). Emulsions are well-known and understood in the drug delivery arts. Second, the verbiage of “are achievable” suggests that Applicant is attempting to imply that drug loading amounts of 50% or higher were not known in the prior art (see, e.g., Reply filed 9/30/2025 at 11-12 at bridging ¶). This is factually incorrect in view of Acharya. Furthermore, if Applicant is alleging or suggesting that the prior art is “inoperable” for such formulations or otherwise suggest “skepticism of experts”, Applicant is directed to MPEP § 2121(I), which notes that the prior art is presumed fully enabled for all that it discloses, and the burden is on the Applicant to rebut the presumption of operability (see, e.g., MPEP § 2121(I); MPEP § 716.07) or otherwise provide support for allegations of skepticism of experts per MPEP § 716.05. No evidence of inoperability or skepticism of experts commensurate in scope with the requirements of MPEP § 716.05 or § 716.07 have been placed on record at this time; critically, arguments of counsel cannot take the place of evidence in the record (see, e.g., In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965). The Examiner’s position is that the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)), including “all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments” (see, e.g., MPEP § 2123(I)). Accordingly, in the absence of objective supporting evidence commensurate in scope with the requirements of MPEP §§ 716 and 716.01, such arguments are not persuasive. As explained in the rejection, all components and methods of formulation were well-known in the prior art, and the combination appears to merely be the predicted and expected outcome.
At page 12, it is the Examiner’s understanding that Applicant discusses the individual teachings of the references or less than the total references set forth in the rejection, rather than the teachings of the references considered in combination (see, e.g., Reply filed 9/30/2025 at 11-12 at bridging ¶ addressing Han alone, 12 at 1st full ¶ addressing Acharya alone, 12 at 2nd full ¶ addressing Han and Acharya in the absence of the primary reference or Mader). 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).
At page 12, it is the Examiner’s understanding that Applicant is alleging that Han and Acharya “discourage” the claimed invention (see, e.g., Reply filed 9/30/2025 at 12 at 2nd full ¶). Such arguments alleging a “teaching away” are not persuasive because neither Han nor Acharya criticize, discredit, or otherwise discourage the solution claimed. Per MPEP § 2145(X)(D)(1),
…the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). See also UCB, Inc. v. Actavis Labs, UT, Inc., 65 F.4th 679, 692, 2023 USPQ2d 448 (Fed. Cir. 2023) ("a reference does not teach away if it merely expresses a general preference for an alternative invention but does not criticize, discredit or otherwise discourage investigation into the invention claimed.
Accordingly, disclosures showing a preference for hydrogel templates by Acharya does not amount to a “teaching away” because it does not criticize, discredit or otherwise discourage the solution claimed, or render the instantly claimed combination less predictable (see previous paragraph).
The Examiner’s position is that the therapeutic drug was known in the prior art and that PLGA emulsions were a well-known and conventional means of drug delivery at the time of filing, and that the invention is the combination of known elements according to known methods to achieve predicted and expected outcomes. This is sufficient to sustain a determination of obviousness per KSR:
A rationale to support a conclusion that a claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded nothing more than predictable results to one of ordinary skill in the art. KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 416, 82 USPQ2d 1385, 1395 (2007).
"[W]hen a patent 'simply arranges old elements with each performing the same function it had been known to perform' and yields no more than one would expect from such an arrangement, the combination is obvious." KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398 , 417 , 127 S. Ct. 1727 , 167 L. Ed. 2d 705 (2007) (quoting Sakraida v. Ag Pro, Inc., 425 U.S. 273 , 282 , 96 S. Ct. 1532 , 47 L. Ed. 2d 784 (1976)).
Here, zero evidence of unexpected results commensurate in scope with the requirements of MPEP §§ 716.01 and 716.02 have been placed on record; accordingly, the prior art elements could have been combined by known methods with no change in their respective functions, and the combination would have yielded nothing more than predictable results to one of ordinary skill in the art. Accordingly, the rejections are maintained as revised above.
Accordingly, all arguments raised by the Applicant have been fully considered but not found persuasive for the reasons set forth above. Therefore, the rejections are maintained as revised above, and all revisions were necessitated by Applicant’s amendments.
Examiner notes that examination could be facilitated by evidence commensurate in scope with the requirements of MPEP § 716.02, showing criticality of range and statistically significant data commensurate in scope with the instant claims.
Conclusion
No claims are allowed.
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/RANDALL L BEANE/ Primary Examiner, Art Unit 1654
1 Zilucoplan (a.k.a., RA101495 or R3193) is a prior art element taught and disclosed by WO2015/191951A2 (Dec. 17, 2015; cited in previous action; see, e.g., WO’941 at Tables on 60 and 100, disclosing SEQ ID NO: 194 as “R3193”, having the structure [cyclo(l,6)] Ac-K-V-E-R-F-D-(N-Me)D-Tbg-Y-azaTrp-E-Y-P-Chg-B28; see also id. at ¶[00268], reducing to practice R3193; see also id. at Substance Table on 156 at Substance 194, identifying it as CAS NO. 1841136-73-9).
2 see, e.g., Search notes showing PubChem Search for 1841136-73-9, 2 pages, created 5/16/2018, also available at https://pubchem.ncbi.nlm.nih.gov/#tab/sidsrcname=ChemIDplus&query=1841136-73-9&input_type=text (last visited 11/15/2024).
3 Cited in Requirement mailed 5/23/2024.
4 Mäder, “RESOMER® - Biodegradeable Polymers for Sutures, Medical Devices, Drug Delivery Systems and Tissue Engineering.”, Material Matters, vol. 6(3):62-66 (2011); hereafter “Mader”.
5 see, e.g., WO’951 at [00133], [00261], defining acronyms such as Chg (i.e., cyclohexylglycine).
6 see, e.g., WO’951 at [00133], defining “B28” as N-epsilon-(PEG24-gamma-glutamic acid-N-alpha-hexadecanoyl)Lys.
7 See also Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327 (1945) at 335, noting that "[r]eading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle."
8 See also KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398 , 417 , 127 S. Ct. 1727 , 167 L. Ed. 2d 705 (2007), noting that "[W]hen a patent 'simply arranges old elements with each performing the same function it had been known to perform' and yields no more than one would expect from such an arrangement, the combination is obvious."
9 Mäder, “RESOMER® - Biodegradeable Polymers for Sutures, Medical Devices, Drug Delivery Systems and Tissue Engineering.”, Material Matters, vol. 6(3):62-66 (2011); hereafter “Mader”; cited in previous action.
10 Han et al., Biodegradable PLGA-Based Microparticles for Producing Sustained-Release Drug Formulations and Strategies for Improving Drug Loading. Front Pharmacol. 2016 Jun 28;7:185. doi: 10.3389/fphar.2016.00185. PMID: 27445821; PMCID: PMC4923250; hereafter “Han”; cited in Requirement mailed 5/23/2024; hereafter “Han”; cited in previous action.
11Acharya et al., The hydrogel template method for fabrication of homogeneous nano/microparticles. J Control Release. 2010 Feb 15;141(3):314-9. doi: 10.1016/j.jconrel.2009.09.032. Epub 2009 Oct 12. PMID: 19822178; cited in previous action.
12 See also Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327 (1945) at 335, noting that "[r]eading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle."
13 See also KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398 , 417 , 127 S. Ct. 1727 , 167 L. Ed. 2d 705 (2007), noting that "[W]hen a patent 'simply arranges old elements with each performing the same function it had been known to perform' and yields no more than one would expect from such an arrangement, the combination is obvious."