DETAILED ACTION
Notice of AIA Status
The present application is subject to the first inventor to file provisions of the Leahy-Smith America Invents Act (AIA ). The application contains or contained at any time at least one claim to a claimed invention having an effective filing date on or after 16 March 2013. Accordingly, the application is being examined under the first inventor to file provisions of the AIA (see MPEP § 2159.02 and § 2159.03).
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) and a qualifying submission, was filed after final rejection. Since this application is eligible for continued examination under 37 CFR § 1.114, and the required fee has been timely paid, the finality of the previous Office Correspondence has been withdrawn pursuant to 37 CFR § 1.114. The applicant's submission filed on 02 July 2026 has been entered (see MPEP § 706.07(h) and 35 U.S.C. § 132(b)).
Information Disclosure Statement
The Information Disclosure Statement, filed 02 July 2026, is acknowledged and has been considered.
Status of the Claims
Amendments to the Claims and Arguments/Remarks filed 02 July 2026, in response to the Office Correspondence dated 02 March 2026, are acknowledged.
The claim listing filed 02 July 2026 are examined. Claims 18, 20, 25, 26, 28-37, and 40-42 are pending. Claims 18, 25, 34, and 36 are currently amended. Claims 40-42 are newly added. Claims 1-17, 19, 21-24, 27, 38, and 39 are canceled.
Response to Amendment
The amendments to claims 18, 25, 34, and 36 and the subject matter of new claims 40-42 are supported by the originally filed disclosure. By way of example, the original disclosure identifies sucrose, trehalose, and specified amino acids including L-leucine as stabilizers; expressly discloses the approximately 15.5% antibody/7.5% excipient/69.5% polymer/7.5% PEG formulation now recited in claim 36; and describes preparing an antibody-containing liquid formulation containing stabilizer and optionally buffering agent and/or surfactant, drying that liquid formulation, homogeneously dispersing the dried material with polymer and plasticizer, and extruding the resulting mixture. Accordingly, no objection under 35 U.S.C. § 132(a) is raised by the amendments addressed herein.
The applicant’s acknowledgment of the withdrawal of the prior objections to the drawings and title and the prior rejections under 35 U.S.C. § 112(b) is noted. The cancellation of claims 22, 38, and 39 renders the outstanding rejections of those claims moot. The applicant’s arguments have been fully considered. To the extent discussed below, certain arguments are persuasive as to the previously stated under 35 U.S.C. § 102 rejection and certain characterizations made in the prior Office Correspondence. Other arguments do not establish patentability for the reasons explained below in the Response to Arguments section.
The rejection of claims 18, 20, 26, and 28-32 under 35 U.S.C. § 102(a)(1) over Trogden is withdrawn. This withdrawal should not be understood as a determination that the several teachings identified above are irrelevant to obviousness under 35 U.S.C. § 103. Anticipation and obviousness are distinct inquiries, and disclosures that do not collectively constitute an anticipating embodiment may nevertheless be pertinent to what the prior art as a whole would have suggested to one of ordinary skill in the art.
The obviousness rejections under 35 U.S.C. § 103 presently applicable to the pending claims are set forth below and presently applicable rejection under 35 U.S.C. § 112(b).
Claim Objections
Claim 34 is objected to because of the following informalities:
Claim 34 recites “hot melting extrusion (HME).” Although that expression also appears at certain locations in the originally filed disclosure, the specification repeatedly defines and uses HME as “hot melt extrusion.” For example, the specification states “HME hot melt extrusion” and describes “hot melt extrusion (HME)” as the pharmaceutical extrusion process used to produce the filaments. The claim should therefore preferably be corrected to “hot melt extrusion (HME)” for consistency with the defined terminology of the disclosure.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. § 112(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.
A claim is indefinite when its language is ambiguous, vague, incoherent, opaque, or otherwise unclear such that the boundaries cannot be determined under the broadest reasonable interpretation (see In re Packard, 751 F.3d 1307, 1311-14 (Fed. Cir. 2014); MPEP § 2173). Absolute precision is not required, but the claim must provide objective boundaries when read in light of the specification and the knowledge of one of ordinary skill (see supplementary judicial guidance concerning objective claim boundaries provided by Nautilus, Inc. v. Biosig Instruments, Inc., 572 U.S. 898, 909-10 (2014); Interval Licensing LLC v. AOL, Inc., 766 F.3d 1364, 1370-71 (Fed. Cir. 2014)).
Claim 35 is rejected under AIA 35 U.S.C. § 112(b), 2nd paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor/inventors, regards as the invention.
Claim 35 recites, in relevant part, “extruding the filament from the heated print head at a temperature above the glass transition temperature of the polymeric material of matrix,” and subsequently recites, “heating the build platform at a temperature below the glass transition temperature of the polymeric matrix.”
The phrase “the polymeric material of matrix” is grammatically incomplete and does not clearly identify the matrix whose glass-transition temperature establishes the temperature boundary of step (a). The later expression “the polymeric matrix” likewise has no explicit antecedent recitation of a “polymeric matrix” in claim 35 or incorporated claim 18. The lack of literal antecedent basis does not invariably cause indefiniteness if the referent is nevertheless reasonably ascertainable. Conversely, a rejection is proper where uncertainty remains as to the element to which “the” or “said” refers (see In re Packard, 751 F.3d 1307, 1311-14 (Fed. Cir. 2014); MPEP § 2173.05(e)).
Here, the problem is not merely the absence of verbatim antecedent terminology. Claim 18 expressly permits “at least one thermoplastic polymeric material,” and claim 20 expressly permits combinations of thermoplastic polymeric materials. Consequently, the incorporated filament may contain more than one polymeric material. Claim 35 nevertheless specifies the printing and platform temperatures relative to “the glass transition temperature” without identifying, when more than one polymeric material or more than one glass transition is present, which glass-transition temperature establishes the claimed boundary (e.g., the glass-transition temperature of a particular polymer component, the lowest or highest glass-transition temperature, or a glass-transition temperature measured for the resulting polymeric matrix or blend).
The specification does not resolve this ambiguity. It describes FDM extrusion through a heated nozzle and states generally that the filament is loaded into the print head using a temperature above “the glass transition temperature,” while the build platform is maintained below “the glass transition temperature of the polymeric matrix” (¶[0042]-[0046]). The disclosure also expressly permits multiple polymeric materials and combinations thereof (¶[0052]). Accordingly, for embodiments containing more than one polymeric material and/or more than one relevant glass transition, the claim does not provide a sufficiently clear boundary for determining whether a particular printing temperature satisfies step (a) or whether a particular build-platform temperature satisfies step (b).
The applicant is required to amend the claim to clearly identify the applicable polymeric matrix/material and the operative glass-transition-temperature criterion, or otherwise establish on the record that a person of ordinary skill in the relevant art would understand a single, definite meaning for these limitations. The applicant must additionally address which glass-transition temperature controls where the filament comprises multiple polymeric materials having more than one relevant glass transition.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. § 103 is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AlA) 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. 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. The 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.
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 underlying obviousness under 35 U.S.C. § 103 are those set forth in Graham v. John Deere Co., 383 U.S. 1, 17-18 (1966), and 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.
The analysis must consider the claim as a whole and provide an articulated reason with a rational underpinning for the proposed modification or combination (see KSR International Co. v. Teleflex Inc., 550 U.S. 398, 418-22 (2007); In re Kahn, 441 F.3d 977, 988 (Fed. Cir. 2006)).
A person of ordinary skill in the art at the relevant time would have been an individual with a combination of education and experience in pharmaceutical formulation, polymer science, and advanced manufacturing technologies. A person of ordinary skill in the art at the relevant time would typically hold an advanced degree (e.g., M.S. or Ph.D.) in Pharmaceutical Sciences, Polymer Chemistry, Materials Science, Chemical Engineering, or a related field, with a focus on drug delivery systems. In addition to formal education, they would have several years (e.g., 3-5+) of industrial or academic research experience in pharmaceutical formulation development, including the stabilization of biologics (especially antibodies) using excipients such as buffering agents, surfactants, and lyoprotectants (e.g., sucrose, trehalose, amino acids).
A person of ordinary skill in the art at the relevant time would understand hot melt extrusion as a well-established continuous manufacturing technique for producing drug-loaded polymeric filaments; would be aware of fused deposition modeling 3D printing, particularly for fabricating implantable drug delivery devices from thermoplastic filaments; and would be familiar with particle engineering techniques such as spray-drying and freeze-drying to produce dry microparticles of biologics.
A person of ordinary skill in the art at the relevant time would possess the practical and theoretical knowledge to select and combine appropriate thermoplastic polymers (e.g., PLGA, PCL, PLA), plasticizers (e.g., PEG), and excipients to achieve a homogeneous, printable filament with the desired drug load and release profile; optimize HME and FDM process parameters (e.g., temperature, screw speed, layer height) to maintain antibody stability and bioactivity, while ensuring the filament's mechanical properties are suitable for 3D printing; characterize the filament and final device using analytical techniques (e.g., HPLC, DSC, TGA, SEM) to assess drug content, uniformity, thermal properties, and morphology; and evaluate the in vitro release kinetics and antibody binding capacity, understanding the critical factors that affect protein aggregation and degradation during thermal processing.
This level of skill is consistent with the multidisciplinary expertise demonstrated in the relevant scientific literature published around the time of the invention, such as the work by Carlier et al., on mAb-loaded 3D-printed implantable devices (2021). A person of ordinary skill in the art at the relevant time would be familiar with such publications and capable of applying the disclosed principles to develop and optimize the claimed filament and device. This definition is consistent with the level of skill and knowledge displayed by the cited prior art references cited below and is appropriate for evaluating the patentability of the instant claimed invention.
During examination, a pending claim is given its broadest reasonable interpretation consistent with the specification, as the claim language would be understood by a person of ordinary skill in the art (see In re Morris, 127 F.3d 1048, 1054-1055 (Fed. Cir. 1997); In re Suitco Surface, Inc., 603 F.3d 1255, 1260 (Fed. Cir. 2010); MPEP § 2111).
Claims 18, 20, 26, 28, 29, 30, 32-34, 41, and 42 are rejected under AIA 35 U.S.C. § 103 as being unpatentable over Wu et al. (US20140086974A1, published 27 March 2014; hereinafter “Wu”), in view of Carlier et al. (Investigation of the parameters used in fused deposition modeling of poly(lactic acid) to optimize 3D printing sessions. Int J Pharm. 2019 Jun 30;565:367-377; hereinafter “Carlier”).
The effective filing date of instant application presently being applied is 01 December 2020. The cited references qualify as prior art because they are published prior to the instant effective filing date, and therefore predate the instant claimed invention.
Wu teaches an extruded biodegradable filament suitable for implantation and comprising a biodegradable thermoplastic polymer matrix and a protein, including an antibody, associated with or dispersed within the matrix (¶[0009]-[0011], ¶[0064]-[0069], ¶[0110]-[0112]). Wu teaches that the biodegradable thermoplastic polymer matrix may comprise poly(D,L-lactide) or poly(D,L-lactide-co-glycolide) (“PLGA”) (¶[0032], ¶[0039]-[0045]).
More specifically, Wu’s Table 1 identifies protein-containing biodegradable implants (extruded filaments) and, in Formulation No. 9, teaches a filament comprising 20% w/w bevacizumab, 6% w/w trehalose, 0.1% w/w polysorbate 20, 1.4% w/w sodium phosphate, and 72.5% w/w RG503H PLGA (p.12, Table 1, Formulation No. 9). Accordingly, Wu teaches an antibody at 20% by weight, within the instant claimed 15–35% range; a thermoplastic polymeric material at 72.5% by weight, within the instant claimed 50-75% range; and an excipient system totaling 7.5% by weight (6% trehalose + 0.1% polysorbate 20 + 1.4% sodium phosphate), within the instant claimed about 5-15% range.
The identity of the excipients also corresponds directly to instant claim 18, wherein trehalose is one of the expressly recited stabilizers, polysorbate 20 is a surfactant, and sodium phosphate is a buffering agent. Wu additionally identifies trehalose and sucrose, polysorbate 20 and 80, PEG 3350, amino acids including arginine and histidine, and combinations thereof as useful excipients (¶[0027]), and expressly identifies sodium phosphate as a suitable buffering agent (Wu ¶ [0028]). Wu’s Formulation No. 9 therefore places the antibody, polymer, and total claimed excipient amounts directly within the claimed numerical ranges.
Wu further teaches that an extruded implant may optionally contain PEG 3350 at 1-20% by weight of the total implant (¶[0111]) and teaches adding PEG 3350 to antibody-containing formulations before drying (¶[0156]). Wu therefore teaches both PEG and an amount substantially overlapping with instant claim 18’s 2-20% PEG limitation. However, Wu does not expressly characterize the PEG as the claimed plasticizer in the exemplified Formulation No. 9.
Carlier supplies this teaching. Carlier investigates thermoplastic filaments comprising PLA and conventional plasticizers, including PEG 400, for HME followed by fused-deposition 3D printing (p. 367, Abstract; p. 387, § 2.1-2.2.2). Carlier fixes the plasticizer content at 10% w/w for filament manufacture and prepares a PLA 10% (w/w) PEG 400 filament (p. 370, Table 3), falling directly within instant claim 18’s approximately 2-20% range.
Carlier further establishes the reason for using PEG as the plasticizer. Addition of 10% PEG 400 lowers the HME processing temperature of PLA from approximately 180°C to 135°C, lowers Tg from approximately 53°C to 34°C, and markedly increases melt-flow behavior (p. 370, left col., ¶2-3). Carlier explains that plasticization permits lower processing/printing temperatures, which is desirable for pharmaceutical components susceptible to degradation.
Thus, it would have been prima facie obvious to one of ordinary skill in the art, prior to the instant effective filing date, to incorporate PEG in an amount within the known useful range, such as Carlier’s 10% w/w, as a plasticizer in Wu’s antibody-containing thermoplastic filament. Wu already identifies PEG 3350 as a component of its extruded protein implants at 1-20% w/w, while Carlier expressly establishes PEG as a thermoplastic filament plasticizer and demonstrates that a 10% concentration improves melt flow and lowers the thermal conditions required for extrusion and printing. A person of ordinary skill in the art would therefore have had reason to use PEG for its known plasticizing function to facilitate thermoplastic processing of Wu’s antibody-containing filament and, particularly, to reduce the thermal burden imposed on the biologic.
The proposed modification is the use of a known material for its known function in a closely analogous thermoplastic extrusion process and would have yielded the predictable effects of reduced Tg, reduced processing temperature, and improved polymer flow, thus is obvious (see KSR International Co. v. Teleflex Inc., 550 U.S. 398, 416-418 (2007); MPEP § 2143). A person of ordinary skill also would have had a reasonable expectation of success because Wu experimentally demonstrates that a full-length monoclonal antibody can withstand lyophilization, incorporation into a polymeric drug-delivery system processed at elevated temperature, and subsequent release while retaining biological activity (¶[0161], ¶[0169]-[0170]). Wu concludes that full-length monoclonal antibodies can retain tertiary structure throughout lyophilization, elevated-temperature processing, and release. Carlier’s PEG modification reduces rather than increases the temperatures required for thermoplastic processing.
The relative proportions of polymer and PEG required to accommodate the plasticizer would have constituted routine formulation adjustment within the disclosed ranges. Where the prior art discloses overlapping ranges or recognizes concentration as a result-effective variable, routine optimization ordinarily supports a prima facie case of obviousness absent evidence of criticality or unexpected results (In re Peterson, 315 F.3d 1325, 1329-30 (Fed. Cir. 2003); In re Aller, 220 F.2d 454, 456 (CCPA 1955); MPEP § 2144.05). Accordingly, instant claim 18 would have been obvious over Wu in view of Carlier.
Regarding instant claim 20, Wu eaches poly(D,L-lactide-co-glycolide) (“PLGA”) and poly(D,L-lactide) as biodegradable polymer matrices for its protein-containing extruded filaments (¶[0032], ¶[0039]-[0045]), and Formulation No. 9 specifically contains 72.5% RG503H PLGA (p.12, Table 1). Thus, Wu teaches at least one polymeric species falling within the alternative group recited by instant claim 20 and is therefore obvious over Wu in view of Carlier.
Regarding instant claim 26, Wu teaches that its polymeric drug-delivery system may be monolithic, with the protein homogeneously distributed throughout the polymeric matrix (¶[0114]). Wu further teaches blending the dry protein-containing powder with the polymer before extrusion (¶[0069], ¶[0149]-[0153]). Because the protein in Wu’s exemplified filaments includes bevacizumab, an antibody, Wu teaches the additional limitation that the active ingredient is homogeneously dispersed in the thermoplastic polymeric material. Accordingly, instant claim 26 would have been obvious over Wu in view of Carlier.
Regarding instant claim 28, Wu’s Formulation No. 9 contains 20% w/w bevacizumab and 6% w/w trehalose (p.12, Table 1). The antibody:stabilizer weight ratio therefore is 20:6 approximately 3.33:1, which lies directly within the instant claimed ratio of 1:1 to 5:1. Accordingly, instant claim 28 would have been obvious over Wu in view of Carlier.
Regarding instant claim 34, Wu teaches the essential sequence of the instant claimed process. Wu teaches preparing an antibody-containing liquid formulation. Example 1 begins with an aqueous Avastin® formulation containing bevacizumab, trehalose, sodium phosphate, and polysorbate 20, and teaches reformulating that antibody solution with selected carbohydrates, salts, surfactants, and optional PEG (¶ [0154]-[0156]). Wu also teaches drying the protein formulation. Wu teaches that protein powder may be prepared by lyophilization or spray drying, with excipients co-lyophilized or co-spray-dried with the protein (¶[0069]). In Example 1 the bevacizumab/excipient liquid formulation is lyophilized to obtain a dry powder (¶[0156]-[0157]).
Wu teaches blending the dry antibody-containing powder with thermoplastic polymer to form a substantially uniform powder mixture (¶[0069], ¶[0149]=[0159]). Wu also teaches hot-melt extrusion of the resulting mixture into a filament, including extrusion at approximately 60-90°C (¶[0069]-[0070], ¶[0159]; claim 14). Thus, Wu teaches the instant claimed liquid formulation, drying, dry antibody-containing particulate material, dispersion with polymer, and HME filament sequence.
As discussed for instant claim 18, Wu additionally teaches PEG as a component of the extruded implant, and Carlier expressly teaches mixing PEG plasticizer with a thermoplastic polymer composition before HME to produce thermoplastic filament. Thus, it would have been prima facie obvious to one of ordinary skill in the art, prior to the instant effective filing date, to introduce Carlier’s PEG plasticizer during Wu’s blending step because that is the conventional point at which components intended to form the melt-extruded matrix are combined. The motivation and reasonable expectation of success are the same as set forth for instant claim 18- PEG was known to improve melt processing and lower thermal processing temperatures, both of which are advantageous when processing an antibody-containing formulation. Accordingly, instant claim 34 would have been obvious over Wu in view of Carlier.
Regarding instant claim 41, Wu teaches trehalose and sucrose as suitable protein excipients (¶[0027]) and teaches a bevacizumab liquid formulation containing trehalose before lyophilization (¶[0154]-[0157]). Wu also teaches co-lyophilizing or co-spray-drying protein and excipients (¶[0069]). Thus, Wu teaches use of a stabilizer species recited in instant claim 41 in the liquid formulation that is subsequently dried. Accordingly, instant claim 41 would have been obvious over Wu in view of Carlier.
Regarding instant claim 42, Wu’s liquid bevacizumab formulation contains sodium phosphate and polysorbate 20, and Wu teaches varying these components before lyophilization (¶[0154]-[0156]). Wu identifies sodium phosphate as a suitable buffering agent (¶[0028]) and polysorbate 20 as a surfactant (¶[0027]). Accordingly, Wu teaches that the liquid formulation subjected to drying may further comprise a buffering agent and a surfactant, as recited in instant claim 42. Instant claim 42 therefore would have been obvious over Wu in view of Carlier.
Regarding instant claims 29 and 33, Wu teaches an implantable drug-delivery filament comprising an antibody and biodegradable thermoplastic polymer (¶[0064]-[0069], ¶[0110]-[0112], Table 1). Wu, however, does not expressly teach forming a three-dimensional device from that filament by fused-deposition 3D printing. Carlier teaches preparing thermoplastic pharmaceutical filaments by HME and subsequently using those filaments in fused-deposition modeling to prepare three-dimensional implantable devices (p. 367, Abstract; pp. 368-369, § 2.2.2-2.2.4; pp. 371-373, § 3.3-3.4).
Thus, it would have been prima facie obvious to one of ordinary skill in the art, prior to the instant effective filing date, to use Carlier’s known FDM technique to construct an implantable drug-delivery device from Wu’s extrudable thermoplastic drug-delivery filament. Wu and Carlier concern compatible thermoplastic filament technology, and Carlier expressly applies FDM to pharmaceutical implant manufacture. FDM would predictably allow Wu’s drug-delivery material to be formed into selectable three-dimensional geometries without requiring a change in the fundamental thermoplastic drug/polymer system.
Application of a known fabrication technique to a known compatible article for its established manufacturing advantages is an obvious use of a known technique to improve a similar device or method in the same way (see KSR International Co. v. Teleflex Inc., 550 U.S. 398, 416-418 (2007); MPEP § 2143). Accordingly, claims instant 29 and 33 would have been obvious over Wu in view of Carlier.
Regarding instant claim 30, Carlier investigates FDM layer thicknesses of 0.1, 0.2, and 0.3 mm (p. 372, Table 4 and § 3.3). Those values correspond to 100, 200, and 300 µm, respectively, and therefore directly overlap the instant claimed range of 100-400 µm. Accordingly, instant claim 30 would have been obvious over Wu in view of Carlier (see In re Peterson, 315 F.3d 1325, 1329-30 (Fed. Cir. 2003)).
Regarding instant claim 32, Carlier states that the infill of its printed devices was set at 100% (p. 372, left col., ¶4). A 100% infill FDM article is a fully filled or solid printed object rather than a deliberately hollow printed object. Thus, it would have been prima facie obvious to one of ordinary skill in the art, prior to the instant effective filing date, to print the Wu implantable drug-delivery device, incorporating modifications of Carlier, including Carlier’s disclosed 100% infill construction. Accordingly, instant claim 32 would have been obvious over Wu in view of Carlier.
Claims 18, 25, and 40 are rejected under AIA 35 U.S.C. § 103 as being unpatentable over Wu et al. (US20140086974A1, published 27 March 2014; hereinafter “Wu”), in view of Carlier et al. (Investigation of the parameters used in fused deposition modeling of poly(lactic acid) to optimize 3D printing sessions. Int J Pharm. 2019 Jun 30;565:367-377; hereinafter “Carlier”), as applied to claim 18 above, and in further view of Morgan et al. (WO2018078186A1, published 03 May 2018; hereinafter “Morgan”).
The effective filing date of instant application presently being applied is 01 December 2020. The cited references qualify as prior art because they are published prior to the instant effective filing date, and therefore predate the instant claimed invention. Wu and Carlier teach the filament of instant claim 18 for the reasons set forth above, from which instant claims 25 and 40 depend, however do not explicitly teach the specific limitations of instant claims 25 and 40. Wu generally teaches amino acid excipients in protein-containing implants, including arginine and histidine (¶[0027]), but does not expressly disclose L-leucine.
Morgan teaches dry antibody-containing particles comprising an antagonistic antibody, leucine, and trehalose, prepared by spray drying (claim 44). Morgan’s VR942 drug product expressly contains antibody drug substance, trehalose dihydrate, and L-leucine, and Morgan defines leucine to encompass isolated stereoisomers including L-leucine (p. 9, ll. 12-13, 19-21). Morgan prepares a first aqueous solution containing leucine and trehalose, a second aqueous solution containing antibody and buffer salt, combines the solutions, and spray-dries the resulting feedstock into antibody/leucine/trehalose particles (claims 40-43). Morgan further identifies trehalose as a stabilizing excipient for proteins (p. 4, l. 20- p. 5, l. 6).
Instant claim 25 requires that the amino acid be selected from L-arginine, L-leucine, L-phenylalanine, or L-proline. Because the alternatives are stated disjunctively, Morgan’s teaching of L-leucine satisfies one claimed species. Thus, it would have been prima facie obvious to one of ordinary skill in the art, prior to the instant effective filing date, to use L-leucine as an amino-acid excipient in the Wu, modified by Carlier, antibody formulation because Morgan expressly demonstrates that L-leucine is compatible with an antibody and trehalose in a dried antibody formulation.
Wu independently teaches the use of amino acids as protein-formulation excipients and teaches drying protein/excipient formulations before incorporation into its polymer matrix. Morgan therefore provides an express example of an antibody-compatible amino acid that a skilled artisan would reasonably have selected from the known class of amino-acid excipients. The modification constitutes selection of one known member from a finite group of known antibody-formulation excipients for its established purpose and would have yielded predictable results (see KSR International Co. v. Teleflex Inc., 550 U.S. 398, 416-421 (2007); MPEP § 2143). Accordingly, instant claim 25 would have been obvious over Wu and Carlier in further view of Morgan.
Instant claim 40 requires that the amino acid be L-leucine. Morgan expressly teaches an antibody-containing dry formulation comprising L-leucine and trehalose, as discussed above. For the same reasons stated with respect to instant claim 25, one of ordinary skill would have had reason to select L-leucine for Wu’s dried antibody/excipient formulation and would reasonably have expected the combination to be successful because Morgan expressly demonstrates its compatibility in a dried antibody formulation. Accordingly, instant claim 40 would have been obvious over Wu and Carlier in view further of Morgan.
Claims 18, 29, and 31 are rejected under AIA 35 U.S.C. § 103 as being unpatentable over Wu et al. (US20140086974A1, published 27 March 2014; hereinafter “Wu”), in view of Carlier et al. (Investigation of the parameters used in fused deposition modeling of poly(lactic acid) to optimize 3D printing sessions. Int J Pharm. 2019 Jun 30;565:367-377; hereinafter “Carlier”), as applied to claims 18 and 29 above, and in further view of of Yang et al. (3D printing and coating to fabricate a hollow bullet-shaped implant with porous surface for controlled cytoxan release. Int J Pharm. 2018 Dec 1;552(1-2):91-98; hereinafter “Yang”).
The effective filing date of instant application presently being applied is 01 December 2020. The cited references qualify as prior art because they are published prior to the instant effective filing date, and therefore predate the instant claimed invention. Wu and Carlier teach the implantable thermoplastic drug-delivery filament and its manufacture into a 3D-printed drug-delivery device rendering the limitations of instant claims 18 and 29 obvious, as discussed above, from which instant claim 31 depends, however do not explicitly require the specific limitation of an internal hollow cavity required by instant claim 31.
Yang teaches a biodegradable PLA drug-delivery implant fabricated by fused-deposition 3D printing in a hollow bullet-shaped configuration (p. 91, Title and Abstract). Yang employs the hollow interior for drug loading and investigates control of release by device architecture, pore size, polymer matrix, and coating (p. 91, Abstract; p. 92, § 2.2; p. 94, § 3.1).
Thus, it would have been prima facie obvious to one of ordinary skill in the art, prior to the instant effective filing date, to use Yang’s known hollow implant architecture when constructing the Wu, modified by Carlier, drug-delivery device where a reservoir configuration, increased internal volume, or alteration of drug-loading/release characteristics was desired. Both Yang and Carlier concern FDM fabrication of biodegradable polymeric pharmaceutical implants. Yang expressly demonstrates that a hollow internal geometry is a successfully implemented design variable for controlling pharmaceutical implant structure and release. Therefore, the modification amounts to selection of a known FDM implant geometry for its known drug-delivery function and would have produced the predictable result of a printed implant having an internal hollow cavity (see KSR International Co. v. Teleflex Inc., 550 U.S. 398, 416-418 (2007)). Accordingly, instant claim 31 would have been obvious over Wu and Carlier in further view of Yang.
Claims 18 and 35 are rejected under AIA 35 U.S.C. § 103 as being unpatentable over Wu et al. (US20140086974A1, published 27 March 2014; hereinafter “Wu”), in view of Carlier et al. (Investigation of the parameters used in fused deposition modeling of poly(lactic acid) to optimize 3D printing sessions. Int J Pharm. 2019 Jun 30;565:367-377; hereinafter “Carlier”), as applied to claim 18 above, and in further view of Spahr et al. (US20200276760A1, published 03 September 2020; hereinafter “Spahr”).
The effective filing date of instant application presently being applied is 01 December 2020. The cited references qualify as prior art because they are published prior to the instant effective filing date, and therefore predate the instant claimed invention. Wu, in view of Carlier, teaches the filament limitations of instant claim 18 and its use in fused-deposition 3D printing of an implantable drug-delivery device, as described above, from which instant claim 35 depends, however does not explicitly teach the specific limitations of instant claim 35.
Regarding instant claim 35, Step (a) loading and extruding above Tg, Carlier teaches loading an HME-produced thermoplastic filament into an FDM printer and extruding the thermoplastic through the printer nozzle to construct an implantable device (pp. 368-369, § 2.2.2-2.2.4; p. 372, § 3.3). Carlier specifically reports that its PLA/10% PEG 400 filament has a Tg of approximately 34°C (p. 370, Table 3), while the PEG-plasticized PLA is printed at deposition temperatures of 155°C, 173°C, and 190°C (p. 372, Table 4). Thus, Carlier teaches extrusion through the heated print head/nozzle at temperatures substantially above the glass-transition temperature of the polymeric matrix, as required by instant claim 35, step (a).
Regarding instant claim 35, step (b), heated build platform below Tg, Carlier teaches deposition of molten thermoplastic onto a build platform and recognizes first-layer adhesion to the build platform as relevant to successful manufacture (p. 372, § 3.3). Carlier does not, however, expressly state that the build platform is heated to a temperature below Tg. Spahr supplies the missing teaching.
Spahr teaches material-extrusion additive manufacturing, including fused-filament fabrication (“FFF”), from thermoplastic filaments (¶[0039]-[0040]). More specifically, Spahr teaches a print head having a nozzle that is heated to extrude melted thermoplastic material (¶[0044]); a print bed or substrate on which the printed part is built, which may itself be heated (¶[0045]); feeding thermoplastic filament to the heated nozzle and moving the nozzle to deposit thermoplastic material (¶[0047]-[0051]); and temperature control of the build bed (¶[0053]). Most significantly, Spahr teaches, “The heated bed may also be at about 160°C, or just under the Tg of the polymer or polymer blend” (¶[0053]). Therefore, Spahr teaches heating a build platform to a temperature below the glass-transition temperature of the polymer or polymer blend, precisely the relationship required by step (b) of instant claim 35.
Regarding instant claim 35, Step (c), layerwise deposition through the nozzle, Carlier further teaches that the thermoplastic flows through the printer nozzle and is deposited onto the build platform. Carlier employs a raft comprising melt filament positioned between the build platform and the device to improve adhesion of the first layer, and teaches incremental movement of the build platform according to the selected layer height as the object is built (p. 372, § 3.3). Thus, Carlier teaches the ordinary layer-by-layer FDM construction required by instant claim 35 step (c).
Thus, it would have been prima facie obvious to one of ordinary skill in the art, prior to the instant effective filing date, to operate the build platform in the Wu, as modified by Carlier, FDM process at a heated temperature just below the Tg of the thermoplastic polymer matrix, as taught by Spahr. Carlier and Spahr address the same basic material-extrusion architecture (i.e., a thermoplastic filament, heated extrusion nozzle, build platform, and successive deposition of polymer material). Carlier expressly recognizes adhesion between the deposited thermoplastic and build platform as important to successful printing.
Spahr teaches build-bed temperature as an adjustable FFF process parameter and teaches operation just below polymer Tg. Spahr further explains that printer process parameters may be adjusted to minimize shrinkage and warping and to obtain desired strength and elongation, and states that its selected process-parameter teachings apply to “any extrusion/melt 3D printer, and preferably to filament printing (e.g. FFF)” (¶[0055]). Thus, a person of ordinary skill in the art would have had a concrete reason to apply Spahr’s heated-bed temperature control to the Carlier pharmaceutical FDM process to improve control of adhesion, shrinkage, warping, and dimensional stability during layerwise deposition. This is not a hindsight selection of an isolated parameter because Spahr expressly identifies bed temperature as a relevant process variable and expressly teaches the claimed relationship to Tg.
The application of Spahr’s known FFF process-control technique to Carlier’s known FFF manufacturing process for its known and predictable purpose is consistent with KSR International Co. v. Teleflex Inc., 550 U.S. 398, 416-418 (2007) and MPEP § 2143, including use of a known technique to improve similar methods in the same way. A person of ordinary skill also would have had a reasonable expectation of success in doing so because Spahr’s relevant teaching concerns the same thermoplastic-filament/FFF process architecture used by Carlier and states that the selected process parameters are applicable generally to extrusion/melt 3D printers, preferably filament printers (¶[0055]).
Moreover, Carlier provides the Tg of its PEG-plasticized thermoplastic composition, thereby enabling the skilled artisan to select a heated-platform temperature below that Tg without undue experimentation. Determination and adjustment of build-bed temperature would have involved ordinary selection of an established printer operating parameter, not development of an unknown manufacturing principle. Accordingly, instant claim 35 would have been obvious over Wu in view of Carlier and further in view of Spahr.
Claims 18 and 36 are rejected under AIA 35 U.S.C. § 103 as being unpatentable over Wu et al. (US20140086974A1, published 27 March 2014; hereinafter “Wu”), in view of Carlier et al. (Investigation of the parameters used in fused deposition modeling of poly(lactic acid) to optimize 3D printing sessions. Int J Pharm. 2019 Jun 30;565:367-377; hereinafter “Carlier”), as applied to claim 18 above, and in further view of Chen et al. (US20040191243A1, published 30 September 2004; hereinafter “Chen”).
The effective filing date of instant application presently being applied is 01 December 2020. The cited references qualify as prior art because they are published prior to the instant effective filing date, and therefore predate the instant claimed invention. Wu, in view of Carlier, teaches the limitations of instant claim 18, as described above, from which instant claim 36 depends, however do not explicitly teach the specific limitations of instant claim 36.
Instant claim 36 requires approximately 15.5% antibody, 7.5% excipient comprising histidine and sucrose or histidine and trehalose, 69.5% thermoplastic polymeric material, and 7.5% plasticizer. Wu’s Formulation No. 9 provides a particularly close composition comprising 20% bevacizumab, 7.5% total excipient, 72.5% PLGA, and no separately identified PEG plasticizer (p. 12, Table 1). Wu separately teaches PEG 3350 at 1-20% w/w of the implant (¶ 0111]), while Carlier teaches 10% w/w PEG 400 expressly functioning as a thermoplastic plasticizer (as described above). Thus, the prior art teaches amounts encompassing or closely bracketing the instant claimed 7.5% PEG plasticizer.
Wu also recognizes antibody loading and excipient loading as formulation variables affecting drug release. Wu demonstrates that varying trehalose content modifies release (¶[0165]) and that varying antibody drug load modifies initial burst and release duration (¶[0166]). Carlier similarly investigates plasticizer concentration as a formulation/process variable affecting extrusion and printability.
Chen supplies further evidence for a particular histidine plus sucrose/trehalose excipient combination. Chen teaches a solid formulation comprising an antibody and histidine in an amount sufficient to stabilize the antibody (¶[0011]; claim 1), and teaches that the formulation may additionally contain sucrose or trehalose (¶ [0011]; claims 2-3). Chen further teaches mixing antibody with a stabilizing amount of histidine, adding additional excipient, and lyophilizing the mixture (¶[0016]-[0017]; claims 10-13). Chen identifies both sucrose and trehalose as suitable cryoprotectants/lyoprotectants for antibody formulations (¶ [0046]). Thus, Chen supplies an express reason to include histidine together with sucrose or trehalose in Wu’s dried antibody formulation: preservation/stabilization of the antibody during solid-state formulation and drying.
Thus, it would have been prima facie obvious to one of ordinary skill in the art, prior to the instant effective filing date, to incorporate Chen’s known histidine-plus-sugar antibody stabilization system into Wu’s antibody-containing formulation because both references concern maintaining antibody stability in dried formulations, and Wu expressly recognizes the importance of preserving antibody structure through drying and elevated-temperature processing. Chen’s histidine/sugar system would have been expected to perform the same known protein-stabilization function in Wu’s dried antibody intermediate.
Regarding the precise percentages of instant claim 36, the claimed values are not expressly disclosed together in a single prior-art formulation. Nevertheless, Wu provides a working filament at 20/7.5/72.5 antibody/excipient/polymer, Wu teaches PEG at 1-20%, and Carlier teaches 10% PEG plasticizer. Wu establishes antibody load and trehalose/excipient load as result-effective formulation variables, while Carlier establishes plasticizer loading as a variable affecting thermoplastic processability. Therefore, it would have been within ordinary formulation skill to adjust the relative amounts of antibody, polymer, excipient, and PEG within these known ranges to accommodate the plasticizer while maintaining 100% total composition and achieving the desired balance of drug load, stability, release, extrusion, and printability.
A composition containing approximately 15.5% antibody, 7.5% excipient, 69.5% polymer, and 7.5% PEG represents an intermediate formulation within or closely bounded by the prior art working concentrations rather than a newly discovered class of composition. Where the prior art recognizes a parameter as affecting the result and teaches the general conditions of the claim, discovery of an optimum or workable value through routine experimentation ordinarily does not confer patentability absent evidence of criticality or unexpected results (see In re Aller, 220 F.2d 454, 456-457 (CCPA 1955); In re Peterson, 315 F.3d at 1329-30; MPEP § 2144.05).
A reasonable expectation of success in doing so is supported by Wu’s experimental demonstration that monoclonal antibody remains biologically active after lyophilization, elevated-temperature polymer processing, and release, and by Chen’s express demonstration that histidine stabilizes antibodies in dried formulations. Accordingly, instant claim 36 would have been obvious over Wu and Carlier in further view of Chen.
Claims 18, 36, and 37 are rejected under AIA 35 U.S.C. § 103 as being unpatentable over Wu et al. (US20140086974A1, published 27 March 2014; hereinafter “Wu”), in view of Carlier et al. (Investigation of the parameters used in fused deposition modeling of poly(lactic acid) to optimize 3D printing sessions. Int J Pharm. 2019 Jun 30;565:367-377; hereinafter “Carlier”), and Chen et al., US 2004/0191243 A1, published September 30, 2004 (“Chen”), as applied to claims 18 and 36 above, and in further view of Morgan et al. (WO2018078186A1, published 03 May 2018; hereinafter “Morgan”).
The effective filing date of instant application presently being applied is 01 December 2020. The cited references qualify as prior art because they are published prior to the instant effective filing date, and therefore predate the instant claimed invention. Wu, in view of Carlier and Chen, teaches the filament limitations of instant claims 18 and 36, as described above, from which instant claim 37 depends, however do not explicitly require the specific limitation of instant claim 37, wherein excipient to further comprise L-leucine.
Morgan teaches an antibody-containing dried particle formulation comprising antibody, trehalose, and L-leucine. Morgan’s VR942 product contains antibody drug substance, trehalose dihydrate, and L-leucine, and Morgan expressly teaches spray drying an aqueous antibody/leucine/trehalose feedstock to produce the resulting dried particles (claims 40-44; p. 9, ll. 12-13).
Thus, it would have been prima facie obvious to one of ordinary skill in the art, prior to the instant effective filing date, to further include L-leucine in the Wu, Carlier, and Chen antibody excipient system because Morgan demonstrates that L-leucine is compatible with an antibody and trehalose in a dried antibody formulation. The proposed modification therefore uses a known antibody formulation excipient in a closely analogous dried antibody formulation and would have been expected to retain the known formulation utility demonstrated by Morgan.
No evidence in the prior art indicates that L-leucine would have been incompatible with the thermoplastic formulation or with Chen’s histidine/trehalose stabilization system. Rather contrarily, Wu permits combinations of protein formulation excipients (¶[0027]), and Morgan demonstrates successful preparation of dried antibody/trehalose/L-leucine particles. Accordingly, instant claim 37 would have been obvious over Wu, Carlier, and Chen in further view of Morgan.
Response to Arguments
Applicant Arguments/Remarks of the reply, filed 02 July 2026, have been fully considered.
The applicant argues that Trogden does not anticipate amended claim 18 because Trogden does not disclose, in a single filament arranged as claimed, the combination of a thermoplastic polymeric material, polyethylene glycol plasticizer, antibody, and the presently required stabilizer selected from sucrose, trehalose, an amino acid, or a combination thereof. Applicant further argues that the disparate disclosures of Trogden cannot be assembled to create an anticipating embodiment.
The applicant’s argument is persuasive with respect to the anticipation rejection of amended claim 18. Anticipation requires that every claim limitation be found, expressly or inherently, in a single prior-art reference, with the elements arranged or combined as required by the claim. Inherency likewise cannot rest upon probability or possibility; the missing limitation must necessarily be present in, or necessarily result from, the prior-art disclosure.
Trogden does expressly disclose more concerning PEG than Applicant’s argument might suggest. In particular, Trogden actually made and tested PLGA implant filaments containing 10 wt% freeze-dried oligonucleotide, 5 wt% PEG-3350, and 85 wt% PLGA, which were heated to approximately 77°C and extruded through a 500 μm nozzle. Trogden therefore contains an actual disclosure of a PEG-containing PLGA filament; the subsequent statement that PEG was unsuitable as Trogden’s preferred release modifier does not erase that disclosure (see Celeritas Technologies, Ltd. v. Rockwell International Corp., 150 F.3d 1354, 1361 (Fed. Cir. 1998), wherein a reference does not cease to disclose subject matter for anticipation merely because the reference disparages the disclosed embodiment).
Trogden also separately identifies antibodies and antibody fragments as suitable therapeutic agents and describes anti-VEGF antibody implants made according to its Example 1 procedure. Trogden further refers to U.S. Patent No. 5,869,079 and expressly states that its cited references are incorporated by reference. Material properly incorporated by reference may be considered part of a single reference for anticipation purposes (see Advanced Display Systems, Inc. v. Kent State University, 212 F.3d 1272, 1282 (Fed. Cir. 2000)).
Nevertheless, these disclosures do not adequately establish anticipation of amended claim 18. Trogden’s PEG filament of Example 4 contains an oligonucleotide, not an antibody, and does not contain the presently required sucrose, trehalose, or amino-acid stabilizer. Conversely, Trogden’s antibody embodiments do not disclose the claimed combination with PEG and the presently specified stabilizer. Moreover, U.S. Patent No. 5,869,079 identifies sucrose as a hydrophilic release accelerator for hydrophobic agents, rather than disclosing sucrose as an antibody stabilizer in the presently claimed PEG-containing filament. The prior rejection therefore depended upon selecting limitations from materially distinct embodiments and disclosures without establishing that Trogden itself describes or necessarily produces the particular combination now required by claim 18. Accordingly, the rejection of claims 18, 20, 26, and 28-32 under 35 U.S.C. § 102(a)(1) over Trogden is withdrawn. The rejection of canceled claim 22 is moot.
The applicant argues that Trogden and Vollrath teach away from the claimed subject matter because Trogden states that PEG was unsuitable as a release modifier and Vollrath states that PEG was eliminated because of its potential negative effect on protein integrity and allergic potential. The applicant additionally argues that Vollrath replaced histidine/trehalose-containing excipients with HP-β-CD and therefore would not have motivated the skilled artisan toward the presently claimed formulation.
These disclosures are relevant and have been considered. The applicant is correct that a reference must be considered in its entirety, including portions that would discourage a person of ordinary skill from pursuing the proposed modification (see MPEP § 2141.02 and § 2145). A reference teaches away where its disclosure would discourage the skilled artisan from following the claimed path or lead the artisan in a divergent direction. The statements concerning PEG, however, must be considered in their technological context rather than treated as categorical exclusions of PEG for every purpose.
Trogden expressly tested PEG-3350 in PLGA filaments. Its adverse conclusion was directed to PEG’s performance as a release modifier for the particular sustained-release system tested, wherein PEG blocked initial burst release but thereafter produced a release rate considered too low for Trogden’s intended therapeutic profile. Amended claim 18, by contrast, expressly characterizes PEG as a plasticizer. Thus, Trogden’s criticism is relevant to motivation but does not establish that the skilled artisan would have regarded PEG as technically unusable for a different formulation function.
Likewise, Vollrath states that PEG as a pore-forming and precipitating agent was eliminated from its particular solid-lipid formulation because of potential effects on protein integrity and allergic potential. That disclosure constitutes evidence discouraging that particular use of PEG and cannot properly be ignored. At the same time, Vollrath reports that earlier PEG-containing solid-lipid formulations had shown promising long-term protein release, including with a monoclonal antibody. Vollrath’s final formulation instead used a freeze-dried protein matrix containing HP-β-CD in a triglyceride implant. Thus, Vollrath does not establish a universal technical prohibition against PEG in antibody-containing delivery systems.
The applicant’s reliance upon AstraZeneca therefore does not establish, as a categorical matter, that any obviousness combination containing Trogden or Vollrath and PEG necessarily fails. Whether the negative statements outweigh other teachings providing motivation depends on the particular proposed modification, the function assigned to PEG, the complete prior-art record, and the reasonable expectations of one of ordinary skill.
The applicant additionally argues that because Trogden and Vollrath did not identify a defect in their respective formulations, there would have been no motivation to modify either formulation. This argument states the obviousness inquiry too narrowly. Neither KSR International Co. v. Teleflex Inc., 550 U.S. 398, 417-21 (2007) nor In re Omeprazole Patent Litigation, 536 F.3d 1361, 1379-81 (Fed. Cir. 2008) establishes a general requirement that the primary reference expressly recognize a defect before modification may be obvious. A reason to modify may arise from an express teaching, a known design need, application of a known technique to improve a similar product, market or design incentives, or other reasoned considerations supported by the prior-art record (see MPEP § 2141, § 2143).
In re Omeprazole Patent Litigation, 536 F.3d 1361, 1379-81 (Fed. Cir. 2008), was fact-specific, wherein the proposed additional sub-coating addressed a problem that the prior art had not recognized, leaving the challenger without a reason to undertake the additional modification. It does not create a rule requiring an expressly identified “flaw” in every reference before references may be combined. The applicant is correct, however, that technical capability alone is insufficient. The question is not merely whether one of ordinary skill could have made the claimed combination, but whether the record provides a reason why that person would have made the modification to arrive at the claimed invention, with a reasonable expectation of success (see Belden Inc. v. Berk-Tek LLC, 805 F.3d 1064, 1073 (Fed. Cir. 2015); Janssen Pharmaceuticals, Inc. v. Teva Pharmaceuticals USA, Inc., 141 F.4th 1367, 1374 et seq. (Fed. Cir. 2025)). The reasonable-expectation inquiry likewise must be tied to successfully achieving the claimed invention.
The applicant’s reliance upon Par Pharmaceutical, Inc. v. TWi Pharmaceuticals, Inc., 773 F.3d 1186, 1194, 1196-98 (Fed. Cir. 2014), is also legally correct insofar as all limitations of the claimed invention must be supplied or suggested by the prior-art combination before motivation and reasonable expectation of success can complete the obviousness analysis. The presently applicable § 103 rejection addresses that requirement separately and is controlling.
The applicant contends that Schneider does not remedy deficiencies in Trogden and that the combination does not teach or suggest a filament and 3D-printed implantable device as claimed. The applicant’s argument is not persuasive.
Schneider expressly states that its polymer composition may be provided as “pellets, sheets, fibers, filaments, etc.” and thereafter shaped by techniques expressly including three-dimensional printing. Schneider further describes filament supplied on a spool, extrusion-based fused deposition modeling, a print head, a platen, and layer-by-layer printing. Thus, Schneider is affirmative evidence that forming macromolecular-drug/polymer compositions into filaments and using those filaments in extrusion-based 3D printing to form implantable devices were known techniques. Accordingly, the applicant is not persuasive to the extent the argument depends upon Schneider itself failing to disclose filament-fed 3D printing of a polymer/macromolecular-drug composition. Schneider expressly does so.
The applicant nevertheless correctly identifies that Schneider’s teaching of 3D printing does not, by itself, supply every compositional limitation now present in amended claim 18. In a combination rejection, however, the references are not required individually to disclose the complete claimed invention. The question is what their combined teachings would have suggested to one of ordinary skill (see In re Keller, 642 F.2d 413, 425 (CCPA 1981); In re Mouttet, 686 F.3d 1322, 1332-33 (Fed. Cir. 2012); MPEP § 2145). The presently applicable § 103 rejection therefore addresses the amended compositional limitations independently. Schneider remains pertinent to the filament-to-3D-printed-device limitation of claim 33.
The applicant argues that Arrighi does not disclose the exact sequence of claim 34 because Arrighi uses poloxamer 407 in the formulation before spray drying and does not itself disclose, after drying, homogeneously dispersing the dry particles with PEG and a thermoplastic polymer before HME. The examiner agrees that Arrighi does not itself expressly disclose the complete sequence of amended claim 34, and Arrighi’s poloxamer 407 should not be treated as though it were chemically identical to the claimed polyethylene glycol.
That observation, however, does not by itself traverse a rejection based on the combined teachings of Trogden and Arrighi (see In re Keller, 642 F.2d 413, 425 (CCPA 1981)). Arrighi is evidence of producing antibody-loaded PLGA microparticles by spray drying, including high antibody loading and preservation of IgG through the encapsulation procedure. Trogden separately teaches a materially relevant subsequent processing sequence: a freeze-dried therapeutic agent is blended with PEG-3350 and powdered PLGA, the blend is heated, and the material is extruded into filament. Thus, the applicant’s observation that Arrighi alone does not perform post-drying blending with PEG does not address the entire basis for using the references together. Nor is it necessary that Arrighi itself supply PEG where that feature is supplied by another reference in the combination.
Similarly, obviousness does not require physically incorporating every feature of one disclosed embodiment bodily into another embodiment. The inquiry is what the combined teachings would have suggested to a person of ordinary skill (see In re Keller, 642 F.2d 413, 425 (CCPA 1981); In re Mouttet, 686 F.3d 1322, 1332-33 (Fed. Cir. 2012); MPEP § 2145 and § 2143.01(VI)). At the same time, the proposed combination cannot properly render the primary reference inoperable for its intended purpose or disregard contrary teachings materially affecting motivation or reasonable expectation of success. The applicant’s arguments concerning the precise amended sequence, motivation for the proposed process modification, and expectation of maintaining antibody integrity have therefore been considered in formulating the presently applicable § 103 rejection of claim 34, which is set forth above.
The applicant argues that Carlier does not disclose “heating the build platform at a temperature below the glass transition temperature of the polymeric matrix.” The applicant’s factual observation concerning the previously cited portions of Carlier is persuasive. Carlier’s disclosure of deposition conditions above the glass-transition temperature and its discussion of cooling, distortion, interlayer bonding, and related FDM parameters do not amount to an express disclosure that the build platform is actively heated to a temperature below Tg.
Accordingly, the prior statement that an unspecified build-platform temperature could simply be assumed to be room temperature does not, standing alone, establish the affirmative claim step of heating the platform and inherency cannot be properly based on a mere possibility or assumption (see Par Pharmaceutical, 773 F.3d at 1195-96, wherein inherency requires necessity, not probability); MPEP § 2112). This does not diminish Schneider’s express disclosure of filament-fed extrusion-based FDM, a movable platen, a print head, and layer-by-layer deposition. It means only that an affirmative evidentiary basis must be provided for the additionally claimed heated-build-platform limitation rather than treating an unheated or unspecified platform as satisfying the limitation.
Accordingly, the previous rationale is not maintained to the extent it relied upon an assumption that Carlier’s build platform was at room temperature and equated that circumstance with affirmatively heating the platform. The currently applicable rejection of claim 35, including the evidentiary basis for the heated-build-platform limitation, is set forth above.
Claims 38 and 39 have been canceled. Accordingly, the prior rejection of claims 38 and 39 is moot. Claims 36 and 37 remain pending. Claim 36 now recites the particular approximate formulation of 15.5 wt% antibody, 7.5 wt% excipient comprising histidine with sucrose or trehalose, 69.5 wt% thermoplastic polymer, and 7.5 wt% plasticizer; claim 37 further requires L-leucine.
The applicant’s argument is persuasive to the extent the prior Office Correspondence may be understood as stating that each ingredient in these precise combinations was expressly disclosed together by Vollrath and Arrighi. That characterization is broader than the cited disclosures support. For example, Vollrath’s final solid-lipid implant formulation uses protein lyophilizate containing HP-β-CD, while Arrighi concerns spray-dried IgG-loaded PLGA microparticles.
Likewise, the proposition that selection of any numerical value lying within a prior-art range is automatically obvious is not the law. Overlap or close numerical proximity may support prima facie obviousness, and optimization of a known result-effective variable ordinarily may be obvious, but the underlying factual predicates must exist. Whether a particular combination of interdependent formulation variables is properly treated as routine optimization depends on the prior art and the evidence concerning result-effectiveness and predictability. The presently applicable § 103 treatment of claims 36 and 37 therefore rests upon the prior-art combination and rationale stated separately in this action rather than the broader characterization in the prior response.
The applicant argues that the originally filed specification demonstrates unexpectedly superior antibody stability for sucrose- and trehalose-containing formulations and further demonstrates maintenance of antibody binding after HME and 3D printing. The applicant relies upon these data as evidence of nonobviousness. The evidence has been considered.
The prior statement that the applicant had provided “no evidence of unexpected results” is not maintained. The specification contains actual comparative data. In particular, Table 2 reports materially lower formation of high-molecular-weight species following HME when sucrose or trehalose was used than when certain alternative excipients, including sorbitol and HP-β-CD, were used. The specification expressly characterizes sucrose and trehalose as more effective at maintaining mAb1 integrity through HME. The specification further reports experiments involving sucrose/trehalose in combination with L-leucine and reports retained antibody/Fab binding activity following manufacture and release from 3D-printed devices. These results constitute probative evidence and have not been disregarded.
Although, the relevant question is whether the results would have been unexpected to a person of ordinary skill in view of the prior art, and the probative scope of the showing must reasonably correspond to the scope of the claims (see MPEP § 716.02(a)-(e); In re Clemens, 622 F.2d 1029, 1035-36 (CCPA 1980); In re Lindner, 457 F.2d 506, 508-09 (CCPA 1972)). For example, amended claim 18 remains considerably broader than the particular examples tested. Claim 18 encompasses thermoplastic polymeric material generally over 50-75 wt%, PEG over about 2-20 wt%, antibody over 15-35 wt%, excipient over about 5-15 wt%, multiple different antibodies, multiple polymers, and stabilizers encompassing sucrose, trehalose, various amino acids, or combinations thereof.
The comparative HME data, by contrast, principally concern particular antibody formulations, a particular PLGA material, particular antibody/stabilizer ratios and loadings, and identified HME conditions. The evidence is therefore entitled to weight but does not, without a showing of a reasonably predictable trend across the claimed genus and ranges, establish that every materially broader embodiment of claim 18 obtains the demonstrated advantage (see In re Clemens, 622 F.2d 1029, 1035-36 (CCPA 1980); In re Lindner, 457 F.2d 506, 508-09 (CCPA 1972); MPEP § 716.02(d)).
The binding-capacity results likewise bear more directly on embodiments actually subjected to HME, 3D printing, and release testing than on a filament claim that does not itself require a specified degree of biological activity, aggregate suppression, particular printing conditions, or particular release performance. This does not make the evidence irrelevant, but it affects the nexus and weight accorded to the evidence for claims having substantially broader scope.
Claims 36 and 37 present a different issue because they more closely track the particular compositions exemplified in the specification. The unexpected-results evidence is accordingly entitled to correspondingly greater weight for those narrower claims. Nevertheless, the evidence must still be weighed against the complete obviousness showing rather than considered in isolation. Evidence of unexpected results does not operate as a separately, all evidence must be reconsidered together. (see Piasecki, 745 F.2d at 1472-73; MPEP § 2142, § 2145).
The applicant’s reliance on Honeywell International Inc. v. Mexichem Amanco Holding S.A. de C.V., 865 F.3d 1348, 1356 (Fed. Cir. 2017), is therefore acknowledged insofar as unpredictability and unexpected properties may weigh against obviousness. The proposition does not mean, however, that the characterization of an art as unpredictable forecloses obviousness whenever the prior art provides a sufficiently specific reason to make the claimed modification and a reasonable expectation of obtaining the claimed subject matter. The evidence must be assessed claim-by-claim against the particular prior-art teachings and proposed modification. Accordingly, the applicant’s experimental evidence has been considered as part of the entire evidentiary record, and the presently stated § 103 rejections set forth elsewhere in this action reflect that consideration.
The applicant’s statement that it is insufficient merely to establish that individual claim elements were separately known is correct. KSR v. Teleflex requires an articulated reason, having rational underpinning, explaining why a person of ordinary skill would have combined or modified the teachings to arrive at the claimed invention (see KSR v. Teleflex, 550 U.S. 398, 415, 416-418 (2007); In re Kahn, 441 F.3d 977, 988 (Fed. Cir. 2006)). This does not require an express teaching in the prior art using the words of the applicant’s claim, an express identification of the same problem solved by the applicant, or an express instruction to make the precise combination. KSR v. Teleflex specifically rejected such a rigid application of the teaching-suggestion-motivation inquiry. The requisite rationale may arise from known design needs, known advantages of a technique, predictable substitution, optimization of known variables where properly established, or other reasoning adequately supported by the record (see MPEP § 2141, § 2143, § 2145).
Similarly, the fact that references concern different particular matrices (e.g., PLGA polymeric implants versus solid-lipid matrices) does not automatically preclude reliance on a secondary reference for a teaching pertinent to antibody stabilization, processing, or another feature. References need not be physically or bodily combined (see In re Keller, 642 F.2d 413, 425, 208 USPQ 871 (1981); In re Mouttet, 686 F.3d 1332-33, 103 U.S.P.Q.2d 1219 (Fed. Cir. 2012). The relevant question is whether their teachings would have suggested the claimed modification to the skilled artisan, while taking into account any incompatibilities, changes in principle of operation, or teachings away.
Finally, the applicant’s reservation of rights concerning subject matter canceled or not presently pursued is noted. Such reservation does not affect the patentability determination of the claims presently pending in this application.
In summary, the applicant’s arguments have been fully considered. The rejection of claims 18, 20, 26, and 28-32 under 35 U.S.C. § 102(a)(1) over Trogden is withdrawn because the present record does not establish that Trogden discloses, expressly or inherently, the presently claimed combination arranged as required by amended claim 18. The rejection of canceled claim 22 is moot. The previous rejections of canceled claims 38 and 39 are likewise moot.
The applicant is correct that Trogden’s and Vollrath’s adverse statements concerning PEG must be considered in the obviousness analysis, that U.S. Patent No. 5,869,079 describes sucrose as a release accelerator rather than as an antibody stabilizer, that Carlier does not expressly disclose the affirmative step of heating its build platform below Tg, and that the originally filed specification contains comparative evidence pertinent to unexpected results. Those matters have been taken into account and have not been disregarded.
The applicant’s arguments are not persuasive, however, to the extent they contend that Trogden contains no disclosure of a PEG-containing PLGA filament, Schneider fails to disclose filament-fed extrusion-based 3D printing of polymer/macromolecular-drug compositions, each secondary reference must independently disclose every limitation of a combination rejection, references cannot be combined merely because their particular exemplified matrices differ, an express defect in the primary reference is invariably required before a modification may be obvious, or the existence of formulation unpredictability or comparative differences automatically resolves the obviousness inquiry.
The rejections under 35 U.S.C. § 103 presently applicable to claims 18, 20, 25, 26, 28-37, and 40-42, together with the specific references, findings, motivation, reasonable expectation of success, and treatment of the applicant’s rebuttal evidence supporting those rejections, are set forth above. Accordingly, the applicant’s request for withdrawal of all outstanding rejections and allowance of the application is respectfully declined.
Conclusion
No claims are allowed.
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/RL Scotland/
Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
Prosecution Insights